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Review ARTICLE

Front. Immunol., 07 August 2019 | https://doi.org/10.3389/fimmu.2019.01873

Microbiota-Immune Interaction in the Pathogenesis of Gut-Derived Infection

Chenyang Wang, Qiurong Li* and Jianan Ren*
  • Research Institute of General Surgery, Jinling Hospital, Medical School, Nanjing University, Nanjing, China

Gut-derived infection is among the most common complications in patients who underwent severe trauma, serious burn, major surgery, hemorrhagic shock or severe acute pancreatitis (SAP). It could cause sepsis and multiple organ dysfunction syndrome (MODS), which are regarded as a leading cause of mortality in these cases. Gut-derived infection is commonly caused by pathological translocation of intestinal bacteria or endotoxins, resulting from the dysfunction of the gut barrier. In the last decades, the studies regarding to the pathogenesis of gut-derived infection mainly focused on the breakdown of intestinal epithelial tight junction and increased permeability. Limited information is available on the roles of intestinal microbial barrier in the development of gut-derived infection. Recently, advances of next-generation DNA sequencing techniques and its utilization has revolutionized the gut microecology, leading to novel views into the composition of the intestinal microbiota and its connections with multiple diseases. Here, we reviewed the recent progress in the research field of intestinal barrier disruption and gut-derived infection, mainly through the perspectives of the dysbiosis of intestinal microbiota and its interaction with intestinal mucosal immune cells. This review presents novel insights into how the gut microbiota collaborates with mucosal immune cells to involve the development of pathological bacterial translocation. The data might have important implication to better understand the mechanism underlying pathological bacterial translocation, contributing us to develop new strategies for prevention and treatment of gut-derived sepsis.

Introduction

Bacterial infections are common complications in critically ill patients, likely leading to sepsis, multiple organ dysfunction, and even death (1). Infection and septic complications contributed to the majority of deaths in these cases, and are regarded as the leading cause for mortality in critical illness (2, 3). Elucidation of the mechanisms underlying the pathogenesis of infection and septic complications in critical illness is therefore of upmost importance, facilitating to develop potentially effective strategies for prevention and treatment.

In critical illness, the gut may serve as the motor of multiple organ dysfunction syndromes (MODS), probably derived from intestinal bacterial translocation and subsequent acute septic responses (4, 5). Early in this decade, studies regarding bacterial translocation mainly focused on the structure and function of intestinal epithelial barrier (6). Disruption of the epithelial barrier and increased gut permeability have been frequently observed in critically ill patients, which was thought playing a central role in the development of bacterial translocation and systemic infections in these cases (7, 8). The gut microbiota has long been recognized as a key component of the intestinal barriers (9). It has been known that small intestinal bacterial overgrowth could pre-dispose to bacterial translocation (10, 11), however, there have been few efforts to characterize the composition and dynamic changes of the gut microbiota in the process, due to technological limitations. Over the past 15 years, the introduction of next-generation DNA sequencing techniques has revolutionized this area of science, allowing us to define the microbial compositions and their potential functions in the intestine (12). Recently, the gut microbiotas in critically ill patients have been determined through high-throughput sequencing analyses, characterized by overgrowth of pathogenic organisms and the loss of commensal bacteria (1316). The gut microbiota dysbiosis could contribute to bacterial translocation by increasing gut permeability and inducing the mucosal immune dysfunction (17). The findings demonstrate that the microbiota is probably an active participant in the development of gut-derived infection, sepsis, and multiple-organ dysfunction in critical illness (18, 19). Thereby, improved knowledge of the gut microbiota composition and function would facilitate more comprehensive understanding of the mechanisms behind the pathogenesis of gut-derived infection in critical illness and the design of new treatment options.

The gut microbiota serves as a critical player in preventing and sometimes in driving enteric infections (20). Trillions of commensal microorganisms residing in the gastrointestinal (GI) tract can compete for adhesion sites with pathogens, and comprise the first line of defense against bacterial translocation (21). Alterations in the intestinal microbiota induced by antibiotics treatment can lead to the translocation of enteric bacteria across the epithelium in mice (22), providing further evidence for the importance of the microbiota in host resistance against pathogens. In addition to this, the gut microbiota has a key role in maintaining the gut homeostasis by establishing and maintaining beneficial interaction with mucosal immune cells and intestinal epithelial cells (23). In critical illness, this interaction could become pathological due to alterations of the gut microbiota, leading to the loss of intestinal homeostasis, bacterial translocation, gut-derived sepsis, and deleterious clinical sequelaes (24). Thereby, it is needed to unravel the changes of the gut microbiota and the underlying mechanisms of microbiota–host interaction in critical illness, contributing to offer new strategies to reconstruct intestinal homeostasis and avoid some of the untoward outcomes.

Based on the current research data, gut microbiota perturbations, host immune deficiencies, and increased intestinal permeability are the three key factors responsible for promoting bacterial translocation and gut-derived infection. Given the crucial role of the microbiota in shaping intestinal barrier integrity, it is interesting to consider whether microbiota dysbiosis and altered microbiota–host interaction is causally linked to gut-derived infection and consequent septic complications. In this review, we presented the changing features of the intestinal microbiota structure and composition in critical illness and the potential roles of these changes in the pathogenesis of gut-derived infection. We also discussed how the gut microbiota drives bacterial translocation through alterations in microbial community architecture, modulation of innate and adaptive immunity, and disruption of the mucosal barrier in critical illness. The data presenting here have highlighted the alterations of the microbiota–immune interaction in critical illness and offer novel paradigms to understand the pathophysiology of gut-derived sepsis. We also reviewed the research advances on other components (fungi, parasites, and viruses) of the gut microbiota and their potential relationships with bacteria and host immunity in human health and diseases. Lastly, we discussed the therapeutic potential to modify the intestinal microbiota with fecal microbiota transplantation (FMT).

Bacterial Translocation and Gut-Derived Infection

Bacterial translocation is defined as the process in which the intestinal bacteria and/or their products spread through the gut barrier into the extra-intestinal sites, including the mesenteric lymph nodes (MLNs), systemic circulation, and distant organs (25, 26). The phenomenon of bacterial translocation was initially described in 1949, when live enteric bacteria were observed in the peritoneal washings from dogs with hemorrhagic shock (27). Until 1990s, however, the translocation of enteric organisms into the mesenteric lymph node (MLN) was identified in surgical patients undergoing laparotomy (2830), which offered direct evidence supporting this concept. Bacterial translocation was also associated with a striking increase in the post-operative sepsis, leading to the generation of the gut origin hypothesis of sepsis. Subsequently, a large amount of clinical studies further confirmed the presence of bacterial translocation in patients with critical illness and its involvement in the development of sepsis (3134). Based on the findings, it began to be accepted that bacterial translocation is a major source of systemic infections and might play an important early step in the pathogenesis of sepsis in critically ill patients (35, 36).

In the last several decades, detection of bacterial translocation in patients is mainly dependent upon culture of peripheral blood (37). Owing to low sensitivity of this method, cultures of blood specimens are often negative, even in the patients with sepsis (38). As a result, specific interventions against infections are probably delayed in some cases, causing lethal complications. It is quite possible that enteric bacteria may translocate into systemic circulation, but escape from detection by culture-based methods. In recent years, the development of 16S rDNA-based molecular techniques has improved the ability to detect the microorganisms, allowing us to define the composition of translocating bacteria into the blood (39, 40). Using denaturing gradient gel electrophoresis, multiple organisms (5–8 bacterial species) were frequently observed in the blood specimens of severe acute pancreatitis (SAP) patients (41). Recent studies with next-generation sequencing techniques showed that a diverse microbiota is present in the blood of septic patients and is mainly composed of gut-associated microorganisms (4244), indicating the possibility for translocation of intestinal microbiota. Dickson et al. demonstrated that the lung microbiome is enriched with gut-associated bacteria both in a murine model of sepsis and in patients with acute respiratory distress syndrome (ARDS) (45). Furthermore, the lower GI tract, rather than the upper respiratory tract, was identified as the likely source community of post-sepsis lung microbiota, providing evidence for gut–lung translocation of intestinal microbiota (45, 46). Based on culture-dependent methods, previous studies have demonstrated that the bacterial translocation is usually characterized by migration of one or several organisms from the gut (29, 30). Discovery and identification of the blood and lung microbiota has prompted us to rethink the notion of bacterial translocation, which might be replaced by translocation of gut microbiota. Although many observations have strongly supported the hypothesis of the gut microbiota translocation, future studies with next-generation sequencing techniques are needed to characterize the microbial landscape in the MLN and distant organs in patients and experimental models. The findings would provide direct evidence for the translocation of intestinal microbiota and give us new perspectives to understand the pathogenesis of gut-derived sepsis. Interestingly, recent studies have revealed that in healthy individuals the blood and lung also harbor a diverse bacterial microbiota (44, 45, 47, 48), suggesting that translocation of intestinal microbiota may present under healthy condition. The observations are consistent with previous opinion that intestinal bacterial translocation probably occurs as a normal physiological event in healthy subjects (49). However, the pathological translocation of enteric bacteria in critically ill patients may increase owing to breakdown of intestinal barrier integrity (50), likely causing the alterations in the blood and lung microbiotas and the pathogenesis of systemic infections and sepsis (44, 45).

Dysbiosis of Intestinal Microbiota and Gut-Derived Infection

In the past few decades, our understanding into the structure and function of the gut microbiota has been largely enriched with advances of culture-independent techniques. The gut microbiota is involved in maintaining host homeostasis, with an important role in nutrition and energy metabolism (51), immune modulation (52), and host defense (53). Recently, numerous studies have highlighted the composition and role of the gut microbiota under a range of intestinal and extraintestinal diseases (5462). The involvement and implication of the gut microbiota in the development of bacterial translocation and gut-derived infection have also been broadly recognized. The harmful roles that the intestinal microbiota plays in critical illness are multifactorial and may be separated into three aspects: disruption of microbial barrier, loss of colonization resistance and metabolic disorder (6365).

Disruption of Microbial Barrier and Gut-Derived Infection

The gut microbiota represents the first barrier of protection against pathogen invasion, and disruption of this barrier is probably required for gut-derived infection in critical illness. Recent data showed that the intestinal microbiotas in critically ill patients in intensive care unit (ICU) are significantly altered, as characterized by overgrowth of opportunistic Proteobacteria and decreases in commensals Firmicutes and Bacteroidetes (1316). Of special note, the presence of specific pathogens at ICU admission was associated with subsequent infection with the same organism for Escherichia coli, Pseudomonas spp., Klebsiella spp., Clostridium difficile, and vancomycin-resistant Enterococcus (66). Furthermore, Enterococcus status at ICU admission was associated with risk for death or all-cause infection, indicating that the gut microbiota alterations have potential impact on mortality or the risk of healthcare-associated infections in critically ill patients (67). The patients with SAP also had significant alterations in the gut microbiota, including reduced microbiota diversity, increased Enterococcus and Enterobacteriaceae, and decreased Bifidobacterium (68). Additionally, the changes of the gut microbiota have been frequently seen in patients who underwent severe trauma (69), serious burn (70, 71), and major surgery (72, 73). The dysbiosis of the microbiota has been linked to occurrence of severely adverse events in critical illness, including sepsis, MODS, and even death (74, 75). Of special note, altered microbiota composition could cause increased penetrability and a deteriorated colonic mucus layer, contributing to lethal colitis and susceptibility to infection by enteric pathogens, such as C. difficile (76) and Citrobacter rodentium (77). Apparently, this is becoming clearer that the gut microbiota seems to provide disease-promoting influences in critically ill patients. A plethora of data from basic research with animal models also supports the prominent role of the gut microbiota dysbiosis in contributing to adverse outcomes in critical illness (78, 79). For instance, intestinal ischemia/reperfusion (I/R) injury could trigger a dysbiosis of gut microbiota and mucosal barrier damage, leading to enteric bacterial translocation and development of septic complications (80, 81). Altogether, the microbiota dysbiosis in critical illness is among the key factors that cause dysfunction of the intestinal barrier, contributing to pathological bacterial translocation and gut-derived infection. Yet, the extent to which this dysbiosis is causative to the subsequent acute septic response and multiple organ failures observed in critical illness remains to be determined.

Decreased Colonization Resistance Against Intestinal Pathogens

The intestinal microbiota plays a critical role in resistance against colonization by exogenous bacterial pathogens, termed colonization resistance (82). This phenomenon has been described over 50 year ago, and it has long been thought as microorganism-mediated direct inhibition (83). Being present in such huge numbers, the microorganisms in intestinal tract can compete for limited nutrition and adherence sites to the epithelia, preventing overgrowth, and invasion of potentially pathogenic microbes. Long-term antibiotic treatment could cause loss of commensal enteric bacteria, and thus decreases this direct inhibition. As a result, antibiotic-resistant bacterial species, such as vancomycin-resistant Enterococcus faecium (63), Gram-negative Enterobacteriaceae (84), and C. difficile (85), could proliferate and dominate mucosal surfaces, preceding severely enteric infection and bloodstream invasion. In addition to its direct roles in nutrition and niche competition, the gut microbiota can also combat invading pathogens indirectly by enhancing host immune defenses (immune-mediated colonization resistance) in the gut. The commensal bacteria are capable of augmenting mucosal immune responses for eradication of invading pathogens by various mechanisms (8688). Overall, both direct and indirect mechanisms could cooperate to provide resistance against colonization and invasion by potential pathogens, preventing the occurrence of bacterial translocation and gut-derived infection. Although the mechanisms underlying colonization resistance remain incompletely defined, there is little doubt that reestablishing colonization resistance after antibiotic treatment could be a potentially effective strategy for prevention and therapy of antibiotic-resistant bacterial infection. Recent studies have proved that the commensal microbiotas can be successfully manipulated to cure C. difficile infection in patients (89), which has been regarded as a consequence of reestablishing microbiota-mediated colonization resistance.

Potential Role of Microbial Metabolic Disorders

The gut microbiota has a huge metabolic activity and can convert host-derived and dietary components (lipids, carbohydrates, proteins, etc.) into various metabolites that are either beneficial or harmful for the host (90). Some of the metabolic products, including lactic acid, short chain fatty acids, bile salts, and bacteriocins are often considered as antimicrobial factors playing a critical role in protection against pathogenic infection (91, 92). On the contrary, a few metabolites deriving from microbial digestion of proteins, such as phenolic and sulfur-containing compounds, are potentially toxic to intestinal epithelial cells (93). The phenol expose could cause an increase of paracellular permeability in a dose-dependent manner, due to destruction of the intercellular tight junctions (94, 95). Likely, the microbiota alterations in critically ill patients might induce metabolic disorders and excessive production of such toxic metabolites, resulting in disruption of intestinal epithelial barrier and bacterial translocation (96, 97).

In total, increasing evidence has demonstrated that the microbiota dysbiosis is closely associated with the development of gut-derived sepsis and subsequent mortality in critically ill patients (19, 98). As such, the gut microbiota has also been successfully used as a therapeutic target in the management of sepsis and MODS (99101). With emerging evidence from clinical trials and basic researches, the causality of the relationship between the microbiota dysbiosis and gut-derived sepsis would be demonstrated. It will raise hope for simple and effective adjunctive therapies based on our expanding knowledge of the gut microbiota that might benefit critically ill patients.

Microbiota-Immune Interaction and Gut-Derived Infection

The intestinal immune system is considered as the last but the most important defense line against invasion of enteric microorganisms. There is a dynamic and complex interaction between the gut microbiota and the mucosal immune system (102). Under normal conditions, the microbiota could maintain a delicate balance with the mucosal immune system, which is extremely important for host health (54). The critical illness and associated medical interventions can cause a rapid and extreme change in the gut microbiota composition and activation of mucosal immune response (103). Consequently, this interaction between the gut microbiota and mucosal immune system is strikingly altered and becomes pathological in nature, providing the possibility for bacterial translocation, gut-derived infection and deleterious clinical sequalae.

Communication Between Gut Microbiota and Innate Immunity

In order to confront the microbial challenges, the intestine has developed a complex immune defense network containing the greatest number and diversity of immune cells in the body. As an important component of the intestinal immune network, the innate immune system plays a pivotal role in maintaining the balance between tolerance to commensal microorganisms and immunity to opportunistic pathogens (104). The innate immune cells in the intestine are usually non-responsive to the great number of commensal microorganisms. Yet, they can sense enteric microbial signals to restrict overgrowth of the pathobionts and assure a beneficial microbiota composition. At the same time, the innate immune cells also can rapidly respond to invading pathogens and prevent migration from the intestinal lumen to systemic circulation and distant organs. Once passing the mucous and epithelial barriers, invading bacteria would be recognized, phagocytosed, and eliminated by mucosal innate immune cells (e.g., macrophages, dendritic cells) under healthy state (105). Since the critically ill patients are usually accompanied by systemic immune deficiencies or immunosuppression, the innate immune cells in intestinal mucosa are likely dysfunctional and fail to eradicate invading pathogens, and thus lead to systemic translocation of intestinal bacteria (106108). Translocating bacteria and their products can activate immune response through recognition of specific pathogen-associated molecular patterns (PAMPs) by host innate immune cells (e.g., neutrophils and macrophages), triggering a systemic inflammatory response (109). Under such pathological conditions, activated neutrophils are excessively recruited into the intestine, which further promotes a dysregulation of innate immune function and cause mucosal injury (110). Alterations of the enteric microenvironment, coupled with medical treatment, lead to an overgrowth in opportunistic pathogenic bacteria and a decrease of commensal bacteria in critical illness (1316). The dysbiotic microbiota, in turn, could aggravate the mucosal immune dysfunction and promote an increase in enteric bacterial translocation, ultimately resulting in gut-derived infection, sepsis, and MODS (111, 112). Unsurprisingly, the interaction between gut microbiota and mucosal innate immunity is severely perturbed during the process. The innate immune dysregulation, microbiota dysbiosis, and bacterial translocation seem to shape a positive-feedback loop, together leading to uncontrollable inflammatory response and septic complications in critical illness. In a mouse model, morphine treatment induced a shift of gut microbiota toward a proinflammatory phenotype, which may be a result of the innate immune changes and commensal bacterial translocation (113115). Yet, fecal microbiota transplant successfully reversed morphine-induced microbial dysbiosis and restored gut immune homeostasis (113). The findings provide evidence supporting the existence of the feedback loop and its potential importance in the pathogenesis of gut-derived infection.

Several antimicrobial molecules generating from goblet cells, Paneth cells, and enterocytes, also have been identified as critical components of the innate immunity (116). These substances, including mucins, defensins, lysozyme, secretory phospholipase A2, and cathelicidins, have strong microbicidal activity and are able to directly kill microbes in the intestine, facilitating maintenance of gut homeostasis (117, 118). The generation and release of such antimicrobial molecules is also regulated by the gut microbes and their products (119, 120). Owing to lack of gut microbial stimulations, the intestinal mucous layer in germ-free mice is remarkably attenuated, despite the numbers of goblet cells are normal (121). Introduction of bacterial products, such as lipopolysaccharide (LPS) or peptidoglycan, can stimulate the release of mucin by goblet cells, leading to a rapid reconstitution of the inner mucous layer (122). The metabolites of the gut microbiota, i.e., butyrate, also can promote release of mucin for maintenance of the mucous barrier (123). The antimicrobials from Paneth cells, including defensins, lysozyme, and secretory phospholipase A2, are also expressed under the control of gut microorganisms (124). In return, the antimicrobial functions of these substances are required for stabilization of the gut microbiota (125) and integrity of the epithelial barrier (116, 126). In mice deficient for principal intestinal mucin (Muc2), there is an increased translocation of commensal and pathogenic bacteria (127), which is closely related to bacterial overgrowth in the intestine. In cynomolgus monkeys, administration of Campath-1H, a humanized monoclonal antibody against CD52, led to a significant decrease in the expression of defensin 5 and lysozyme in Paneth cells, altering the composition of the gut microbiota toward a pathogenic state (128). Likewise, it has been reported that decreased expression of α-defensins due to loss of Paneth cells can induce an expansion of pathogenic bacteria and a reduction in gut microbial diversity, leading to bacterial translocation (129). In addition, a lack of the antimicrobial cathelecidin can cause more severe disruption of intestinal mucosa in the colitis mouse models induced by dextran sodium sulfate (130). Evidently, diminished release of antimicrobial molecules is involved in increased bacterial translocation and is, at least in part, responsible for the pathogenesis of gut-derived infection.

In addition to bacterial translocation, one of the most interesting aspects regarding gut microbiota and host innate immunity involves C. difficile infection (CDI) and C. difficile-associated diarrhea (CDAD) (131). Many studies have indicated that the composition and diversity of the fecal microbiota in patients with CDI are pronouncedly altered, and the dysbiosis is associated with the infection and its resistance to antibiotic therapy (132, 133). A variety of factors, including antibiotics, NSAIDs, acid suppressing agents, and ages, can cause the microbiota dysbiosis. The loss of the protective microbial barrier allows for the formation of an ecological niche that favors the growth of C. difficile, and then leads to CDI and CDAD. Several mechanisms, such as alterations of fermentative metabolism (especially SCFAs), alterations of bile acid metabolism, and imbalance of antimicrobial substances production, have been proposed to explain the involvement of the microbiota in the process of the infection (131). Unsurprising, the innate immune system also participates in the pathogenesis of CDI, which is mainly mediated via toxin-dependent mechanism (134). Following colonization and growth of C. difficile in the intestinal tract, the innate immune cells (135, 136), including intestinal mast cells, macrophages, monocytes, and dendritic cells, are activated by C. difficile toxins, through the surface and intracellular innate immune sensors, for instance, the inflammasome and the TLR4, TLR5, and NOD1 signaling pathways (137). Multiple proinflammatory cytokines (IL-12, IL-18, IFN-γ, IL-1β, TNF-α) and chemokines (MIP-1a, MIP-2, IL-8, leptin) are produced in the process, which may be responsible for host inflammatory damages and the histopathological features associated with CDI, such as fluid accumulation, edema, increased mucosal permeability, mast cell degranulation, epithelial cell death, and intense local neutrophilic infiltration (138). Collectively, the microbiota dysbiosis and impaired innate immune response could play crucial roles in triggering C. difficile colonization and growth, and in the development of CDAD.

Crosstalk Between Gut Microbiota and Mucosal Adaptive Immunity

Despite characterized by tolerance to enteric microorganisms, the intestinal immune system has the daunting task of protecting us from pathogenic insults. Apart from the innate immunity, a highly sophisticated adaptive immune system also has been evolved in the gut (139), which are of upmost importance for prevention of bacterial translocation and gut-derived infection. When the enteric microorganisms cross the epithelium, the adaptive immune cells in the intestine are activated by antigen-presenting cells (macrophages, dendritic cells) to eradicate pathogens and establish long-lasting protective immunity (140). In the intestine, there is a huge and diverse population of T lymphocytes, forming a large part of the adaptive immune response. Many studies have suggested that loss of mucosal T cells has significant adverse effects on the maintenance of intestinal barrier integrity and defense of enteric infection, leading to increased morbidity (141, 142). In burn-injured rats, translocation of intestinal bacteria to MLN and systemic circulation is markedly increased following depletion of T cells (143). Gut I/R can induce a significant reduction in T-cell numbers and variations in lymphocyte phenotypes in intestinal mucosa, leading to enteric bacterial translocation and development of septic complications (144, 145). Depletion of intestinal mucosal lymphocytes induced by Campath-1H could cause dysbiosis of gut microbiota (128, 146, 147) and disruption of intestinal epithelial barriers (148, 149). Similar to the observations, severe impairment of gut barrier integrity was also seen in intestinal transplanted patients receiving Campath-1H administration (150, 151), which might be a major reason for high incidence of infectious complications after small bowel transplantation. In both septic patients and animal sepsis models, the lymphocytes within the intestinal epithelium undergo significant apoptosis, leading to pathologic bacterial translocation and gut-derived sepsis (152165).

The adaptive immune system in the gut mucosa is mainly composed of intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs) (156). They are essential to the adaptive immune response in intestinal mucosa, and have been shown to play a critical role in defending against the invasion of pathogens and infections. When the adaptive immune system is disrupted, the translocation of intestine-derived bacteria occurs and could trigger systemic inflammatory response and the onset of sepsis. γδ T cells are a unique subset of T cells with a distinct T-cell receptor (TCR), and serve as a key controller for the adaptive immune response to a broad range of pathogens (157). Intraepithelial γδ T lymphocytes can prevent mucosal dissemination of bacteria through the secretion of cytokines and antimicrobial molecules following mucosal injury (158). In the absence of intraepithelial γδ T cells, the host control of invasive bacteria is compromised and invasive bacteria populations are expanded (159). Additionally, the reduction of γδ T cells in the gut mucosa could induce transition of non-invasive intestinal bacterial types toward more invasive, causing bacterial translocation into the systemic circulation and pathological infections. In septic patients, γδ T cells in peripheral blood are significantly reduced, and this decrease is closely associated with the high mortality rate caused by infectious complications (160, 161).

The gut microbiota is actively involved in shaping and maintaining normal adaptive immune system in intestinal mucosa (139). The phenotypic differentiations of specific lymphocyte lineages in the mucosal immune system are reliant on the distinct component of the microbiota. In germ-free mice, the gut adaptive immune system is underdeveloped, and introduction of the commensal bacteria can induce enrichment and differentiations of mucosal lymphocytes (162164). Development of the adaptive immune cell diversifications represents an establishment of a complete “firewall” in the gut, which could prevent against the translocation of indigenous bacteria and pathogen infection (165). The gut microbiota also plays an important role in modulating the production of secretory IgA, mainly targeting against the enteric commensals and their antigens (166, 167). In the absence of IgA, the gut commensal bacteria could more easily enter the lamina propria and submucosal tissue by leaky barrier, leading to enteric bacterial translocation (168170). The individuals with secretory IgA deficiency have a tendency to develop gut-derived infections and functional disorders of the intestinal tract (171, 172). The interaction between gut microbiota and mucosal immunity is extremely complex. Consequently, the precise mechanism by which the alteration in commensal bacteria-specific adaptive immunity crosstalk involves the invasion and translocation of enteric bacteria remains incompletely clear and needs to be further elucidated.

Other Organisms Beyond Bacteria in the Intestinal Tract

In addition to the bacteria, the human intestinal microbiota also contains fungi, viruses, parasites, and other organisms. Despite representing a smaller fraction of the gut microbiota, they also play a crucial role in maintaining host health and in driving the development of the intestinal diseases.

Gut Fungal Microbiota

In GI tract, the fungi comprise a dynamic and ecologically diverse microbial community, termed the gut mycome. The fungal microbiota has been regarded as a critical player for the development of fungal infections and intestinal diseases, through interacting with enteric bacteria and host immune system (173). In ICU patients, the fungal overgrowth in the gut is frequently presented, which is usually considered as a result of commensal enteric bacteria loss after antibiotic or immunosuppressive therapy (174). Subsequently, the fungal pathogens, such as Candida and Aspergillus, could translocate impaired intestinal barrier into the bloodstream, leading to the fungemia. In a non-human primate model with lymphocyte depletion, the gut fungal microbiota is also perturbed, together with a dysbiosis of the bacterial flora (147). The findings indicate that a complex crosstalk may exist between the fungal and bacterial microbiota in the gut. It has been shown that Candida albicans has an ability to modify the bacterial microbiota (175), however, the detailed mechanisms underlying this interaction are still not well-known. There is also a complex interaction between the fungal microbiota and host immune system, which is mainly mediated via an innate immune receptor Dectin-1 (176). After recognizing β-1,3-glucans (a component of the fungal cell walls), Dectin-1 could activate intracellular signals through CARD9, resulting in release of inflammatory cytokines and induction of Th17-mediated immune responses (176, 177). Deficiencies in either Dectin-1 or CARD9 can lead to enhanced susceptibility to pathogenic fungal infections in humans and mice (178, 179), and are closely associated with ulcerative colitis in humans (180, 181). With improved understanding into host-fungus relationships, several fungal species with beneficial effects have been utilized in many acute and chronic diseases. For example, Saccharomyces boulardii has showed significant efficacy in preventing antibiotic associated diarrhea (182) and relapse of C. difficile infection (183). Despite these advances, in-depth studies on gut mycome composition and their relationships with gut bacteria, host immunity and related diseases are still warranted.

Intestinal Parasites

The intestinal parasites, mainly including Blastocystis and Amoebozoa, represent a unique microeukaryotic population, also termed gut eukaryome. Over the past few decades, the advances of DNA-based molecular techniques have enabled us to better estimate the presence of the intestinal parasites and its roles playing in human health and gastrointestinal diseases (184). Recent studies with real-time PCR showed that single-celled parasites, such as Blastocystis and Dientamoeba, are far more common than previously anticipated, even in developed countries (185, 186). Intriguingly, these parasites are most common in individuals with a healthy gut, while less prevalent in patients with irritable bowel syndrome (IBS) (187), and even less common in patients with inflammatory bowel disease (IBD) (188). The observations suggest that the parasites may be beneficial to human health rather than culprits of diseases (189). However, the parasites infection is possibly present in some individuals, which may be associated with specific ecological conditions in the gut, such as the microbiota dysbiosis. Gilchrist et al. showed that a high parasite burden was coupled with increased abundance of Prevotella copri in Bangladeshi children with Entamoeba histolytica infection (190). In a mouse model with n amoebic colitis, the microbiota dysbiosis induced by antibiotic treatment can increase the severity of amoebic colitis and delay the clearance of E. histolytica (191). Giardia infection was also related to the dysbiosis of gut microbiota, as characterized by an increase of facultatively and strictly aerobic bacteria (192). In contrast to this, some animal experiments showed that probiotics can prevent or modulate parasite infection, supporting the association of the gut microbiota with the parasites (193). Taking all these studies into account, it appears that the presence of intestinal parasites, are closely linked to certain microbial communities. However, the causative link between the presence of a given parasite and the microbiota dysbiosis is still incompletely clear. The gut microbiota may not only be driving the susceptibility to, but also the outcome of, parasite infection (194). Future investigations should be designed to strengthen our knowledge regarding associations between parasites and gut microbiota, and also explore whether the parasites can be transplanted to a diseased recipient as a potential therapy for functional and/or organic bowel diseases as well as metabolic disorders.

Gut Virome

The human gut virome is composed of two main players: microbial viruses (bacteriophages) and eukaryotic viruses (195). It is estimated that the human GI tract contains ~1015 bacteriophages, which represent the most abundant member of the gut virome (196). The vast majority of bacteriophages in the gut are a DNA phage named crAssphage (cross-assembly phage), mainly belonging to the family Podoviridae (197). Similar to the bacterial microbiome, the gut viral communities are established at birth and evolve over time to become “adult-like” virome (198, 199). The structure and composition of the virome are also influenced by age, host genetics and environmental factors, such as diet, antibiotic use, and location (198202). The viruses also have cross-kingdom interaction with the bacteria and other constituents of the intestinal microbiota, which are usually beneficial to host health and sometimes could increase the risk of disease (203). Owing to their ability to kill host bacteria, the phages can play a role in maintenance of the intestinal homeostasis through affecting the structure and function of enteric bacterial community (204). Under certain conditions, however, changes of the phage populations could induce intestinal dysbiosis and contribute directly to the development of intestinal diseases, such as IBD (205). To explain the mechanisms underlying phage-driven intestinal dysbiosis, several hypothetical models (206), including “Kill the Winner” model, “Biological Weapon” model, and “Community Shuffling” model, have been put forward to elucidate the complex interaction between the phages and bacteria during the process. In addition to these, the phages can also transfer genes (i.e., bacteriophage transcription factors) into bacteria to change their phenotypes and further control their biological functions, which is termed as the “Emerging New Bacterial Strain” model. Meanwhile, enteric bacteria also develop defense mechanisms against the bacteriophages, through the restriction modification system (207), hiding membrane receptors (208), increasing production of competitive inhibitors (209), self-destruction (210), and CRISPR-Cas systems (211). The detailed mechanisms that maintain the balance between bacteriophages and bacterial populations and result in the intestinal dysbiosis and diseased states have been documented in the review article by Mukhopadhya et al. (212). Development and implementation of metagenomic techniques have allowed us to study the “entire virome” composition and its interaction with other elements of the gut microbiome. With discovery and identification of new viral genomic sequences in the coming years, our understanding on the gut virome as a cohesive ecological unit that can affect the intestinal homeostasis and lead to diseases will continue to improve.

Manipulation of Gut Microbiota for Treatment of Gut-Derived Sepsis

Considering the gut microbiota dysbiosis as one of the most important factors that can lead to pathologically bacterial translocation and systemic infection, it may be feasible to develop novel therapeutic strategies against gut-derived sepsis by modulating the microbiota. More than 90% of the commensal organisms would be lost during the early stage of the critical illness insults, thereby, it may be impossible that a single or several probiotic species would be able to completely replenish the diversity of the gut microbiota (213). Transfer of healthy donor feces containing thousands of microbial species, termed FMT, would facilitate replenishment of diminished commensal bacteria and guide the patient's microbiota toward a healthy state (214). In the last several years, FMT has been successfully utilized in the treatment of recurrent CDI (215, 216). Yet, FMT is scarcely used in the treatment of septic patients, due to that in such cases antibiotic therapy is frequent and its continuation would adversely influence remodeling of the microbiota after FMT. Recently, it has been reported on the use of FMT in septic patients with MODS and non-C. difficile diarrhea, refractory to standard medical management (99101). At 2–3 weeks of post-FMT, the patients had resolution in their diarrhea and significant decreases in the blood levels of the inflammatory mediators, such as TNF-α, interleukin (IL)-1β, IL-6, and C-reactive protein. Following FMT, the stool microbiotas in the patients showed marked alterations toward that of the donors, with growing Firmicutes and reducing Proteobacteria. Even though this is a serial of case reports, the improved clinical outcomes in these patients following FMT are still exciting. This success raises the possibility for the use of the unconventional therapeutic procedure in the clinical management of gut-derived sepsis and MODS which is commonly complicated in critically ill patients. Although the efficacy of FMT observed in such cases reports remains to be further validated, manipulation of the microbiota with FMT for therapeutic benefits represents a new avenue in the future care of critically ill patients (16, 75, 217219). Nonetheless, such early experiences with FMT curing ICU patients have strengthened enthusiasm for broader its use in critical illness.

Concluding Remarks

The interplay between gut microbiota and host immune is exquisitely complex. Exploration of the relationship between the gut microbiota alterations and host immunological disorders has significant potential to enhance our understanding and future treatment of relevant diseases. Abundant evidence has demonstrated that disturbance of the microbiota-immune relationship is a key event in the development of pathological bacterial translocation (220, 221). However, studies of the microbiota-immune interaction in critical illness remain in their infancy, and the underlying mechanisms are still incompletely clear. Beyond just describing effects of the microbiota dysbiosis on mucosal immune cell phenotypes, future investigations need to move toward unraveling the molecular mechanisms of the interaction in the pathogenesis of gut-derived infection. Systems biology studies based gut metagenomics and immunogenomics under the conditions of critical illness have fundamental importance for identifying the critical signal pathways and molecules that promote translocation of enteric microorganisms. Elucidation of the cross-regulation of gene expression between commensal bacteria and cells of the mucosal immune system will provide us mechanistic understanding on the complex interaction in critical illness. The knowledge would enable the field to enter a stage in which interventional strategies could be designed to improve the immune defense against invading microorganisms while protecting from pathological bacterial translocation to systemic circulation. With deeper understanding of this interaction, the precision manipulations that can restrict bacterial translocation may be possible and offer new strategies to avoid some of the untoward outcomes related to gut-derived infection in critically ill patients.

Author Contributions

CW wrote the original draft and revised the manuscript. QL reviewed and edited the manuscript. JR critically revised the manuscript. All authors read and approved the final version of the manuscript for submission.

Funding

This work was supported by the National Natural Science Foundation of China (81801971, 81772052, and 81571881), National Basic Research Program (973 Program) in China (2013CB531403), and National High-tech R&D Program (863 Program) of China (2012AA021007).

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

1. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. (1992) 20:864–74. doi: 10.1097/00003246-199206000-00025

CrossRef Full Text | Google Scholar

2. Schorr CA, Dellinger RP. The Surviving Sepsis Campaign: past, present and future. Trends Mol Med. (2014) 20:192–4. doi: 10.1016/j.molmed.2014.02.001

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Moore FA, Moore EE. Evolving concepts in the pathogenesis of postinjury multiple organ failure. Surg Clin North Am. (1995) 75:257–77. doi: 10.1016/S0039-6109(16)46587-4

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Meng M, Klingensmith NJ, Coopersmith CM. New insights into the gut as the driver of critical illness and organ failure. Curr Opin Crit Care. (2017) 23:143–8. doi: 10.1097/MCC.0000000000000386

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Hassoun HT, Kone BC, Mercer DW, Moody FG, Weisbrodt NW, Moore FA. Post–injury multiple organ failure: the role of the gut. Shock. (2001) 15:1–10. doi: 10.1097/00024382-200115010-00001

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol. (2009) 9:799–809. doi: 10.1038/nri2653

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Fink MP. Intestinal epithelial hyperpermeability: update on the pathogenesis of gut mucosal barrier dysfunction in critical illness. Curr Opin Crit Care. (2003) 9:143–51. doi: 10.1097/00075198-200304000-00011

PubMed Abstract | CrossRef Full Text | Google Scholar

8. De–Souza DA, Greene LJ. Intestinal permeability and systemic infections in critically ill patients: effect of glutamine. Crit Care Med. (2005) 33:1125–35. doi: 10.1097/01.CCM.0000162680.52397.97

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, et al. Diversity of the human intestinal microbial flora. Science. (2005) 308:1635–8. doi: 10.1126/science.1110591

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Bauer TM, Schwacha H, Steinbrückner B, Brinkmann FE, Ditzen AK, Aponte JJ, et al. Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxemia. Am J Gastroenterol. (2002) 97:2364–70. doi: 10.1111/j.1572-0241.2002.05791.x

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Pardo A, Bartoli R, Lorenzo–Zuniga V, Planas R, Vinado B, Riba J, et al. Effect of cisapride on intestinal bacterial overgrowth and bacterial translocation in cirrhosis. Hepatology. (2000) 31:858–63. doi: 10.1053/he.2000.5746

PubMed Abstract | CrossRef Full Text | Google Scholar

12. The Human Microbiome Project Consortium. Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature. (2012) 486:207–14. doi: 10.1038/nature11234

CrossRef Full Text | Google Scholar

13. Zaborin A, Smith D, Garfield K, Quensen J, Shakhsheer B, Kade M, et al. Membership and behavior of ultra–low–diversity pathogen communities present in the gut of humans during prolonged critical illness. MBio. (2014) 5:e01361–14. doi: 10.1128/mBio.01361-14

PubMed Abstract | CrossRef Full Text | Google Scholar

14. McDonald D, Ackermann G, Khailova L, Baird C, Heyland D, Kozar R, et al. Extreme dysbiosis of the microbiome in critical illness. mSphere. (2016) 1:e00199–16. doi: 10.1128/mSphere.00199-16

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Ojima M, Motooka D, Shimizu K, Gotoh K, Shintani A, Yoshiya K, et al. Metagenomic analysis reveals dynamic changes of whole gut microbiota in the acute phase of intensive care unit patients. Dig Dis Sci. (2016) 61:1628–34. doi: 10.1007/s10620-015-4011-3

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Lankelma JM, van Vught LA, Belzer C, Schultz MJ, van der Poll T, de Vos WM, et al. Critically ill patients demonstrate large interpersonal variation in intestinal microbiota dysregulation: a pilot study. Intensive Care Med. (2017) 43:59–68. doi: 10.1007/s00134-016-4613-z

CrossRef Full Text | Google Scholar

17. Gómez-Hurtado I, Santacruz A, Peiró G, Zapater P, Gutiérrez A, Pérez-Mateo M, et al. Gut microbiota dysbiosis is associated with inflammation and bacterial translocation in mice with CCl4–induced fibrosis. PLoS ONE. (2011) 6:e23037. doi: 10.1371/journal.pone.0023037

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Dickson RP. The microbiome and critical illness. Lancet Respir Med. (2016) 4:59–72. doi: 10.1016/S2213-2600(15)00427-0

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Klingensmith NJ, Coopersmith CM. The gut as the motor of multiple organ dysfunction in critical illness. Crit Care Clin. (2016) 32:203–12. doi: 10.1016/j.ccc.2015.11.004

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Leser TD, Mølbak L. Better living through microbial action: the benefits of the mammalian gastrointestinal microbiota on the host. Environ Microbiol. (2009) 11:2194–206. doi: 10.1111/j.1462-2920.2009.01941.x

PubMed Abstract | CrossRef Full Text | Google Scholar

21. Natividad JM, Verdu EF. Modulation of intestinal barrier by intestinal microbiota: pathological and therapeutic implications. Pharmacol Res. (2013) 69:42–51. doi: 10.1016/j.phrs.2012.10.007

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Knoop KA, McDonald KG, Kulkarni DH, Newberry RD. Antibiotics promote inflammation through the translocation of native commensal colonic bacteria. Gut. (2016) 65:1100–9. doi: 10.1136/gutjnl-2014-309059

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Kaiko GE, Stappenbeck TS. Host–microbe interactions shaping the gastrointestinal environment. Trends Immunol. (2014) 35:538–48. doi: 10.1016/j.it.2014.08.002

PubMed Abstract | CrossRef Full Text | Google Scholar

24. Wischmeyer PE, McDonald D, Knight R. Role of the microbiome, probiotics, and ‘dysbiosis therapy' in critical illness. Curr Opin Crit Care. (2016) 22:347–53. doi: 10.1097/MCC.0000000000000321

PubMed Abstract | CrossRef Full Text | Google Scholar

25. Wolochow H, Hildebrand G, Lammanna C. Translocation of microorganisms across the intestinal wall of the rat: effect of microbial size and concentration. J Infect Dis. (1966) 116:523–8. doi: 10.1093/infdis/116.4.523

PubMed Abstract | CrossRef Full Text | Google Scholar

26. Berg RD, Garlington AW. Translocation of certain indigenous bacteria from the gastrointestinal tract to the mesenteric lymph nodes and other organs in the gnotobiotic mouse model. Infect Immun. (1979) 23:403–11.

PubMed Abstract | Google Scholar

27. Schweinburg FB, Frank HA, Frank ED, Heimberg F, Fine J. Transmural migration of intestinal bacteria during peritoneal irrigation in uremic dogs. Proc Soc Exp Biol Med. (1949) 71:150–3. doi: 10.3181/00379727-71-17114

PubMed Abstract | CrossRef Full Text | Google Scholar

28. Sedman PC, Macfie J, Sagar P, Mitchell CJ, May J, Mancey-Jones B, et al. The prevalence of gut translocation in humans. Gastroenterology. (1994):107:643–9. doi: 10.1016/0016-5085(94)90110-4

PubMed Abstract | CrossRef Full Text | Google Scholar

29. O'Boyle C, MacFie J, Mitchell C, Johnstone D, Sagar P, Sedman P. Microbiology of bacterial translocation in humans. Gut. (1998) 42:29–35. doi: 10.1136/gut.42.1.29

PubMed Abstract | CrossRef Full Text | Google Scholar

30. MacFie J, O'Boyle C, Mitchell CJ, Buckley PM, Johnstone D, Sudworth P. Gut origin of sepsis: a prospective study investigating associations between bacterial translocation, gastric microflora, and septic morbidity. Gut. (1999) 45:223–8. doi: 10.1136/gut.45.2.223

PubMed Abstract | CrossRef Full Text | Google Scholar

31. Woodcock NP, Sudheer V, El–Barghouti N, Perry EP, MacFie J. Bacterial translocation in patients undergoing abdominal aortic aneurysm repair. Br J Surg. (2000) 87:439–42. doi: 10.1046/j.1365-2168.2000.01417.x

PubMed Abstract | CrossRef Full Text | Google Scholar

32. Chin KF, Kallam R, O'Boyle C, MacFie J. Bacterial translocation may influence long–term survival in colorectal cancer patients. Dis Colon Rectum. (2006) 50:323–30. doi: 10.1007/s10350-006-0827-4

PubMed Abstract | CrossRef Full Text | Google Scholar

33. MacFie J, Reddy BS, Gatt M, Jain PK, Sowdi R, Mitchell CJ. Bacterial translocation studied in 927 patients over 13 years. Br J Surg. (2006) 93:87–93. doi: 10.1002/bjs.5184

PubMed Abstract | CrossRef Full Text | Google Scholar

34. Reddy BS, MacFie J, Gatt M, Macfarlane-Smith L, Bitzopoulou K, Snelling AM. Commensal bacteria do translocate across the intestinal barrier in surgical patients. Clin Nutr. (2007) 26:208–15. doi: 10.1016/j.clnu.2006.10.006

PubMed Abstract | CrossRef Full Text | Google Scholar

35. MacFie J. Current status of bacterial translocation as a cause of surgical sepsis. Br Med Bull. (2004) 71:1–11. doi: 10.1093/bmb/ldh029

PubMed Abstract | CrossRef Full Text | Google Scholar

36. Deitch EA. Gut–origin sepsis: evolution of a concept. Surgeon. (2012) 10:350–6. doi: 10.1016/j.surge.2012.03.003

PubMed Abstract | CrossRef Full Text | Google Scholar

37. Mylotte JM, Tayara A. Blood cultures: clinical aspects and controversies. Eur J Clin Microbiol Infect Dis. (2000) 19:157–63. doi: 10.1007/s100960050453

PubMed Abstract | CrossRef Full Text | Google Scholar

38. Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA. (2009) 302:2323–9. doi: 10.1001/jama.2009.1754

PubMed Abstract | CrossRef Full Text | Google Scholar

39. Ecker DJ, Sampath R, Li H, Massire C, Matthews HE, Toleno D, et al. New technology for rapid molecular diagnosis of bloodstream infections. Expert Rev Mol Diagn. (2010) 10:399–415. doi: 10.1586/erm.10.24

PubMed Abstract | CrossRef Full Text | Google Scholar

40. Buehler SS, Madison B, Snyder SR, Derzon JH, Cornish NE, Saubolle MA, et al. Effectiveness of practices to increase timeliness of providing targeted therapy for inpatients with bloodstream infections: a laboratory medicine best practices systematic review and meta–analysis. Clin Microbiol Rev. (2016) 29:59–103. doi: 10.1128/CMR.00053-14

PubMed Abstract | CrossRef Full Text | Google Scholar

41. Li Q, Wang C, Tang C, He Q, Li N, Li J. Bacteremia in the patients with acute pancreatitis as revealed by 16S rRNA gene–based techniques. Crit Care Med. (2013) 41:1938–50. doi: 10.1097/CCM.0b013e31828a3dba

CrossRef Full Text | Google Scholar

42. Gosiewski T, Ludwig-Galezowska AH, Huminska K, Sroka–Oleksiak A, Radkowski P, Salamon D, et al. Comprehensive detection and identification of bacterial DNA in the blood of patients with sepsis and healthy volunteers using next–generation sequencing method–the observation of DNAemia. Eur J Clin Microbiol Infect Dis. (2017) 36:329–36. doi: 10.1007/s10096-016-2805-7

PubMed Abstract | CrossRef Full Text | Google Scholar

43. Grumaz S, Stevens P, Grumaz C, Decker SO, Weigand MA, Hofer S, et al. Next–generation sequencing diagnostics of bacteremia in septic patients. Genome Med. (2016) 8:73. doi: 10.1186/s13073-016-0326-8

PubMed Abstract | CrossRef Full Text | Google Scholar

44. Li Q, Wang C, Tang C, Zhao X, He Q, Li J. Identification and characterization of blood and neutrophil–associated microbiomes in patients with severe acute pancreatitis using next–generation sequencing. Front Cell Infect Microbiol. (2018) 8:5. doi: 10.3389/fcimb.2018.00005

PubMed Abstract | CrossRef Full Text | Google Scholar

45. Dickson RP, Singer BH, Newstead MW, Falkowski NR, Erb–Downward JR, Standiford TJ, et al. Enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome. Nat Microbiol. (2016) 1:161113. doi: 10.1038/nmicrobiol.2016.113

PubMed Abstract | CrossRef Full Text | Google Scholar

46. Dickson RP, Martinez FJ, Huffnagle GB. The role of the microbiome in exacerbations of chronic lung diseases. Lancet. (2014) 384:691–702. doi: 10.1016/S0140-6736(14)61136-3

PubMed Abstract | CrossRef Full Text | Google Scholar

47. Pa?ssé S, Valle C, Servant F, Courtney M, Burcelin R, Amar J, et al. Comprehensive description of blood microbiome from healthy donors assessed by 16S targeted metagenomic sequencing. Transfusion. (2016) 56:1138–47. doi: 10.1111/trf.13477

CrossRef Full Text | Google Scholar

48. Potgieter M, Bester J, Kell DB, Pretorius E. The dormant blood microbiome in chronic, inflammatory diseases. FEMS Microbiol Rev. (2015) 39:567–91. doi: 10.1093/femsre/fuv013

PubMed Abstract | CrossRef Full Text | Google Scholar

49. Brenchley JM, Douek DC. Microbial translocation across the GI tract. Annu Rev Immunol. (2012) 30:149–73. doi: 10.1146/annurev-immunol-020711-075001

PubMed Abstract | CrossRef Full Text | Google Scholar

50. Wiest R, Lawson M, Geuking M. Pathological bacterial translocation in liver cirrhosis. J Hepatol. (2014) 60:197–209. doi: 10.1016/j.jhep.2013.07.044

PubMed Abstract | CrossRef Full Text | Google Scholar

51. Tremaroli V, Bäckhed F. Functional interactions between the gut microbiota and host metabolism. Nature. (2012) 489:242–9. doi: 10.1038/nature11552

PubMed Abstract | CrossRef Full Text | Google Scholar

52. Hooper LV, Macpherson AJ. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat Rev Immunol. (2010) 10:159–69. doi: 10.1038/nri2710

PubMed Abstract | CrossRef Full Text | Google Scholar

53. Kamada N, Chen GY, Inohara N, Núñez G. Control of pathogens and pathobionts by the gut microbiota. Nat Immunol. (2013) 14:685–90. doi: 10.1038/ni.2608

PubMed Abstract | CrossRef Full Text | Google Scholar

54. Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol. (2009) 9:313–23. doi: 10.1038/nri2515

PubMed Abstract | CrossRef Full Text | Google Scholar

55. Morgan XC, Tickle TL, Sokol H, Gevers D, Devaney KL, Ward DV, et al. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol. (2012) 13:R79. doi: 10.1186/gb-2012-13-9-r79

PubMed Abstract | CrossRef Full Text | Google Scholar

56. Ridaura VK, Faith JJ, Rey FE, Cheng J, Duncan AE, Kau AL, et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science. (2013) 341:1241214. doi: 10.1126/science.1241214

PubMed Abstract | CrossRef Full Text | Google Scholar

57. Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, et al. A metagenome–wide association study of gut microbiota in type 2 diabetes. Nature. (2012) 490:55–60. doi: 10.1038/nature11450

PubMed Abstract | CrossRef Full Text | Google Scholar

58. Bisgaard H, Li N, Bonnelykke K, Chawes BL, Skov T, Paludan-Müller G, et al. Reduced diversity of the intestinal microbiota during infancy is associated with increased risk of allergic disease at school age. J Allergy Clin Immunol. (2011) 128:646–52. doi: 10.1016/j.jaci.2011.04.060

PubMed Abstract | CrossRef Full Text | Google Scholar

59. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. (2011) 472:57–63. doi: 10.1038/nature09922

PubMed Abstract | CrossRef Full Text | Google Scholar

60. Qin N, Yang F, Li A, Prifti E, Chen Y, Shao L, et al. Alterations of the human gut microbiome in liver cirrhosis. Nature. (2014) 513:59–64. doi: 10.1038/nature13568

PubMed Abstract | CrossRef Full Text | Google Scholar

61. Wang C, Li Q, Li J. Gut microbiota and its implications in small bowel transplantation. Front Med. (2018) 12:239–48. doi: 10.1007/s11684-018-0617-0

PubMed Abstract | CrossRef Full Text | Google Scholar

62. Wong SH, Zhao L, Zhang X, Nakatsu G, Han J, Xu W, et al. Gavage of fecal samples from patients with colorectal cancer promotes intestinal carcinogenesis in germ–free and conventional mice. Gastroenterology. (2017) 153:1621–33. doi: 10.1053/j.gastro.2017.08.022

PubMed Abstract | CrossRef Full Text | Google Scholar

63. Ubeda C, Taur Y, Jenq RR, Equinda MJ, Son T, Samstein M, et al. Vancomycin–resistant Enterococcus domination of intestinal microbiota is enabled by antibiotic treatment in mice and precedes bloodstream invasion in humans. J Clin Invest. (2010) 120:4332–41. doi: 10.1172/JCI43918

PubMed Abstract | CrossRef Full Text | Google Scholar

64. Andersen K, Kesper MS, Marschner JA, Konrad L, Ryu M, Kumar Vr S, et al. Intestinal dysbiosis, barrier dysfunction, and bacterial translocation account for CKD–related systemic inflammation. J Am Soci Nephrol. (2016) 28:76–83. doi: 10.1681/ASN.2015111285

PubMed Abstract | CrossRef Full Text | Google Scholar

65. Alverdy JC, Krezalek MA. Collapse of the microbiome, emergence of the pathobiome, and the immunopathology of sepsis. Crit Care Med. (2017) 45:337–47. doi: 10.1097/CCM.0000000000002172

PubMed Abstract | CrossRef Full Text | Google Scholar

66. Freedberg DE, Zhou MJ, Cohen ME, Annavajhala MK, Khan S, Moscoso DI, et al. Pathogen colonization of the gastrointestinal microbiome at intensive care unit admission and risk for subsequent death or infection. Intensive Care Med. (2018) 44:1203–11. doi: 10.1007/s00134-018-5268-8

CrossRef Full Text | Google Scholar

67. Ruppé É, Lisboa T, Barbier F. The gut microbiota of critically ill patients: first steps in an unexplored world. Intensive Care Med. (2018) 44:1561–4. doi: 10.1007/s00134-018-5309-3

PubMed Abstract | CrossRef Full Text | Google Scholar

68. Tan C, Ling Z, Huang Y, Cao Y, Liu Q, Cai T, et al. Dysbiosis of intestinal microbiota associated with inflammation involved in the progression of acute pancreatitis. Pancreas. (2015) 44:868–75. doi: 10.1097/MPA.0000000000000355

PubMed Abstract | CrossRef Full Text | Google Scholar

69. Howard BM, Kornblith LZ, Christie SA, Conroy AS, Nelson MF, Campion EM, et al. Characterizing the gut microbiome in trauma: significant changes in microbial diversity occur early after severe injury. Trauma Surg Acute Care Open. (2017) 2:e000108. doi: 10.1136/tsaco-2017-000108

PubMed Abstract | CrossRef Full Text | Google Scholar

70. Shimizu K, Ogura H, Asahara T, Nomoto K, Matsushima A, Hayakawa K, et al. Gut microbiota and environment in patients with major burns – a preliminary report. Burns. (2015) 41:e28–33. doi: 10.1016/j.burns.2014.10.019

PubMed Abstract | CrossRef Full Text | Google Scholar

71. Wang X, Yang J, Tian F, Zhang L, Lei Q, Jiang T, et al. Gut microbiota trajectory in patients with severe burn: a time series study. J Crit Care. (2017) 42:310–6. doi: 10.1016/j.jcrc.2017.08.020

PubMed Abstract | CrossRef Full Text | Google Scholar

72. Jin Y, Liu Y, Zhao L, Zhao F, Feng J, Li S, et al. Gut microbiota in patients after surgical treatment for colorectal cancer. Environ Microbiol. (2018) 21:772–83. doi: 10.1111/1462-2920.14498

PubMed Abstract | CrossRef Full Text | Google Scholar

73. Cong J, Zhu H, Liu D, Li T, Zhang C, Zhu J, et al. A pilot study: changes of gut microbiota in post–surgery colorectal cancer patients. Front Microbiol. (2018) 9:2777. doi: 10.3389/fmicb.2018.02777

PubMed Abstract | CrossRef Full Text | Google Scholar

74. Lyons JD, Ford ML, Coopersmith CM. The microbiome in critical illness: firm conclusions or bact to square one? Dig Dis Sci. (2016) 61:1420–1. doi: 10.1007/s10620-016-4092-7

PubMed Abstract | CrossRef Full Text | Google Scholar

75. Haak BW, Wiersinga WJ. The role of the gut microbiota in sepsis. Lancet Gastroenterol Hepatol. (2017) 2:135–43. doi: 10.1016/S2468-1253(16)30119-4

PubMed Abstract | CrossRef Full Text | Google Scholar

76. Bien J, Palagani V, Bozko P. The intestinal microbiota dysbiosis and Clostridium difficile infection: is there a relationship with inflammatory bowel disease? Ther Adv Gastroenterol. (2013) 6:53–68. doi: 10.1177/1756283X12454590

PubMed Abstract | CrossRef Full Text | Google Scholar

77. Wlodarska M, Willing B, Keeney KM, Menendez A, Bergstrom KS, Gill N, et al. Antibiotic treatment alters the colonic mucus layer and predisposes the host to exacerbated Citrobacter rodentium–induced colitis. Infect Immun. (2011) 79:1536–45. doi: 10.1128/IAI.01104-10

PubMed Abstract | CrossRef Full Text | Google Scholar

78. Souza DG, Vieira AT, Soares AC, Pinho V, Nicoli JR, Vieira LQ, et al. The essential role of the intestinal microbiota in facilitating acute inflammatory responses. J Immunol. (2004) 173:4137–46. doi: 10.4049/jimmunol.173.6.4137

PubMed Abstract | CrossRef Full Text | Google Scholar

79. Zhu Y, He C, Li X, Cai Y, Hu J, Liao Y, et al. Gut microbiota dysbiosis worsens the severity of acute pancreatitis in patients and mice. J Gastroenterol. (2018) 54:347–58. doi: 10.1007/s00535-018-1529-0

PubMed Abstract | CrossRef Full Text | Google Scholar

80. Wang F, Li Q, Wang C, Tang C, Li J. Dynamic alteration of the colonic microbiota in intestinal ischemia–reperfusion injury. PLoS ONE. (2012) 7:e42027. doi: 10.1371/journal.pone.0042027

PubMed Abstract | CrossRef Full Text | Google Scholar

81. Wang F, Li Q, He Q, Geng Y, Tang C, Wang C, et al. Temporal variations of the ileal microbiota in intestinal ischemia and reperfusion. Shock. (2013) 39:96–103. doi: 10.1097/SHK.0b013e318279265f

PubMed Abstract | CrossRef Full Text | Google Scholar

82. Buffie CG, Pamer EG. Microbiota–mediated colonization resistance against intestinal pathogens. Nat Rev Immunol. (2013) 13:790–801. doi: 10.1038/nri3535

PubMed Abstract | CrossRef Full Text | Google Scholar

83. van der Waaij D, Berghuis-de Vries JM, Lekkerkerk-van der Wees JEC. Colonization resistance of the digestive tract in conventional and antibiotic–treated mice. J Hyg. (1971) 69:405–11. doi: 10.1017/S0022172400021653

PubMed Abstract | CrossRef Full Text | Google Scholar

84. Lupp C, Robertson ML, Wickham ME, Sekirov I, Champion OL, Gaynor EC, et al. Host–mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe. (2007) 2:119–29. doi: 10.1016/j.chom.2007.06.010

CrossRef Full Text | Google Scholar

85. Buffie CG, Jarchum I, Equinda M, Lipuma L, Gobourne A, Viale A, et al. Profound alterations of intestinal microbiota following a single dose of clindamycin results in sustained susceptibility to Clostridium difficile–induced colitis. Infect Immun. (2012) 80:62–73. doi: 10.1128/IAI.05496-11

PubMed Abstract | CrossRef Full Text | Google Scholar

86. Diehl GE, Longman RS, Zhang JX, Breart B, Galan C, Cuesta A, et al. Microbiota restricts trafficking of bacteria to mesenteric lymph nodes by CX3CR1hi cells. Nature. (2013) 494:116–20. doi: 10.1038/nature11809

CrossRef Full Text | Google Scholar

87. Farache J, Koren I, Milo I, Gurevich I, Kim KW, Zigmond E, et al. Luminal bacteria recruit CD103+ dendritic cells into the intestinal epithelium to sample bacterial antigens for presentation. Immunity. (2013) 38:581–95. doi: 10.1016/j.immuni.2013.01.009

PubMed Abstract | CrossRef Full Text | Google Scholar

88. Wingender G, Stepniak D, Krebs P, Lin L, McBride S, Wei B, et al. Intestinal microbes affect phenotypes and functions of invariant natural killer T cells in mice. Gastroenterology. (2012) 143:418–28. doi: 10.1053/j.gastro.2012.04.017

PubMed Abstract | CrossRef Full Text | Google Scholar

89. van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. (2013) 368:407–15. doi: 10.1056/NEJMoa1205037

PubMed Abstract | CrossRef Full Text | Google Scholar

90. Kamada N, Kim YG, Sham HP, Vallance BA, Puente JL, Martens EC, et al. Regulated virulence controls the ability of a pathogen to compete with the gut microbiota. Science. (2012) 336:1325–9. doi: 10.1126/science.1222195

PubMed Abstract | CrossRef Full Text | Google Scholar

91. de Sablet T, Chassard C, Bernalier-Donadille A, Vareille M, Gobert AP, Martin C. Human microbiota–secreted factors inhibit Shiga toxin synthesis by enterohemorrhagic Escherichia coli O157:H7. Infect Immun. (2009) 77:783–90. doi: 10.1128/IAI.01048-08

PubMed Abstract | CrossRef Full Text | Google Scholar

92. Rea MC, Clayton E, O'Connor PM, Shanahan F, Kiely B, Ross RP, et al. Antimicrobial activity of lacticin 3,147 against clinical Clostridium difficile strains. J Med Microbiol. (2007) 56:940–6. doi: 10.1099/jmm.0.47085-0

PubMed Abstract | CrossRef Full Text | Google Scholar

93. Hamer HM, De Preter V, Windey K, Verbeke K. Functional analysis of colonic bacterial metabolism: relevant to health? Am J Physiol Gastrointest Liver Physiol. (2012) 302:G1–9. doi: 10.1152/ajpgi.00048.2011

PubMed Abstract | CrossRef Full Text | Google Scholar

94. Hughes R, Kurth MJ, McGilligan V, McGlynn H, Rowland I. Effect of colonic bacterial metabolites on Caco−2 cell paracellular permeability in vitro. Nutr Cancer. (2008) 60:259–66. doi: 10.1080/01635580701649644

PubMed Abstract | CrossRef Full Text | Google Scholar

95. McCall IC, Betanzos A, Weber DA, Nava P, Miller GW, Parkos CA. Effects of phenol on barrier function of a human intestinal epithelial cell line correlate with altered tight junction protein localization. Toxicol Appl Pharmacol. (2009) 241:61–70. doi: 10.1016/j.taap.2009.08.002

PubMed Abstract | CrossRef Full Text | Google Scholar

96. Cox LM, Yamanishi S, Sohn J, Alekseyenko AV, Leung JM, Cho I, et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell. (2014) 158:705–21. doi: 10.1016/j.cell.2014.05.052

PubMed Abstract | CrossRef Full Text | Google Scholar

97. Johnson S, Gerding DN. Clostridium difficile–associated diarrhea. Clin Infect Dis. (1998) 26:1027–36. doi: 10.1086/520276

PubMed Abstract | CrossRef Full Text | Google Scholar

98. Lyons JD, Coopersmith CM. Pathophysiology of the gut and the microbiome in the host response. Pediatr Crit Care Med. (2017) 18:S46–9. doi: 10.1097/PCC.0000000000001046

PubMed Abstract | CrossRef Full Text | Google Scholar

99. Li Q, Wang C, Tang C, He Q, Zhao X, Li N, et al. Therapeutic modulation and reestablishment of the intestinal microbiota with fecal microbiota transplantation resolves sepsis and diarrhea in a patient. Am J Gastroenterol. (2014) 109:1832–4. doi: 10.1038/ajg.2014.299

PubMed Abstract | CrossRef Full Text | Google Scholar

100. Li Q, Wang C, Tang C, He Q, Zhao X, Li N, et al. Successful treatment of severe sepsis and diarrhea after vagotomy utilizing fecal microbiota transplantation: a case report. Crit Care. (2015) 19:37. doi: 10.1186/s13054-015-0738-7

PubMed Abstract | CrossRef Full Text | Google Scholar

101. Wei Y, Yang J, Wang J, Yang Y, Huang J, Gong H, et al. Successful treatment with fecal microbiota transplantation in patients with multiple organ dysfunction syndrome and diarrhea following severe sepsis. Crit Care. (2016) 20:332. doi: 10.1186/s13054-016-1491-2

PubMed Abstract | CrossRef Full Text | Google Scholar

102. Maynard CL, Elson CO, Hatton RD, Weaver CT. Reciprocal interactions of the intestinal microbiota and immune system. Nature. (2011) 489:231–41. doi: 10.1038/nature11551

PubMed Abstract | CrossRef Full Text | Google Scholar

103. Schuijt TJ, van der Poll T, de Vos WM, Wiersinga WJ. The intestinal microbiota and host immune interactions in the critically ill. Trends Microbiol. (2013) 21:221–9. doi: 10.1016/j.tim.2013.02.001

PubMed Abstract | CrossRef Full Text | Google Scholar

104. Thaiss CA, Zmora N, Levy M, Elinav E. The microbiome and innate immunity. Nature. (2016) 535:65–74. doi: 10.1038/nature18847

PubMed Abstract | CrossRef Full Text | Google Scholar

105. Levy M, Kolodziejczyk AA, Thaiss CA, Elinav E. Dysbiosis and the immune system. Nat Rev Immunol. (2017) 17:219–32. doi: 10.1038/nri.2017.7

PubMed Abstract | CrossRef Full Text | Google Scholar

106. van der Poll T, van de Veerdonk FL, Scicluna BP, Netea MG. The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol. (2017) 17:407–20. doi: 10.1038/nri.2017.36

PubMed Abstract | CrossRef Full Text | Google Scholar

107. Matthew J, Delano A, Ward P. Sepsis–induced immune dysfunction: can immune therapies reduce mortality? J Clin Invest. (2016) 126:23–31. doi: 10.1172/JCI82224

CrossRef Full Text | Google Scholar

108. Hotchkiss RS, Monneret G, Payen D. Sepsis–induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. (2013) 13:862–74. doi: 10.1038/nri3552

PubMed Abstract | CrossRef Full Text | Google Scholar

109. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. (2006) 124:783–801. doi: 10.1016/j.cell.2006.02.015

PubMed Abstract | CrossRef Full Text | Google Scholar

110. Amulic B, Cazalet C, Hayes GL, Metzler KD, Zychlinsky A. Neutrophil function: from mechanisms to disease. Annu Rev Immunol. (2012) 30:459–89. doi: 10.1146/annurev-immunol-020711-074942

PubMed Abstract | CrossRef Full Text | Google Scholar

111. McKenney PT, Pamer EG. From hype to hope: the gut microbiota in enteric infectious disease. Cell. (2015) 163:1326–32. doi: 10.1016/j.cell.2015.11.032

PubMed Abstract | CrossRef Full Text | Google Scholar

112. Jacobs MC, Haak BW, Hugenholtz F, Wiersinga WJ. Gut microbiota and host defense in critical illness. Curr Opin Crit Care. (2017) 23:257–63. doi: 10.1097/MCC.0000000000000424

PubMed Abstract | CrossRef Full Text | Google Scholar

113. Banerjee S, Sindberg G, Wang F, Meng J, Sharma U, Zhang L, et al. Opioid–induced gut microbial disruption and bile dysregulation leads to gut barrier compromise and sustained systemic inflammation. Mucosal Immunol. (2016) 9:1418–28. doi: 10.1038/mi.2016.9

PubMed Abstract | CrossRef Full Text | Google Scholar

114. Meng J, Yu H, Ma J, Wang J, Banerjee S, Charboneau R, et al. Morphine induces bacterial translocation in mice by compromising intestinal barrier function in a TLR–dependent manner. PLoS ONE. (2013) 8:e54040. doi: 10.1371/journal.pone.0054040

PubMed Abstract | CrossRef Full Text | Google Scholar

115. Meng J, Banerjee S, Li D, Sindberg GM, Wang F, Ma J, et al. Opioid exacerbation of Gram–positive sepsis, induced by gut microbial modulation, is rescued by IL−17A neutralization. Sci Rep. (2015) 5:10918. doi: 10.1038/srep10918

PubMed Abstract | CrossRef Full Text | Google Scholar

116. Ostaff MJ, Stange EF, Wehkamp J. Antimicrobial peptides and gut microbiota in homeostasis and pathology. EMBO Mol Med. (2013) 5:1465–83. doi: 10.1002/emmm.201201773

PubMed Abstract | CrossRef Full Text | Google Scholar

117. Johansson ME, Hansson GC. Immunological aspects of intestinal mucus and mucins. Nat Rev Immunol. (2016) 16:639–49. doi: 10.1038/nri.2016.88

PubMed Abstract | CrossRef Full Text | Google Scholar

118. Vaishnava S, Behrendt CL, Ismail AS, Eckmann L, Hooper LV. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host–microbial interface. Proc Natl Acad Sci USA. (2008) 105:20858–63. doi: 10.1073/pnas.0808723105

PubMed Abstract | CrossRef Full Text | Google Scholar

119. Jakobsson HE, Rodríguez-Piñeiro AM, Schütte A, Ermund A, Boysen P, Bemark M, et al. The composition of the gut microbiota shapes the colon mucus barrier. EMBO Rep. (2015) 16:164–77. doi: 10.15252/embr.201439263

PubMed Abstract | CrossRef Full Text | Google Scholar

120. Kamada N, Seo SU, Chen GY, Nunez G. Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol. (2013) 13:321–35. doi: 10.1038/nri3430

PubMed Abstract | CrossRef Full Text | Google Scholar

121. Johansson ME, Jakobsson HE, Holmén-Larsson J, Schütte A, Ermund A, Rodríguez-Piñeiro AM, et al. Normalization of host intestinal mucus layers requires long–term microbial colonization. Cell Host Microbe. (2015) 18:582–92. doi: 10.1016/j.chom.2015.10.007

PubMed Abstract | CrossRef Full Text | Google Scholar

122. McGuckin MA, Lindén SK, Sutton P, Florin TH. Mucin dynamics and enteric pathogens. Nat Rev Microbiol 2011; 9: 265–78. doi: 10.1038/nrmicro2538

PubMed Abstract | CrossRef Full Text | Google Scholar

123. Johansson ME, Sjövall H, Hansson GC. The gastrointestinal mucus system in health and disease. Nat Rev Gastroenterol Hepatol. (2013) 10:352–61. doi: 10.1038/nrgastro.2013.35

PubMed Abstract | CrossRef Full Text | Google Scholar

124. Clemente JC, Ursell LK, Parfrey LW, Knight R. The impact of the gut microbiota on human health: an integrative view. Cell. (2012) 148:1258–70. doi: 10.1016/j.cell.2012.01.035

PubMed Abstract | CrossRef Full Text | Google Scholar

125. Meade KG, O'Farrelly C. β-Defensins: farming the microbiome for homeostasis and health. Front Immunol. (2019) 9:3072. doi: 10.3389/fimmu.2018.03072

PubMed Abstract | CrossRef Full Text | Google Scholar

126. Mukherjee S, Hooper LV. Antimicrobial defense of the intestine. Immunity. (2015) 42:28–39. doi: 10.1016/j.immuni.2014.12.028

PubMed Abstract | CrossRef Full Text | Google Scholar

127. Bergstrom KS, Kissoon-Singh V, Gibson DL, Ma C, Montero M, Sham HP, et al. Muc2 protects against lethal infectious colitis by disassociating pathogenic and commensal bacteria from the colonic mucosa. PLoS Pathog. (2010) 6:e1000902. doi: 10.1371/journal.ppat.1000902

PubMed Abstract | CrossRef Full Text | Google Scholar

128. Li Q, Zhang Q, Wang C, Tang C, Li N, Li J. Influence of alemtuzumab on the intestinal Paneth cells and microflora in macaques. Clin Immunol. (2010) 136:375–86. doi: 10.1016/j.clim.2010.05.004

PubMed Abstract | CrossRef Full Text | Google Scholar

129. Teltschik Z, Wiest R, Beisner J, Nuding S, Hofmann C, Schoelmerich J, et al. Intestinal bacterial translocation in rats with cirrhosis is related to compromised Paneth cell antimicrobial host defense. Hepatology. (2012) 55:1154–63. doi: 10.1002/hep.24789

PubMed Abstract | CrossRef Full Text | Google Scholar

130. Koon HW, Shih DQ, Chen J, Bakirtzi K, Hing TC, Law I, et al. Cathelicidin signaling via the Toll–like receptor protects against colitis in mice. Gastroenterology. (2011) 141:1852–63. doi: 10.1053/j.gastro.2011.06.079

PubMed Abstract | CrossRef Full Text | Google Scholar

131. Bibbò S, Lopetuso LR, Ianiro G, Rienzo TD, Gasbarrini A, Cammarota G. Role of microbiota and innate immunity in recurrent Clostridium difficile infection. J Immunol Res. (2014) 2014:462740. doi: 10.1155/2014/462740

PubMed Abstract | CrossRef Full Text | Google Scholar

132. Khouts A, Dicksved J, Jansson JK, Sadowsky MJ. Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent Clostridium difficile-associated diarrhea. J Clin Gastroenterol. (2010) 44:354–60. doi: 10.1097/MCG.0b013e3181c87e02

CrossRef Full Text | Google Scholar

133. Manges AR, Labbe A, Loo VG, Atherton JK, Behr MA, Masson L, et al. Comparative metagenomic study of alterations to the intestinal microbiota and risk of nosocomial Clostridium difficile-associated disease. J Infect Dis. (2010) 202:1877–84. doi: 10.1086/657319

CrossRef Full Text | Google Scholar

134. Jafari NV, Kuehne SA, Bryant CE, Elawad M, Wren BW, Minton NP, et al. Clostridium difficile modulates host innate immunity via toxin-independent and dependent mechanism(s). PLoS ONE. (2013) 8:e69846. doi: 10.1371/journal.pone.0069846

PubMed Abstract | CrossRef Full Text | Google Scholar

135. Meyer GKA, Neetz A, Brandes G, Tsikas D, Butterfield JH, Just L, et al. Clostridium difficile toxins A and B directly stimulate human mast cells. Infect Immun. (2007) 75:3868–76. doi: 10.1128/IAI.00195-07

PubMed Abstract | CrossRef Full Text | Google Scholar

136. Warny M, Keates AC, Keates S, Castagliuolo I, Zacks JK, Aboudola S, et al. p38 MAP kinase activation by Clostridium difficile toxin A mediates monocyte necrosis, IL-8 production, and enteritis. J Clin Invest. (2000) 105:1147–56. doi: 10.1172/JCI7545

PubMed Abstract | CrossRef Full Text | Google Scholar

137. Hasegawa M, Yamazaki T, Kamada N, Tawaratsumida K, Kim YG, Núñez G, et al. Nucleotidebinding oligomerization domain 1 mediates recognition of Clostridium difficile and induces neutrophil recruitment and protection against the pathogen. J Immunol. (2011)186:4872–80. doi: 10.4049/jimmunol.1003761

CrossRef Full Text | Google Scholar

138. Ishida Y, Maegawa T, Kondo T, Kimura A, Iwakura Y, Nakamura S, et al. Essential involvement of IFN-γ in Clostridium difficile toxin A-induced enteritis. J Immunol. (2004) 172:3018–25. doi: 10.4049/jimmunol.172.5.3018

PubMed Abstract | CrossRef Full Text | Google Scholar

139. Honda K, Littman DR. The microbiota in adaptive immune homeostasis and disease. Nature. (2016) 535:75–84. doi: 10.1038/nature18848

PubMed Abstract | CrossRef Full Text | Google Scholar

140. Slack E, Hapfelmeier S, Stecher B, Velykoredko Y, Stoel M, Lawson MA, et al. Innate and adaptive immunity cooperate flexibly to maintain host–microbiota mutualism. Science. (2009) 325:617–20. doi: 10.1126/science.1172747

PubMed Abstract | CrossRef Full Text | Google Scholar

141. Gautreaux MD, Deitch EA, Berg RD. T lymphocytes in host defense against bacterial translocation from the gastrointestinal tract. Infect Immun. (1994) 62:2874–84.

PubMed Abstract | Google Scholar

142. Owens WE, Berg RD. Bacterial translocation from the gastrointestinal tract of athymic (nu/nu) mice. Infect Immun. (1980) 27:461–7.

PubMed Abstract | Google Scholar

143. Choudhry MA, Fazal N, Goto M, Gamelli RL, Sayeed MM. Gut-associated lymphoid T cell suppression enhances bacterial translocation in alcohol and burn injury. Am J Physiol Gastrointest Liver Physiol. (2002) 282:G937–47. doi: 10.1152/ajpgi.00235.2001

PubMed Abstract | CrossRef Full Text | Google Scholar

144. Fukatsu K, Sakamoto S, Hara E, Ueno C, Maeshima Y, Matsumoto I, et al. Gut ischemia-reperfusion affects gut mucosal immunity: a possible mechanism for infectious complications after severe surgical insults. Crit Care Med. (2006) 34:182–7. doi: 10.1097/01.CCM.0000196207.86570.16

PubMed Abstract | CrossRef Full Text | Google Scholar

145. Cerqueira NF, Hussni CA, Yoshida WB. Pathophysiology of mesenteric ischemia/reperfusion: a review. Acta Cir Bras. (2005) 20:336–43. doi: 10.1590/S0102-86502005000400013

PubMed Abstract | CrossRef Full Text | Google Scholar

146. Li Q, Wang C, Tang C, He Q, Li N, Li J. Reciprocal interaction between intestinal microbiota and mucosal lymphocyte in cynomolgus monkeys after alemtuzumab treatment. Am J Transplant. (2013) 13:899–910. doi: 10.1111/ajt.12148

PubMed Abstract | CrossRef Full Text | Google Scholar

147. Li Q, Wang C, Tang C, He Q, Li J. Lymphocyte depletion following alemtuzumab induction disrupts intestinal fungal microbiota in cynomolgus monkeys. Transplantation. (2014) 98:951–9. doi: 10.1097/TP.0000000000000373

CrossRef Full Text | Google Scholar

148. Qu LL, Lyu YQ, Jiang HT, Shan T, Zhang JB, Li QR, et al. Effect of alemtuzumab on intestinal intraepithelial lymphocytes and intestinal barrier function in cynomolgus model. Chin Med J. (2015) 128:680–6. doi: 10.4103/0366-6999.151675

PubMed Abstract | CrossRef Full Text | Google Scholar

149. Li Q, Zhang Q, Wang C, Tang C, Li N, Li J. The response of intestinal stem cell and epithelium after alemtuzumab administration. Cell Mol Immunol. (2011) 8:325–32. doi: 10.1038/cmi.2011.10

CrossRef Full Text | Google Scholar

150. Li Q, Zhang Q, Wang C, Li Y, Li T, Li N, et al. Alteration of tight junctions in intestinal transplantation induced by Campath-1H. Clin Immunol. (2009) 132:141–3. doi: 10.1016/j.clim.2009.03.511

PubMed Abstract | CrossRef Full Text | Google Scholar

151. Li Q, Wang C, Zhang Q, Tang C, Li N, Ruan B, et al. Use of 18S ribosomal DNA polymerase chain reaction–denaturing gradient gel electrophoresis to study composition of fungal community in 2 patients with intestinal transplants. Hum Pathol. (2012) 43:1273–81. doi: 10.1016/j.humpath.2011.09.017

PubMed Abstract | CrossRef Full Text | Google Scholar

152. Hotchkiss RS, Coopersmith CM, Karl IE. Prevention of lymphocyte apoptosis–a potential treatment of sepsis? Clin Infect Dis. (2005) 41:S465–9. doi: 10.1086/431998

PubMed Abstract | CrossRef Full Text | Google Scholar

153. Lang JD, Matute-Bello G. Lymphocytes, apoptosis and sepsis: making the jump from mice to humans. Crit Care. (2009) 13:109. doi: 10.1186/cc7144

PubMed Abstract | CrossRef Full Text | Google Scholar

154. Hotchkiss RS, Swanson PE, Cobb JP, Jacobson A, Buchman TG, Karl IE. Apoptosis in lymphoid and parenchymal cells during sepsis: findings in normal and T- and B-cell-deficient mice. Crit Care Med. (1997) 25:1298–307. doi: 10.1097/00003246-199708000-00015

PubMed Abstract | CrossRef Full Text | Google Scholar

155. Hotchkiss RS, Osmon SB, Chang KC, Wagner TH, Coopersmith CM, Karl IE. Accelerated lymphocyte death in sepsis occurs by both the death receptor and mitochondrial pathways. J Immunol. (2005) 174:5110–8. doi: 10.4049/jimmunol.174.8.5110

PubMed Abstract | CrossRef Full Text | Google Scholar

156. Delano MJ, Ward PA. The immune system's role in sepsis progression, resolution, and long-term outcome. Immunol Rev. (2016) 274:330–53. doi: 10.1111/imr.12499

PubMed Abstract | CrossRef Full Text | Google Scholar

157. Ismail AS, Severson KM, Vaishnava S, Behrendt CL, Yu X, Benjamin JL, et al. Gammadelta intraepithelial lymphocytes are essential mediators of host–microbial homeostasis at the intestinal mucosal surface. Proc Natl Acad Sci USA. (2011) 108:8743–8. doi: 10.1073/pnas.1019574108

PubMed Abstract | CrossRef Full Text | Google Scholar

158. Holtmeier W, Kabelitz D. Gammadelta T cells link innate and adaptive immune responses. Chem Immunol Allergy. (2005) 86:151–83. doi: 10.1159/000086659

PubMed Abstract | CrossRef Full Text | Google Scholar

159. Tomasello E, Bedoui S. Intestinal innate immune cells in gut homeostasis and immunosurveillance. Immunol Cell Biol. (2013) 91:201–3. doi: 10.1038/icb.2012.85

PubMed Abstract | CrossRef Full Text | Google Scholar

160. Grimaldi D, Le Bourhis L, Sauneuf B, Dechartres A, Rousseau C, Ouaaz F, et al. Specific MAIT cell behaviour among innate-like T lymphocytes in critically ill patients with severe infections. Intensive Care Med. (2014) 40:192–201. doi: 10.1007/s00134-013-3163-x

PubMed Abstract | CrossRef Full Text | Google Scholar

161. Andreu-Ballester JC, Tormo-Calandín C, Garcia-Ballesteros C, Pérez-Griera J, Amigó V, Almela-Quilis A, et al. Association of γδ T cells with disease severity and mortality in septic patients. Clin Vaccine Immunol. (2013) 20:738–46. doi: 10.1128/CVI.00752-12

PubMed Abstract | CrossRef Full Text | Google Scholar

162. Bandeira A, Mota-Santos T, Itohara S, Degermann S, Heusser C, Tonegawa S, Coutinho A. Localization of gamma/delta T cells to the intestinal epithelium is independent of normal microbial colonization. J Exp Med. (1990) 172:239–44. doi: 10.1084/jem.172.1.239

PubMed Abstract | CrossRef Full Text | Google Scholar

163. Suzuki H, Jeong KI, Itoh K, Doi K. Regional variations in the distributions of small intestinal intraepithelial lymphocytes in germ-free and specific pathogen-free mice. Exp Mol Pathol. (2002) 72:230–5. doi: 10.1006/exmp.2002.2433

PubMed Abstract | CrossRef Full Text | Google Scholar

164. Kawaguchi M, Nanno M, Umesaki Y, Matsumoto S, Okada Y, Cai Z, et al. Cytolytic activity of intestinal intraepithelial lymphocytes in germ-free mice is strain dependent and determined by T cells expressing gamma delta T-cell antigen receptors. Proc Natl Acad Sci USA. (1993) 90:8591–4. doi: 10.1073/pnas.90.18.8591

PubMed Abstract | CrossRef Full Text | Google Scholar

165. Macpherson AJ, Slack E, Geuking MB, McCoy KD. The mucosal firewalls against commensal intestinal microbes. Semin Immunopathol. (2009) 31:145–9. doi: 10.1007/s00281-009-0174-3

PubMed Abstract | CrossRef Full Text | Google Scholar

166. Pabst O. New concepts in the generation and functions of IgA. Nat Rev Immunol. (2012) 12:821–32. doi: 10.1038/nri3322

PubMed Abstract | CrossRef Full Text | Google Scholar

167. Pabst O, Cerovic V, Hornef M. Secretory IgA in the coordination of establishment and maintenance of the microbiota. Trends Immunol. (2016) 37:287–96. doi: 10.1016/j.it.2016.03.002

PubMed Abstract | CrossRef Full Text | Google Scholar

168. Johansen FE, Pekna M, Norderhaug IN, Haneberg B, Hietala MA, Krajci P, et al. Absence of epithelial immunoglobulin A transport, with increased mucosal leakiness, in polymeric immunoglobulin receptor/secretory component-deficient mice. J Exp Med. (1999) 190:915–22. doi: 10.1084/jem.190.7.915

PubMed Abstract | CrossRef Full Text | Google Scholar

169. Mantis NJ, Rol N, Corthésy B. Secretory IgA's complex roles in immunity and mucosal homeostasis in the gut. Mucosal Immunol. (2011) 4:603–611. doi: 10.1038/mi.2011.41

PubMed Abstract | CrossRef Full Text | Google Scholar

170. Wei M, Shinkura R, Doi Y, Maruya M, Fagarasan S, Honjo T. Mice carrying a knock-in mutation of Aicda resulting in a defect in somatic hypermutation have impaired gut homeostasis and compromised mucosal defense. Nat Immunol. (2011) 12:264–70. doi: 10.1038/ni.1991

PubMed Abstract | CrossRef Full Text | Google Scholar

171. Quan CP, Berneman A, Pires R, Avrameas S, Bouvet JP. Natural polyreactive secretory immunoglobulin A autoantibodies as a possible barrier to infection in humans. Infect Immun. (1997) 65:3997–4004.

PubMed Abstract | Google Scholar

172. Spencer J, Klavinskis LS, Fraser LD. The human intestinal IgA response; burning questions. Front Immunol. (2012) 3:108. doi: 10.3389/fimmu.2012.00108

PubMed Abstract | CrossRef Full Text | Google Scholar

173. Ianiro G, Bruno G, Lopetuso L, Beghella FB, Laterza L, D'Aversa F, et al. Role of yeasts in healthy and impaired gut microbiota: the gut mycome. Curr Pharm Des. (2014) 20:4565–9. doi: 10.2174/13816128113196660723

PubMed Abstract | CrossRef Full Text | Google Scholar

174. Santamaría R, Rizzetto L, Bromley M, Zelante T, Lee W, Cavalieri D, et al. Systems biology of infectious diseases: a focus on fungal infections. Immunobiology. (2011) 216:1212–27. doi: 10.1016/j.imbio.2011.08.004

PubMed Abstract | CrossRef Full Text | Google Scholar

175. Mason KL, Erb Downward JR, Mason KD, Falkowski NR, Eaton KA, Kao JY, et al. Candida albicans and bacterial microbiota interactions in the cecum during recolonization following broad-spectrum antibiotic therapy. Infect Immun. (2012) 80:3371–80. doi: 10.1128/IAI.00449-12

PubMed Abstract | CrossRef Full Text | Google Scholar

176. Cheng SC, van de Veerdonk FL, Lenardon M, Stoffels M, Plantinga T, Smeekens S, et al. The dectin-1/inflammasome pathway is responsible for the induction of protective T-helper 17 responses that discriminate between yeasts and hyphae of Candida albicans. J Leukoc Biol. (2011) 90:357–66. doi: 10.1189/jlb.1210702

PubMed Abstract | CrossRef Full Text | Google Scholar

177. Taylor PR, Tsoni SV, Willment JA, Dennehy KM, Rosas M, Findon H, et al. Dectin-1 is required for beta-glucan recognition and control of fungal infection. Nat Immunol. (2007) 8:31–8. doi: 10.1038/ni1408

PubMed Abstract | CrossRef Full Text | Google Scholar

178. Ferwerda B, Ferwerda G, Plantinga TS, Willment JA, van Spriel AB, Venselaar H, et al. Human dectin-1 deficiency and mucocutaneous fungal infections. N Engl J Med. (2009) 361:1760–7. doi: 10.1056/NEJMoa0901053

PubMed Abstract | CrossRef Full Text | Google Scholar

179. Glocker EO, Hennigs A, Nabavi M, Schäffer AA, Woellner C, Salzer U, et al. A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N Engl J Med. (2009) 361:1727–35. doi: 10.1056/NEJMoa0810719

PubMed Abstract | CrossRef Full Text | Google Scholar

180. Franke A, Balschun T, Sina C, Ellinghaus D, Häsler R, Mayr G, et al. Genome-wide association study for ulcerative colitis identifies risk loci at 7q22 and 22q13 (IL17REL). Nat Genet. (2010) 42:292–4. doi: 10.1038/ng.553

PubMed Abstract | CrossRef Full Text | Google Scholar

181. McGovern DP, Gardet A, Törkvist L, Goyette P, Essers J, Taylor KD, et al. Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat Genet. (2010) 42:332–7. doi: 10.1038/ng.549

PubMed Abstract | CrossRef Full Text | Google Scholar

182. Zocco MA, Garcovich M, Gasbarrini A. Saccharomyces boulardii and antibiotic-associated diarrhea: effectiveness of prophylactic use. Am J Gastroenterol. (2012) 107:1441. doi: 10.1038/ajg.2012.222

PubMed Abstract | CrossRef Full Text | Google Scholar

183. McFarland LV. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol. (2006) 101:812–22. doi: 10.1111/j.1572-0241.2006.00465.x

PubMed Abstract | CrossRef Full Text | Google Scholar

184. Stensvold CR, van der Giezen M. Associations between gut microbiota and common luminal intestinal parasites. Trends Parasitol. (2018) 34:369–77. doi: 10.1016/j.pt.2018.02.004

PubMed Abstract | CrossRef Full Text | Google Scholar

185. Scanlan PD, Stensvold CR, Cotter PD. Development and application of a Blastocystis subtype-specific PCR assay reveals that mixed-subtype infections are common in a healthy human population. Appl Environ Microbiol. (2015) 81:4071–6. doi: 10.1128/AEM.00520-15

PubMed Abstract | CrossRef Full Text | Google Scholar

186. Raser D, Simonsen J, Nielsen HV, Stensvold CR, Mølbak K. Dientamoeba fragilis in Denmark: epidemiological experience derived from four years of routine real-time PCR. Eur J Clin Microbiol Infect Dis. (2013) 32:1303–10. doi: 10.1007/s10096-013-1880-2

CrossRef Full Text | Google Scholar

187. Krogsgaard LR, Engsbro AL, Stensvold CR, Nielsen HV, Bytzer P. The prevalence of intestinal parasites is not greater among individuals with irritable bowel syndrome: a population-based case-control study. Clin Gastroenterol Hepatol. (2015) 13:507–13. doi: 10.1016/j.cgh.2014.07.065

CrossRef Full Text | Google Scholar

188. Petersen AM, Stensvold CR, Mirsepasi H, Engberg J, Friis-Møller A, Porsbo LJ, et al. Active ulcerative colitis associated with low prevalence of Blastocystis and Dientamoeba fragilis infection. Scand J Gastroenterol. (2013) 48:638–9. doi: 10.3109/00365521.2013.780094

PubMed Abstract | CrossRef Full Text | Google Scholar

189. Luke J, Stensvold CR, Jirku-Pomajbíková K, Parfrey LW. Are human intestinal eukaryotes beneficial or commensals? PLoS Pathog. (2015) 11:e1005039. doi: 10.1371/journal.ppat.1005039

CrossRef Full Text | Google Scholar

190. Gilchrist CA, Petri SE, Schneider BN, Reichman DJ, Jiang N, Begum S, et al. Role of the gut microbiota of children in diarrhea due to the protozoan parasite Entamoeba histolytica. J Infect Dis. (2016) 213:1579–85. doi: 10.1093/infdis/jiv772

PubMed Abstract | CrossRef Full Text | Google Scholar

191. Watanabe K, Gilchrist CA, Uddin MJ, Burgess SL, Abhyankar MM, Moonah SN, et al. Microbiome-mediated neutrophil recruitment via CXCR2 and protection from amebic colitis. PLoS Pathog. (2017) 13:e1006513. doi: 10.1371/journal.ppat.1006513

PubMed Abstract | CrossRef Full Text | Google Scholar

192. Barash NR, Maloney JG, Singer SM, Dawson SC. Giardia alters commensal microbial diversity throughout the murine gut. Infect Immun. (2017) 85:e00948–16. doi: 10.1128/IAI.00948-16

PubMed Abstract | CrossRef Full Text | Google Scholar

193. Vitetta L, Saltzman ET, Nikov T, Ibrahim I, Hall S. Modulating the gut micro-environment in the treatment of intestinal parasites. J Clin Med. (2016) 5:E102. doi: 10.3390/jcm5110102

PubMed Abstract | CrossRef Full Text | Google Scholar

194. Berrilli F, Di Cave D, Cavallero S, D'Amelio S, Interactions between parasites and microbial communities in the human gut. Front Cell Infect Microbiol. (2012) 2:141. doi: 10.3389/fcimb.2012.00141

CrossRef Full Text | Google Scholar

195. Virgin HW. The virome in mammalian physiology and disease. Cell. (2014) 157:142–50. doi: 10.1016/j.cell.2014.02.032

PubMed Abstract | CrossRef Full Text | Google Scholar

196. Dalmasso M, Hill C, Ross RP. Exploiting gut bacteriophages for human health. Trends Microbiol. (2014) 22:399–405. doi: 10.1016/j.tim.2014.02.010

PubMed Abstract | CrossRef Full Text | Google Scholar

197. Guerin E, Shkoporov A, Stockdale SR, Clooney AG, Ryan FJ, Sutton TDS, et al. Biology and taxonomy of crAss-like bacteriophages, the most abundant virus in the human gut. Cell Host Microbe. (2018) 24: 653–64. doi: 10.1016/j.chom.2018.10.002

PubMed Abstract | CrossRef Full Text | Google Scholar

198. Lim ES, Zhou Y, Zhao G, Bauer IK, Droit L, Ndao IM, et al. Early life dynamics of the human gut virome and bacterial microbiome in infants. Nat Med. (2015) 21:1228–34. doi: 10.1038/nm.3950

PubMed Abstract | CrossRef Full Text | Google Scholar

199. Lim ES, Wang D, Holtz LR. The bacterial microbiome and virome milestones of infant development. Trends Microbiol. (2016) 24:801–10. doi: 10.1016/j.tim.2016.06.001

PubMed Abstract | CrossRef Full Text | Google Scholar

200. Reyes A, Blanton LV, Cao S, Zhao G, Manary M, Trehan I, et al. Gut DNA viromes of Malawian twins discordant for severe acute malnutrition. Proc Natl Acad Sci USA. (2015) 112:11941–6. doi: 10.1073/pnas.1514285112

PubMed Abstract | CrossRef Full Text | Google Scholar

201. Reyes A, Haynes M, Hanson N, Angly FE, Heath AC, Rohwer F, et al. Viruses in the faecal microbiota of monozygotic twins and their mothers. Nature. (2010) 466:334–8. doi: 10.1038/nature09199

PubMed Abstract | CrossRef Full Text | Google Scholar

202. Holtz LR, Cao S, Zhao G, Bauer IK, Denno DM, Klein EJ, et al. Geographic variation in the eukaryotic virome of human diarrhea. Virology. (2014) 468–70:556–64. doi: 10.1016/j.virol.2014.09.012

CrossRef Full Text | Google Scholar

203. Hunter P. The secret garden's gardeners: research increasingly appreciates the crucial role of gut viruses for human health and disease. EMBO Rep. (2013) 14: 683–5. doi: 10.1038/embor.2013.104

PubMed Abstract | CrossRef Full Text | Google Scholar

204. Brussow H, Canchaya C, Hardt WD. Phages and the evolution of bacterial pathogens: from genomic rearrangements to lysogenic conversion. Microbiol Mol Biol Rev. (2004) 68:560–602. doi: 10.1128/MMBR.68.3.560-602.2004

PubMed Abstract | CrossRef Full Text | Google Scholar

205. Norman JM, Handley SA, Baldridge MT, Droit L, Liu CY, Keller BC, et al. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell. (2015) 160:447–60. doi: 10.1016/j.cell.2015.01.002

PubMed Abstract | CrossRef Full Text | Google Scholar

206. De Paepe M, Leclerc M, Tinsley CR, Petit M-A. Bacteriophages: an underestimated role in human and animal health? Front Cell Infect Microbiol. (2014) 4:39. doi: 10.3389/fcimb.2014.00039

PubMed Abstract | CrossRef Full Text | Google Scholar

207. Bickle TA, Krüger D. Biology of DNA restriction. Microbiol Rev. (1993) 57:434–50.

PubMed Abstract | Google Scholar

208. Nordström K, Forsgren A. Effect of protein A on adsorption of bacteriophages to Staphylococcus aureus. J Virol. (1974) 14:198–202.

PubMed Abstract | Google Scholar

209. Destoumieux-Garzón D, Duquesne S, Peduzzi J, Goulard C, Desmadril M, Letellier L, et al. The iron–siderophore transporter FhuA is the receptor for the antimicrobial peptide microcin J25: role of the microcin Val11–Pro16 β-hairpin region in the recognition mechanism. Biochem J. (2005) 389:869–76. doi: 10.1042/BJ20042107

PubMed Abstract | CrossRef Full Text | Google Scholar

210. Labrie SJ, Samson JE, Moineau S. Bacteriophage resistance mechanisms. Nat Rev Microbiol. (2010) 8:317–27. doi: 10.1038/nrmicro2315

PubMed Abstract | CrossRef Full Text | Google Scholar

211. Stern A, Mick E, Tirosh I, Sagy O, Sorek R. CRISPR targeting reveals a reservoir of common phages associated with the human gut microbiome. Genome Res. (2012) 22:1985–94. doi: 10.1101/gr.138297.112

PubMed Abstract | CrossRef Full Text | Google Scholar

212. Mukhopadhya I, Segal JP, Carding SR, Hart AL, Hold GL. The gut virome: the ‘missing link' between gut bacteria and host immunity? Ther Adv Gastroenterol. (2019) 12:1–17. doi: 10.1177/1756284819836620

PubMed Abstract | CrossRef Full Text | Google Scholar

213. McClave SA, Patel J, Bhutiani N. Should fecal microbial transplantation be used in the ICU? Curr Opin Crit Care. (2018) 24:105–11. doi: 10.1097/MCC.0000000000000489

PubMed Abstract | CrossRef Full Text | Google Scholar

214. Kelly CR, Kahn S, Kashyap P, Laine L, Rubin D, Atreja A, et al. Update on fecal microbiota transplantation 2015: indications, methodologies, mechanisms, and outlook. Gastroenterology. (2015) 149:223–37. doi: 10.1053/j.gastro.2015.05.008

PubMed Abstract | CrossRef Full Text | Google Scholar

215. Ianiro G, Maida M, Burisch J, Simonelli C, Hold G, Ventimiglia M. Efficacy of different faecal microbiota transplantation protocols for Clostridium difficile infection: a systematic review and meta-analysis. United Eur Gastroenterol J. (2018) 6:1232–44. doi: 10.1177/2050640618780762

PubMed Abstract | CrossRef Full Text | Google Scholar

216. Quraishi MN, Widlak M, Bhala N, Moore D, Price M, Sharma N, et al. Systematic review with meta-analysis: the efficacy of faecal microbiota transplantation for the treatment of recurrent and refractory Clostridium difficile infection. Aliment Pharmacol Ther. (2017) 46:479–93. doi: 10.1111/apt.14201

PubMed Abstract | CrossRef Full Text | Google Scholar

217. Haak BW, Levi M, Wiersinga WJ. Microbiota–targeted therapies on the intensive care unit. Curr Opin Crit Care. (2017) 23:167–74. doi: 10.1097/MCC.0000000000000389

PubMed Abstract | CrossRef Full Text | Google Scholar

218. Klingensmith NJ, Coopersmith CM. Fecal microbiota transplantation for multiple organ dysfunction syndrome. Crit Care. (2016) 20:398. doi: 10.1186/s13054-016-1567-z

PubMed Abstract | CrossRef Full Text | Google Scholar

219. Haak BW, Prescott HC, Wiersinga WJ. Therapeutic potential of the gut microbiota in the prevention and treatment of sepsis. Front Immunol. (2018) 9:2042. doi: 10.3389/fimmu.2018.02042

PubMed Abstract | CrossRef Full Text | Google Scholar

220. Levy M, Thaiss CA, Elinav E. Metagenomic cross-talk: the regulatory interplay between immunogenomics and the microbiome. Genome Med. (2015) 7:120. doi: 10.1186/s13073-015-0249-9

PubMed Abstract | CrossRef Full Text | Google Scholar

221. Schmidt TSB, Raes J, Bork P. The human gut microbiome: from association to modulation. Cell. (2018) 172:1198–215. doi: 10.1016/j.cell.2018.02.044

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: gut-derived infection, gut microbiota, mucosal immunity, intestinal epithelium, bacterial translocation, intestinal barrier

Citation: Wang C, Li Q and Ren J (2019) Microbiota-Immune Interaction in the Pathogenesis of Gut-Derived Infection. Front. Immunol. 10:1873. doi: 10.3389/fimmu.2019.01873

Received: 02 February 2019; Accepted: 24 July 2019;
Published: 07 August 2019.

Edited by:

Julien Diana, Institut National de la Santé et de la Recherche Médicale (INSERM), France

Reviewed by:

Rita Carsetti, Bambino Gesù Children Hospital (IRCCS), Italy
Gianluca Ianiro, Università Cattolica del Sacro Cuore, Italy

Copyright © 2019 Wang, Li and Ren. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Qiurong Li, liqiurongjue@126.com; Jianan Ren, Jiananr@gmail.com