Edited by: Martin G. Klotz, Washington State University Tri-Cities, United States
Reviewed by: Jeffrey David Galley, Baylor College of Medicine, United States; Christopher A. Lowry, University of Colorado Boulder, United States; Glenn J. Treisman, Johns Hopkins University, United States
This article was submitted to Microbial Physiology and Metabolism, a section of the journal Frontiers in Microbiology
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Stress, a ubiquitous part of daily human life, has varied biological effects which are increasingly recognized as including modulation of commensal microorganisms residing in the gastrointestinal tract, the gut microbiota. In turn, the gut microbiota influences the host stress response and associated sequelae, thereby implicating the gut microbiota as an important mediator of host health. This narrative review aims to summarize evidence concerning the impact of psychological, environmental, and physical stressors on gut microbiota composition and function. The stressors reviewed include psychological stress, circadian disruption, sleep deprivation, environmental extremes (high altitude, heat, and cold), environmental pathogens, toxicants, pollutants, and noise, physical activity, and diet (nutrient composition and food restriction). Stressors were selected for their direct relevance to military personnel, a population that is commonly exposed to these stressors, often at extremes, and in combination. However, the selected stressors are also common, alone or in combination, in some civilian populations. Evidence from preclinical studies collectively indicates that the reviewed stressors alter the composition, function and metabolic activity of the gut microbiota, but that effects vary across stressors, and can include effects that may be beneficial or detrimental to host health. Translation of these findings to humans is largely lacking at present. This gap precludes concluding with certainty that transient or cumulative exposures to psychological, environmental, and physical stressors have any consistent, meaningful impact on the human gut microbiota. However, provocative preclinical evidence highlights a need for translational research aiming to elucidate the impact of stressors on the human gut microbiota, and how the gut microbiota can be manipulated, for example by using nutrition, to mitigate adverse stress responses.
The human body is host to trillions of microorganisms collectively known as the human microbiota (
Co-evolution with this non-human genome has resulted in a largely mutualistic bi-directional relationship between host and gut microbiota. The host provides a hospitable environment and nutrients, and, in turn, the gut microbiota shapes immune system development and function (
It is increasingly recognized that stress modulates gut microbiota community structure and activity, and may be one causal factor in dysbiosis (
Growing evidence linking stress to dysbiosis and health decrements suggests that the gut microbiota could be an underappreciated mediator of stress responses and associated sequelae in military personnel. In support, recent studies have begun to link gut microbes and their metabolites with GI permeability, inflammation, GI symptomology, and psychological metrics in military personnel engaged in multiple-stressor training events (
There is growing recognition that supporting a healthy and resilient gut microbiota may contribute to health and performance optimization in military personnel (
Resident gut microbes include bacteria, archaea, viruses, and yeast and other fungi whose population densities progressively increase from 103 to 104 cells/mL content in the acidic environment of the stomach to ∼1011 cells/mL content in the colon (
Although there is no consensus on what constitutes a healthy or dysbiotic gut microbiota (
Putative health-promoting and health-compromising characteristics and functions of the human gut microbiota.
Characteristic | Effect |
---|---|
High species/genetic diversity | Associated with better health and resilience to perturbation |
Genera commonly used in probiotics; linked to multiple favorable health effects including increased resistance to infection and diarrheal disease, immune-enhancement, anti-carcinogenic, vitamin production, and secretion of anti-microbial compounds | |
Butyrate producers | |
Anti-inflammatory, butyrate producer | |
Increased butyrate production | Major energy source of colonocytes, anti-inflammatory, regulates cell growth and differentiation, anti-carcinogenic, improved gut barrier function, reduced colonic pH |
Carbohydrate fermentation/increased short-chain fatty acid (butyrate, acetate, propionate) production | Reduced colonic pH, pathogen inhibition, anti-inflammatory, anti-carcinogenic, energy source for peripheral tissues, enhanced mineral absorption |
Low diversity/high pathogen load | Compromised gut barrier integrity, local and systemic inflammation |
Proteobacteria (includes family |
Phyla which produces pro-inflammatory lipopolysaccharide |
Protein fermentation | Production of potentially carcinogenic/toxic compounds ( |
Sulfate/sulfite-reducing bacteria e.g., |
Production of toxic H2S |
Mucin degradation > synthesis | Compromises gut barrier integrity, facilitates bacterial translocation to epithelium, provides sulfates for H2S |
A healthy gut microbiota might also be considered a community in which beneficial microbes predominate, while dysbiosis may be characterized by a dominance of one or a few harmful microbes (
The classic examples of beneficial microbes are the genera,
At the other end of the spectrum are harmful microbes. Although many commensals would be harmful if they were to enter systemic circulation, and a dominance of any one taxa may be undesirable, Enterobacteriaceae, a family including the gut commensals
To what extent other taxa are generally beneficial or harmful is less clear. In one comprehensive expert review (
Ultimately, the identification of individual taxa as potentially beneficial or harmful is also based on a microbe’s metabolic activity. As such, a healthy gut microbiota might be considered one in which the synthesis of potentially beneficial compounds exceeds that of potentially harmful compounds. Although gut microbes metabolize host-derived compounds (e.g., mucins, sloughed cells), the primary sources of metabolic substrates for the gut microbiota are undigested nutrients from the diet. The metabolites produced by gut microbiota metabolism of these nutrients and their potential health effects have been extensively reviewed (
Undigested carbohydrates are the preferred substrate of many gut microbes, and are fermented by cross-feeding consortia into the SCFA acetate, propionate, and butyrate (
Proteins and amino acids are catabolized by gut microbes into a variety of products including SCFA, BCFA,
Polyphenols are ubiquitous compounds found in plant foods which have poor bioavailability in the small intestine (
Lastly, although not a dietary nutrient, bile acids are secreted in response to ingestion of fat. Gut microbes modify bile acids, forming secondary bile acids that act as signaling molecules in multiple metabolic pathways, and which may be health-promoting or health-degrading (
Taken together, a greater proportion of carbohydrate and plant polyphenol metabolites and some secondary bile acids relative to metabolites of protein fermentation and other secondary or un-modified bile acids may be health-promoting. However, the inability to directly measure production of these compounds in the colon has precluded definitive conclusions regarding health effects, and current consensus is that there is insufficient evidence to consider these compounds either individually or in combination as biomarkers of a healthy or dysbiotic microbiota (
Related to, but separate, from distinguishing healthy and dysbiotic microbiomes is the search for biomarkers within the gut microbiota that may predict response to an intervention, or disease risk. For example,
Although stressors can be varied in nature, the biological stress response is coordinated primarily by the HPA axis and SNS. Stressor-induced activation of the HPA axis and SNS stimulates the release of glucocorticoids, catecholamines, and other hormones (
Several pathways by which stress mediates gut microbiota community structure and activity have been elucidated (
The effects of individual military-relevant psychological, environmental, and physical stressors on the gut microbiota are reviewed below. For each stressor we briefly describe underpinning mechanisms, and then focus on evidence regarding stressor-induced changes in gut microbiota composition, function and metabolic activity. Because of a relative lack of relevant human studies, evidence from both animal models and experimental human studies is discussed.
Psychological stress has now been associated with multiple GI disorders (
In support, a growing evidence base links psychological stressors to changes in the murine gut microbiota. Commonly used methods of inducing psychological stress in adult rodents include social defeat/disruption, restraint, and water-avoidance. These models generally induce anxiety-like behaviors, activate the HPA-axis and SNS, induce inflammation, alter GI function and permeability, and modulate immune activity (
An additional military-relevant rodent stress model is that of chronic unpredictable mild stress. This model involves subjecting rodents to multiple psychological, environmental, and physical stressors over several weeks, and has been shown to induce depressive-, anxiety- and despair-like behaviors (
Additional preclinical studies have likewise begun to link psychological stress-induced changes in the gut microbiota to functional consequences in the host. Using an
The effects of psychological stress on the human gut microbiota are largely unexplored (
Longitudinal studies examining effects of military-relevant stressors on human gut microbiota composition and metabolites.
Reference | Design | Microbiota method | Results- Microbiota | Results- Microbiota metabolites |
---|---|---|---|---|
16S rRNA gene sequencing | Changes in relative abundance of 58% of genera (e.g., ↑ |
Fecal metabolome: Changes in microbiota linked to changes in 69 metabolites affected by training; e.g., ↓secondary bile acids, amino acid fermentation metabolites; ↑ |
||
Plasma metabolome:Changes in microbiota linked to changes in 30 metabolites affected by training; e.g., ↑amino acid fermentation metabolites; ↓benzoate metabolites; ↑↓secondary bile acids | ||||
Targeted; culture | ↓Lactic acid bacteria post-exam | NA | ||
16S rRNA gene sequencing | No reported effects of stress | NA | ||
16S rRNA gene sequencing | ↓Tenericutes | |||
↑Firmicutes:Bacteroidetes ratio, Coriobacteriaceae, Erysipelotrichaceae | ||||
16S rRNA gene sequencing | No effects | NA | ||
Targeted; FISH | ↑Gammaproteobacteria, Enterobacteriaceae ↓ |
NA | ||
Targeted; culture | ↑Total anaerobes, |
↓Fecal α-amylase activity↑Fecal proteinase, β-gluronidase, alakaline phosphatase activity | ||
↓Total aerobes, phosphatase producers | ||||
Targeted; qPCR 16S rRNA gene sequencing; SM | ↑ |
|||
16S rRNA gene sequencing | No changes in relative abundance of any taxa over time | NA | ||
16S rRNA gene sequencing | Diarrhea vs. no-diarrhea post infection: Transient ↓diversity; ↑ |
NA | ||
16S rRNA gene sequencing | Lean-exercise: ↓ |
Lean-exercise: ↑Fecal acetate, propionate, butyrate | ||
Lean-washout: ↑ |
Lean-washout: ↓Fecal propionate, butyrate | |||
Obese-exercise: ↑ |
Obese-exercise: ↔Fecal acetate, butyrate, propionate | |||
Obese-washout: ↓ |
Obese-washout: ↔Fecal acetate, butyrate, propionate | |||
In summary, current evidence indicates that psychological stress induces myriad physiologic effects that could influence the gut microbiota. Animal studies report stress-induced changes in gut microbiota composition that while varied, have frequently included reduced
Circadian rhythms are the endogenous ∼24 h rhythmic patterns displayed by most organisms, and are central mediators of physiology and behavior (
The murine gut microbiota, its genome, and its biogeography show diurnal rhythmicity that appears to be driven largely, but not completely (
Disrupting host circadian rhythms mostly abolishes rhythmicity in the gut microbiota and its genome, and alters gut microbiota composition and metabolic activity with potentially deleterious health effects (
To what extent circadian disruption impacts the human gut microbiota is largely unexplored. Variations in human gut microbiota composition and related metabolites (butyrate and propionate) were recently associated with time of day (
In summary, the murine gut microbiota, and possibly the human gut microbiota, exhibit diurnal oscillations that appear to be largely associated with feeding and fasting cycles, and, possibly, diet composition. Disruption of this rhythmicity may have deleterious effects on the gut microbiota resulting in alterations in host–microbe crosstalk that impact host gene expression, and physiology. However, the evidence base is limited to animal models and translation to humans is needed.
Sleep restriction has been associated with several physiologic effects that could alter the GI environment and hence impact the gut microbiota. First, inadequate sleep (<7 h/night) is thought to activate a classical stress response as evidenced by increased HPA-axis activity and cortisol release, although this response has not been observed in all studies (reviewed in
Few studies have examined the effects of sleep restriction on the gut microbiota, and results of those that have are inconsistent. In rats, intestinal overgrowth of total aerobes, and total facultative anaerobes, including several pro-inflammatory and pathogenic species, was documented following 10 days of near total sleep deprivation (
Results from human studies are scarce and similarly inconsistent (
Common sequelae of high altitude (≥2500 m) exposure include GI symptoms such as appetite loss, indigestion, nausea, vomiting, gas, and abdominal pain which are attributable in part to the hypobaric hypoxia of high altitude (
Few studies have examined the effects of hypobaric hypoxia on gut microbiota composition. In rats, exposure to hypobaric hypoxia has been associated with physical decrements in intestinal morphology (
Human studies conducted in high altitude environments have been observational and likewise unable to separate effects of hypobaric hypoxia from potentially confounding factors such as dehydration, foodborne pathogens, undernutrition, and increased physical activity (
Collectively, these studies suggest that high altitude expeditions are associated with increases in abundance of pro-inflammatory taxa, while associations with potentially beneficial taxa are inconsistent. However, the evidence base is sparse and limited. Randomized, controlled trials are needed to determine the independent effects of hypobaric hypoxia on the gut microbiota, and the subsequent implications for health and performance.
Acute cold exposure elicits multiple physiologic responses that collectively serve to maintain body temperature within the normal physiologic range. Responses include activation of the SNS, cutaneous vasoconstriction which helps insulate the body’s core, and increased skeletal muscle contractile activity which increases metabolic heat production (
Recent evidence suggests that cold exposure induces alterations in the murine gut microbiota which may, in turn, promote physiologic adaptations to cold in the host. In mammals, physiologic adaptations following repeated or chronic cold exposure include a blunted physiologic response to cold, enhanced heat conservation, and/or a more pronounced thermogenic response (
The mechanisms underlying detrimental effects of heat stress on gut barrier function have been expertly reviewed (
Several animal studies have documented changes in the gut microbiota due to environmental heat stress. Changes included reduced gut microbiota diversity (
Acute infectious diarrhea is considered a major public health issue in both developed and developing nations due to the myriad infectious bacteria, viruses and parasites that can be transmitted through foodborne and other environmental vectors (
Few studies have examined changes in the gut microbiota during or following TD. In one cross-sectional study, gut microbiota composition after returning from travel was associated with both the presence of TD during travel and the causative pathogen (
An additional consideration is the differential effects of antibiotics commonly used to treat TD on the gut microbiota. Very generally antibiotics induce a stress response within the gut microbiota (
To what extent antibiotic treatment impacts restoration of the gut microbiota following TD is unclear. However, evidence suggesting that perturbations to the gut microbiota during TD (
Concern over adverse health effects resulting from occupational exposures of military personnel to environmental toxicants and pollutants during training or deployment is longstanding. Moreover, future military deployments will likely occur in urban environments where risk of exposure to toxic industrial chemicals and toxic industrial materials is high (
Exposures to environmental toxicants have been studied mainly for long term systemic health effects on respiratory illness (
Polyaromatic hydrocarbons are persistent organic compounds that can bioaccumulate in organisms, and are known environmental and food-borne contaminants (
Particulate matter is a component of air pollution that could trigger and accelerate development of GI diseases, particularly in genetically susceptible individuals (
In summary, although the specific effects differ, a growing evidence base indicates that environmental toxicants and pollutants may elicit changes in microbiota composition and metabolic activity (although not always both), changes in GI function, and, in some cases, GI inflammation. A limitation of this evidence base is that, commonly, high doses of toxic compounds are used for relatively short periods of time in small animals. In contrast, most human exposures to these compounds are at lower doses over longer periods of time. As such, to what extent findings from animal and
The high prevalence of hearing problems in military personnel and veterans (
There are several pathways by which physical activity may impact the gut microbiota (
Several recent reviews have comprehensively characterized the effects of exercise training on murine gut microbiota composition (
To our knowledge, only one study has longitudinally examined the effects of physical activity on the human gut microbiota. In that trial, 3 days/weeks of moderate intensity exercise over 6 weeks was shown to differentially impact gut microbiota composition and fecal SCFA content of previously sedentary lean and obese adults (
In summary, physiologic responses to physical activity range along a spectrum of beneficial to potentially harmful which varies with the novelty, frequency, intensity, and duration of activity. That physical activity alters gut microbiota composition and function, perhaps favorably, is supported by a rapidly growing collection of rodent studies. However, findings have been inconsistent and likely vary with the novelty, frequency, intensity and duration of activity. The effect of physical activity on the human gut microbiota remains largely unexplored.
Diet is a predominant factor influencing gut microbiota composition and activity. Both species abundances and metabolic outputs of the human gut microbiota respond within days to changes in diet (
Emerging evidence indicates that changes in gut microbiota composition may contribute to decrements in gut health during food restriction. Animal models consistently report altered gut microbiota composition during acute (1–3 days) (
In healthy humans, complete food deprivation for extended periods is uncommon. However, interrelationships between food restriction and the gut microbiota are increasingly being studied in the context of treatments for overweight and obesity. A recent meta-analysis of those studies (
Although manipulating food intake without altering dietary macronutrient composition has been shown to impact gut microbiota composition in healthy adults (
Within the varied diets of most healthy humans, NDC provide the primary carbon source for many gut microbes. NDC-containing foods often include multiple NDC types that are diverse in structure, composition, degree of polymerization, and in the types of glycosidic bonds within the polymer. The myriad enzymes required to metabolize this diversity are contained not within individual species of the gut microbiota, but within the collective genome of the gut microbiota (
Similar to carbohydrates, proteins provide fermentative substrate to the gut microbiota. The primary proteolytic species in the human gut belong to the genera
Unlike carbohydrate and protein, the primary effects of dietary fat on the gut microbiota are thought to be more indirect and mediated by bile acid secretion, and through modulation of GI inflammation and barrier integrity (
Animal models have consistently demonstrated changes in gut microbiota composition in response to high fat diets (≥40% total energy intake) which can generally, but not exclusively, be considered unfavorable (e.g., decreased
Animal studies using multiple simplified diets comprised of different combinations of individual macronutrient sources (
Low NDC intakes may also stress the human gut microbiota, particularly when coupled with high fat, and possibly high protein intakes. In support, reducing carbohydrate and NDC intakes while increasing fat intake reproducibly reduced the abundance of
Randomized clinical trials examining effects of diet macronutrient or energy manipulation on human gut microbiota composition and metabolites.
Reference | Design1 | Microbiota method | Results- Microbiota | Results- Microbiota metabolites |
---|---|---|---|---|
Targeted; FISH | lowCHO vs modCHO: ↓ |
lowCHO vs. modCHO: ↓Fecal butyrate; ↔fecal acetate, propionate, BCFA, NH3 | ||
Both diets: ↓Total bacteria, |
Both diets: ↓Fecal acetate, propionate, butyrate, isovalerate, valerate, NH3 | |||
Targeted; FISH | lowCHO vs. modCHO: ↓ |
NA | ||
Both diets: ↓total bacteria, |
||||
Targeted; FISH | lowCHO vs. modCHO: ↓ |
lowCHO vs. modCHO: ↓Fecal acetate, butyrate, total SCFA, plant-derived phenolics, fatty acid-derived bacterial metabolites; ↑Fecal pH, N-nitroso compounds | ||
Both diets: ↓total bacteria | Both diets: ↑Fecal isovalerate, valerate, |
|||
16S rRNA gene sequencing | No effects of diet on fecal or rectal mucosa microbiota | Fecal metabolome: ↓butyrate and ↑AA-derived bacterial metabolites (e.g., BCFA) which differed by PRO group | ||
Urine metabolome: ↑AA-derived bacterial metabolites (e.g., BCFA) which differed by PRO group | ||||
Plasma metabolome: No differences between groups in bacterially derived metabolites | ||||
16S rRNA gene sequencing | No differences between groups | NA | ||
Both groups: ↑Bacteroidete |
||||
Targeted; culture | lowCHO vs. high CHO: ↓Total anaerobes, |
lowCHO vs. high CHO: ↓Fecal acetate, butyrate, total SCFA; ↔fecal pH and NH3, urinary phenols and |
||
16S rRNA gene sequencing; SM | Shifts in composition within 24 h, but no differences between diets. | NA | ||
DGGE | No differences | highPRO vs lowPRO: ↑Urinary |
||
Targeted; FISH | highMUFA: ↓Total bacteria | ↔Acetate, butyrate, propionate, valerate, caproate | ||
highCHO + highGI: ↑ |
||||
highCHO: ↑ |
||||
highCHO + lowGI: ↑ |
||||
16S rRNA gene sequencing | Animal diet: Transient change in diversity, changes in 22 bacterial clusters, ↑bile acid tolerant and putrefactive taxa (e.g., |
Animal vs plant-metabolites: ↓Fecal acetate, butyrate; ↑fecal isovalerate, isobutyrate, deoxycholic acid (secondary bile acid) | ||
Plant diet: Changes in 3 clusters, ↓ |
Animal vs. plant-gene expression: ↑bile salt hydrolases, sulfite reductases, AA catabolism; ↓AA biosynthesis | |||
16S rRNA gene sequencing | Overeating: ↓ |
NA | ||
Extreme dietary shifts appear to have more robust effects on the human gut microbiota. In support,
Diet-mediated changes in microbiota composition and function cannot always be solely attributed to altered dietary macronutrient composition because micronutrient intakes are often also altered. In support, growing evidence indicates that plant polyphenols favorably modulate gut microbiota composition and metabolic activity (
Iron and zinc are perhaps the best studied minerals with respect to how variations in mineral intakes impact the gut microbiota.
In summary, changes in the absolute and relative amounts of nutrients consumed in the diet alters host physiology, and nutrient availability and environmental conditions in the colon. Animal studies have demonstrated that both total food deprivation and low NDC intakes stress the gut microbiota initiating an adaptive response characterized by an increased abundance of mucolytic and, in some cases, pro-inflammatory taxa, an increased abundance and expression of genes involved in mucus degradation (e.g., mucin), a reduced abundance of beneficial butyrate-producing taxa, and a reduced diversity and expression of genes encoding carbohydrate degrading enzymes (
Similar adaptive responses have also been reported in a limited number of human studies although effects may be somewhat more subtle than reported in animals absent of substantial changes in diet. As such, to what extent different dietary macro- and micro-nutrients “stress” the gut microbiota when consumed in excess or in inadequate amounts is unresolved. Finding an answer to the question is difficult in part because nutrients are not consumed in isolation. Both the amounts and proportions of macro- and micro-nutrients in the diet, as well as factors impacting nutrient digestibility and bioavailability (e.g., food processing/cooking, nutrient-nutrient interactions, host physiology, gut microbiota composition) will determine the ultimate impact of diet on the gut microbiota. Additionally, it is worth noting that recent studies have suggested that non-nutritive dietary components such as the artificial sweetener saccharin (
There is increasing recognition that humans are ‘superorganisms’ or ‘holobionts’ comprised of an integrated network of human cells and microorganisms whose dynamic bidirectional interactions react and respond to environmental pressures to influence health (
Military-relevant stressors and the gut microbiota. Military personnel can be exposed to extremes and combinations of psychological, environmental (e.g., altitude, heat, cold, and noise) and physical (e.g., physical activity, sleep deprivation, and circadian disruption) stressors. These stressors induce central stress responses that ultimately alter gastrointestinal and immune function which may lead to changes in gut microbiota composition, function and metabolic activity. Other stressors such as diet, enteric pathogens, environmental toxicants and pollutants, and antibiotics can alter gut microbiota composition and activity through direct effects on the gut microbiota, and indirectly through effects on gastrointestinal and immune function. Stress-induced changes in the gastrointestinal environment may elicit unfavorable changes in gut microbiota composition, function and metabolic activity resulting in a dysbiosis that further compromises gastrointestinal function, and facilitates translocation of gut microbes and their metabolites into circulation. Alternately, evidence suggests that some stressors (e.g., healthy diet, cold, and physical activity) may favorably modulate the gut microbiota. To what extent these changes impact the health, and physical and cognitive performance of military personnel is currently unknown.
Military personnel frequently operate in austere environments in which they are exposed to a variety of stressors that challenge health, cognition, and physical function. Transient health decrements associated with exposure to these stressors [e.g., musculoskeletal injury (
Nonetheless, the provocative preclinical evidence reviewed highlights a need for translational research aiming to elucidate the impact of psychological, environmental and physical stressors on the human gut microbiota, and the associated health implications. This work will transcend military applications given the increasing exposure of many civilian populations to similar stressors. Research will need to integrate longitudinal investigations conducted in field settings with tightly controlled randomized clinical trials and complementary
All the authors contributed to the literature review, manuscript writing, and critical review of the manuscript. All the authors approved the final manuscript. JPK had primary responsibility for the final content.
The opinions or assertions contained herein are the private views of the author(s) and are not to be construed as official or as reflecting the views of the Army or the Department of Defense. Citation of commercial organizations or trade names in this report does not constitute an official Department of the Army endorsement or approval of the products or services of these organizations. Approved for public release (U18-137); distribution is unlimited.
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.
We thank Mr. Steve Smith from the Strategic Communication Group at the Natick Soldier Research, Development and Engineering Center for developing the manuscript figure.
branched-chain fatty acid
entertoxigenic
gastrointestinal
hypothalamic-pituitary-adrenal
non-digestible carbohydrate
polycyclic aromatic hydrocarbons
particulate matter
short-chain fatty acid
sympathetic nervous system
travelers’ diarrhea