Probiotics serve a broad spectrum of health-related purposes, which include improving oral and intestinal health, preventing diarrhea, strengthening the immune system, lowering serum cholesterol levels, and exhibiting various beneficial effects such as antimicrobial, anti-biofilm, antioxidant, anti-inflammatory, and anti-diabetic properties. It’s important to note that these health-promoting qualities are contingent on the specific probiotic strain in use, and each exerts its effects through distinct mechanisms (Pique et al., 2019). Probiotics have several benefits: (i) reduce vulnerability to infections; (ii) reduce lactose intolerance, relieve allergic episodes and respiratory infections; (iii) reduce serum cholesterol and blood pressure; (iv) prevent the intestine from gastritis and diarrhea; (v) prevent urogenital and vaginal infections and (vi) reduce the chances of colon cancer (Reid et al., 2003).

Some probiotic strains have been found to produce a range of small molecules that can have specific localized effects. These molecules encompass acetylcholine, oxytocin, norepinephrine, dopamine, serotonin, tryptamine, and gamma-aminobutyric acid. Furthermore, research on rats has indicated that probiotics can influence adrenocorticotropic hormone levels and corticosterone levels (Liang et al., 2015).

Before embarking on clinical trials, several in vitro tests are available to assess the effectiveness of probiotics. These include methods such as the agar spot test, agar well diffusion test, microdilution assays, antibiofilm assessments, 3D cell cultures, and the utilization of human tissues and animal models (Papadimitriou et al., 2015). Furthermore, probiotics have shown potential in aiding various medical conditions, including but not limited to constipation, diarrhea, polycystic ovary syndrome, ulcerative colitis, stress and anxiety, inflammatory bowel disease, breast cancer, and diabetes (Bodke and Jogdand, 2022). Probiotics also exert antimicrobial effects and modulate the mucosal immune system through several mechanisms summarized in Figure 2.

Probiotic bacteria have been found to significantly influence the immune system by releasing anti-inflammatory cytokines within the gut. They can potentially impact various types of immune cells, including dendritic cells, monocytes, natural killer (NK) cells, macrophages, lymphocytes, and epithelial cells. A key mechanism of action involves the activation of pattern recognition receptors (PRRs) found on both immune and non-immune cells (Ferlazzo et al., 2011). However, the precise molecular interactions between probiotics and the host organism still need to be fully understood and require further research. Specific strains of Lactobacillus sp. have been found to influence cytokine production, while Bifidobacterium sp. strains have been associated with promoting immune tolerance (Djaldetti and Bessler, 2017; Azad et al., 2018). Oral administration of probiotic strains like L. plantarum, L. acidophilus, B. breve, and B. lactis influence the release of proinflammatory cytokines through toll-like receptor signaling pathways (Yao et al., 2017; Asgari et al., 2018). These varying regulatory activities are associated with the structural characteristics of the probiotic strains, the range of mediators they release, and the different immune pathways they activate simultaneously (Hoffmann et al., 2014).

Bifidobacterium sp. and Lactobacillus sp. play significant roles in modulating various aspects of the immune system, including the humoral response, cell-mediated responses, and non-specific immunity. Probiotics such as these can enhance the secretion of immunoglobulin IgA, thus influencing humoral immunity and helping the body defend against invading pathogens. A similar effect was observed when individuals consumed yogurt containing L. casei and L. acidophilus, resulting in a substantial increase in IgA-producing plasma cells (Cristofori et al., 2021). Moreover, research conducted by Hasan and collaborators demonstrated the ability of heat-killed probiotic Bacillus sp. SJ-10 to act as a potent modulator of the innate immune response. This research was conducted in olive bream, underscoring the broad applicability of probiotics in enhancing the innate immune system’s capabilities (Hasan et al., 2019).

The commensal microbiota maintains the epithelial environment’s balance by stimulating the production of epithelial repair factors and regulating the immune response, safeguarding against epithelial damage. When administered orally, probiotics activate TLR signaling, producing cytokines that activate macrophages and influence intestinal epithelial cells (IEC) and immune cells within the lamina propria. This activation, in turn, stimulates regulatory T cells to release IL-10. Probiotics exhibit immunomodulatory effects that impact humoral immunity, cell-mediated immunity, and the non-specific immune response (Maldonado Galdeano et al., 2019). The regulation of proinflammatory cytokines by probiotics has been shown to decrease inflammation in the gingival area (Ma et al., 2023). Among the commonly used probiotic strains are various Lactobacillus and Bifidobacterium sp., including L. acidophilus, L. casei, L. rhamnosus, L. reuteri, L. johnsonii, L. gasseri, B. longum, B. bifidum, and B. infantis. Several studies have highlighted the significance of L. fermentum and L. gasseri in healthy individuals, as they are responsible for inhibiting periodontal pathogens such as Porphyromonas gingivalis, Prevotella intermedia, and Aggregatibacter actinomycetemcomitans. This inhibition is achieved through various mechanisms, including the production of hydrogen peroxide, antibacterial substances like bacteriocins, and the generation of inorganic acids. By doing so, these probiotic strains contribute to maintaining the dynamic balance of normal microbiota, ultimately restoring homeostasis (Jansen et al., 2021).

Probiotics present a promising approach to combat the rise of antibiotic-resistant bacteria (Knipe et al., 2021). Probiotics employ several key antimicrobial mechanisms to achieve this goal, including competitive exclusion, intestinal barrier function improvement by enhancing mucin and tight junction protein expression, antimicrobial molecule secretion, and immune system regulation (Silva et al., 2020).

The antimicrobial activity of probiotics relies significantly on their ability to produce antimicrobial peptides, which play a central role in competitively excluding pathogens. Lactobacillus strains, in particular, have demonstrated significant antimicrobial activity against various pathogens, including Klebsiella sp., Clostridium difficile, Shigella sp., E. coli, P. aeruginosa, S. mutans, and S. aureus (Prabhurajeshwar and Chandrakanth, 2019). They employ multiple strategies to outcompete and inhibit these pathogenic bacteria, including producing lactic acid, bacteriocin, and hydrogen peroxide, inhibiting the adhesion of pathogenic bacteria to the mucosa and improving the immune response (Plaza-Diaz et al., 2017).

The intestinal barrier serves as a critical line of defense to maintain the homeostasis of the intestine. It accomplishes this by performing various mechanical, chemical, immune, and microbial barrier functions (Vancamelbeke and Vermeire, 2017). Probiotics can improve and reinforce the integrity of the gut barrier through various mechanisms, including upregulating genes and protein expression involved in tight junction signaling. Probiotics can also regulate the apoptosis and proliferation of intestinal epithelial cells, contributing to barrier repair and maintenance (Gou et al., 2022). For instance, L. acidophilus can induce rapid and strain-specific enhancement of intestinal epithelial tight junction barrier function. This effect is mediated through TLR complexes, specifically TLR-2/TLR-1 and TLR-2/TLR-6. Strengthening tight junctions helps protect against intestinal inflammation (Al-Sadi et al., 2021). Probiotics can induce mucin expression and promote mucus secretion by goblet cells. Studies have demonstrated that treating mucus-secreting colon epithelial cells with supernatants from a probiotic-rich yogurt mixture can elevate mucin protein expression, including MUC2, a vital constituent of the protective mucus layer. CDX2, a regulator of MUC2 expression, is also influenced by probiotics (Chang et al., 2021).

The primary method by which Lactobacillus strains exhibit antimicrobial activity is by releasing substances called bacteriocins (La Storia et al., 2020). Bacteriocins are antimicrobial peptides that combat many bacteria, including Gram-positive and Gram-negative species. Interestingly, the bacteria that produce these bacteriocins have developed specific mechanisms to protect themselves from the action of their antimicrobial peptides (Perez-Ramos et al., 2021). Both Bifidobacterium and Lactobacillus strains are known to be producers of bacteriocins. These antimicrobial peptides function through various means, which include inhibition of lipid II, a critical component of bacterial cell membranes, prevention of peptidoglycan synthesis, and pore formation. The pore formation process often involves a receptor known as the mannose-phosphotransferase system, as depicted in Figure 3 and Martinez et al. (2013).

The antioxidant properties of probiotics can be attributed to several actions. Probiotics can chelate metal ions, such as iron, thereby reducing their availability for catalyzing the production of harmful ROS. Certain probiotic strains can synthesize antioxidant metabolites, including vitamins like C and E, glutathione, and various ROS-scavenging enzymes, which help mitigate oxidative stress. Probiotics can stimulate the host’s production of antioxidants or enhance dietary antioxidants’ absorption, bolstering the body’s overall antioxidant capacity. Probiotics can influence oxidative stress and inflammation by modulating signaling pathways, ultimately regulating ROS production. Some probiotic strains can downregulate enzymes responsible for ROS generation, such as NADPH oxidase, leading to decreased ROS levels and reduced oxidative stress. Probiotics also play a role in shaping the composition of the intestinal microbiota, indirectly impacting gut health and potentially contributing to the reduction of oxidative stress (Wang et al., 2017).

Nuclear factor erythroid 2–related factor 2 (Nrf2) is a component belonging to the cap’n’collar transcription factor family and comprises seven NEH domains. In response to OS, Nrf2 plays a critical role in the ubiquitin-dependent signaling pathway (Seminotti et al., 2021). When ROS levels are elevated, Nrf2 disengages from its constant inhibitor, Keap1, migrates to the nucleus, and forms a complex with antioxidant response element (ARE) sequences, thereby initiating the transcription of genes involved in antioxidation, such as NQO1, GST, HMOX1, GCL, and GSH. Substantial research suggests that the activation of Nrf2 can inhibit oxidative stress and inflammation, thus potentially averting conditions like UC (Trivedi et al., 2016).

Probiotics are thought to activate the Nrf2 system in the host, representing a crucial mechanism underlying their antioxidant properties. Several in vitro studies have illuminated the role of Nrf2 pathway activation in mediating the antioxidant effects of specific probiotic strains such as B. infantis, C. butyricum, and L. casei Shirota in the context of intestinal injury (Ehrlich et al., 2020; Dou et al., 2021). TLRs activation has also been shown to stimulate Nrf2-ARE signaling and heme oxygenase-1 (HO-1) both in vivo and in vitro (Nadeem et al., 2016). Moreover, several studies have documented that the activation of TLR-Nrf2 signaling by Lactobacillus sp. could account for their antioxidant advantages within the gastrointestinal systems of piglets (Yang et al., 2022).

Oxidative stress arises from either the cumulative production of ROS or the inadequate scavenging activity of the antioxidant system, resulting in a disturbance in the body’s redox balance (Pizzino et al., 2017). Whether taken alone or alongside food, probiotic consumption has demonstrated the capacity to enhance antioxidant activity, thereby mitigating tissue damage caused by oxidative processes (Wang et al., 2017). Among the various antioxidant activities exhibited by probiotic strains such as Lactobacillus sp., Bifidobacterium sp., and Propionibacterium sp., it has been observed that P. freudenreichii displays the highest antioxidant activity (Amaretti et al., 2013). These probiotics release potent antioxidant compounds, including vitamin E, vitamin C, glutathione, beta-carotene, superoxide dismutase (SOD), polysaccharides, prototypical coenzyme I (NADH), and certain unidentified substances, all of which contribute to the promotion of gut health (Hemarajata and Versalovic, 2013). Additionally, probiotics can reduce oxidative stress by inhibiting cytokine production and decreasing levels of interleukin 1 and tumor necrosis factor-alpha while simultaneously increasing glutathione (GSH) levels (Pourrajab et al., 2022).

Various Lactobacillus strains, including L. johnsonii, L. reuteri, L. brevis and L. fermentans have been observed to activate the NF-κB pathway. In studies conducted with rats, this activation has been associated with reduced OS and inflammation in the intestinal tract (Pan et al., 2016; Wu et al., 2018). Interestingly, genetically engineered Lactobacillus strains expressing superoxide dismutase (SOD) have also shown similar positive effects. Additionally, Bifidobacterium sp. has been found to downregulate ROS production and inhibit the NF-κB pathway, contributing to the modulation of the intestinal immune system and protecting the intestinal epithelium (Yao et al., 2021). The interaction between SIRT1 and Nrf2/ARE is a critical component of the antioxidant defense system. SIRT1 facilitates the nuclear translocation of Nrf2, consequently elevating the expression of antioxidant proteins and phase II detoxification enzymes. In rats with aging-induced colitis, treatment with Lactobacillus C29 led to a decrease in plasma levels of ROS, malondialdehyde (MDA), and C-reactive protein while also increasing SIRT1 expression (Kim et al., 2019). Moreover, the mitigation of high-fat-diet-induced ulcerative colitis (UC) by administering B. longum and L. plantarum is linked to the activation of SIRT1. Additionally, studies have shown that activated SIRT2 can deacetylate forkhead box proteins (FOXO1a and FOXO3a), thereby augmenting the expression of antioxidant enzymes under the regulation of FoxO (Kitada et al., 2019). The activation of manganese superoxide dismutase (Mn-SOD)/SOD2 by B. longum and L. acidophilus to reduce cellular ROS levels, mediated by SIRT2, has been reported (Guo et al., 2017). Additionally, LGG has been shown to prevent H2O2-induced disruption of tight junctions in the human intestinal epithelium, possibly mediated through the ERK1/2 pathway (Zheng et al., 2022). Heat-killed and active L. brevis have effectively ameliorated subtotal duodenal and colonic injury caused by dextran sulfate sodium by mitigating oxidative stress and inflammation through a p38-MAPK-mediated pathway (Jiang et al., 2018).

In summary, probiotics exhibit antioxidant properties through several mechanisms, including scavenging free radicals, chelation of metal ions, regulation of antioxidant enzyme expression, and modulation of the gut microbiota. These effects are mediated at the molecular level by the influence of probiotics on various signaling pathways, such as Nrf-2, NF-κB, MAPK, and SIRTs, allowing them to exert their beneficial antioxidant effects.

Probiotics represent a promising avenue in the search for safe and natural alternatives to manage hypercholesterolemia and reduce the risk of cardiovascular disease (Chang et al., 2019). Widely distributed in human and animal body sites, including the intestines, mouth, respiratory tract, and reproductive tract, probiotic strains like Bacteroides are gaining attention for their contribution to cardiovascular health improvement (You et al., 2023). He and collaborators isolated 66 Bacteroides strains from healthy adult fecal samples and compared their ability to assimilate cholesterol. In vitro assessments of bile salt hydrolase activity revealed favorable probiotic characteristics in these strains, including a high survival rate during simulated gastrointestinal digestion, excellent adhesion capabilities, susceptibility to antibiotics, and the absence of hemolysis or virulence genes. Furthermore, the strains exhibited notable bile salt deconjugation activities associated with regulating cholesterol metabolism. The strains also displayed an upregulation of the BT_416 gene, which is linked to cholesterol. This provides valuable insights into a potential molecular mechanism underlying their cholesterol-reducing activity, suggesting a pathway through which these strains may contribute to improving cardiovascular health (He et al., 2023). Ruiz-Tovar and collaborators conducted a prospective non-randomized study to investigate the effect of L. kefiri and a hypocaloric diet on cardiovascular risk markers. The addition of L. kefiri to a low-calorie diet increased weight loss and further improved the glycemic and lipid profile and also caused a further improvement in obesity-associated dysbiosis, mainly by increasing the muconutritive and regulatory (e.g., Bifidobacterium spp., Akkermansia muciniphila) microbiome, and decreasing the Firmicutes/Bacteroidetes ratio (Ruiz-Tovar et al., 2023). In addition, recent studies demonstrated that chronic consumption of probiotics, oats, soymilk, and apples may decrease diastolic blood pressure, triglycerides, total cholesterol, and insulin levels and significantly increase high-density lipoprotein cholesterol, beneficially affecting cardiometabolic health (Naseri et al., 2022; Pavlidou et al., 2022; Hasanpour et al., 2023; Pushpass et al., 2023; Zarezadeh et al., 2023). A cross-sectional study involving a group of 190 schoolchildren from public schools in Brazil aimed to evaluate the fecal abundance of Bifidobacterium spp. and their relationship with food consumption and anthropometric characteristics. The results revealed that a high abundance of Bifidobacterium spp. is associated with a low prevalence of hyperglycemia and cardiovascular risk markers (Menezes et al., 2023). Two meta-analyses consisting of 16 randomized controlled trials investigating the role of several probiotics (L. acidophilus, B. bifidum, L. reuteri, L. fermentum, and L. rhamnosus) in treating coronary artery disease and lowering blood pressure, blood lipid, and blood glucose was conducted recently. These studies showed that adding probiotics to conventional medications for coronary artery disease reduced the levels of low-density lipoprotein cholesterol, fasting glucose, and hypersensitive C-reactive protein and increased the levels of high-density lipoprotein cholesterol and nitric oxide (Lei et al., 2023; Liu L. et al., 2023). Similarly, a retrospective cohort study of 4,837 participants aged 65 years or older found that subjects who used probiotics experienced a reduced risk of all-cause mortality by nearly 41% and cardiovascular mortality by 52% (Shen et al., 2023).

An ongoing open-label, randomized, controlled clinical trial (Chinese Clinical Trials Registry ChiCTR2000038797) involving 2,594 adult patients diagnosed with acute myocardial infarction aims to assess the effects of probiotics on in-hospital mortality and the incidence of major adverse cardiovascular events. Patients will receive a bifidobacteria triple viable capsule (B. longum, L. acidophilus, and E. faecalis) twice a day, along with standard treatment, for a maximum of 30 days or standard treatment strategy without the bifidobacterium triple live capsule. This clinical trial will provide evidence for probiotics as a complementary treatment for acute myocardial infarction (Chen et al., 2023).

In the case of stroke, probiotics can ameliorate neurological deficits, decreasing cerebral volume loss and inhibiting neuronal apoptosis by sustaining intestinal barrier function, such as increasing tight junctions, decreasing intestinal injury, and modulating gut microbiota (Wu and Chiou, 2021; Savigamin et al., 2022). A recent meta-analysis including 26 randomized controlled trials (2,216 patients) was conducted to explore the efficacy and safety of probiotics in stroke patients. The results showed a significantly lower incidence of gastrointestinal complications, a lower incidence of infection, a shorter length of hospital stay, and a lower dysbacteriosis rate in the probiotics group, suggesting that probiotics significantly improve the status of stroke patients (Chen et al., 2022).

One of the primary benefits of probiotics in the oral cavity is their ability to reduce inflammation. Probiotics play a role in preserving the health of gums and teeth by actively countering harmful microorganisms in the mouth. As a form of natural medicine, probiotics are generally considered safe and are not expected to yield adverse effects. Notably, L. acidophilus and B. lactis have gained recognition for their effectiveness in combating fungal infections in the oral environment (Lesan et al., 2017).

Oral probiotics should adhere to specific criteria to be effective without causing adverse effects. They should not ferment sugars, as this fermentation can decrease pH and potentially promote dental caries. Additionally, they should be capable of adhering to and colonizing all oral cavity tissues (Saiz et al., 2021). The oral cavity hosts a diverse community of bacteria belonging to several phyla, including Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, Spirochaetes, and Fusobacteria, as revealed by research (Hernandez et al., 2022). These bacteria are typically normal commensals in healthy individuals, with Candida sp. among the most commonly observed organisms (Baumgardner, 2019).

The most common strains being a pillar in the probiotics development are Lactobacillus and Bifidobacterium sp. Notable strains within the Lactobacillus sp. include L. acidophilus, L. johnsonii, L. rhamnosus, L. casei, L. reuteri, and L. gasseri. These probiotic strains are associated with beneficial effects on oral health. They achieve this by engaging with toll-like receptor (TLR) signaling, which contributes to epithelial homeostasis by producing repair factors and immune regulation. This mechanism is crucial for protecting against epithelial injury. Furthermore, these probiotics play a role in regulating the release of inflammatory cytokines such as IL-1β and TNF-α, effectively reducing gingival inflammation (Ma et al., 2023).

Urogenital infections, including yeast vaginitis, bacterial vaginosis (BV), urinary tract infections (UTI), and non-sexually transmitted urogenital infections, constitute common reasons for women to seek gynecological care (Al-Badr and Al-Shaikh, 2013). The composition of normal vaginal commensals in healthy women can vary in premenopausal and postmenopausal stages. In healthy premenopausal women, Lactobacillus species typically predominate. These Lactobacillus species include L. delbrueckii, L. brevis, L. crispatus, L. casei, L. jensenii, L. fermentum, L. plantarum, L. reuteri, L. salivarius, L. rhamnosus, L. gasseri, and L. vaginalis (Petrova et al., 2015). Several factors contribute to these variations, including vaginal pH, glycogen levels, hormonal variations (especially estrogen fluctuations), and the menstrual cycle. Together, these factors affect the colonization and attachment of pathogens to vaginal epithelial cells. Elevated estrogen levels in healthy premenopausal women encourage the adherence of lactobacilli while discouraging the colonization of other pathogens. Conversely, in postmenopausal women, estrogen levels decrease, leading to changes in the vaginal microbiota that can contribute to urogenital infections (Witkin, 2015). Bacterial vaginosis (BV), the most prevalent urogenital infection, is primarily attributed to decreased Lactobacillus species and subsequent overgrowth of Gram-negative anaerobes (Mestrovic et al., 2021).

Probiotics offer a promising approach to restoring the balance of commensal organisms in the vagina, which can disrupt the growth of pathogenic organisms and inhibit biofilm formation (Barrea et al., 2023). Reid and collaborators initially reported the idea of repopulating the vagina with lactobacilli through oral probiotics (Reid et al., 2001). Lactobacillus sp. combat vaginal pathogens through various mechanisms, including the production of antimicrobial agents like bacteriocins (Gaspar et al., 2018) and biosurfactants that alter the surface tension of the environment, preventing pathogen adhesion and further inhibiting their spread in the bladder. Lactobacilli also play a crucial role in maintaining vaginal pH (Ballini et al., 2018). Research has shown that administering the probiotic Lactobacillus rhamnosus GR-1 to premenopausal women can increase the expression levels of antimicrobial defenses (Barrea et al., 2023). A randomized, double-blind, placebo-controlled pilot study included 81 premenopausal adult women who experienced recurrent UTIs. The study aimed to evaluate a product containing two Lactobacilli strains and cranberry extract to prevent recurrent UTIs in premenopausal women. The results demonstrated that this product was safe and effective in preventing recurrent UTIs in this group (Koradia et al., 2019). Another study led by Armstrong and collaborators, conducted as part of a phase 2b trial, investigated the impact of the LACTIN-V product based on L. crispatus on genital immunology and vaginal microbiota. The findings from this study revealed the role of LACTIN-V in reducing genital inflammation, serving as a biomarker of epithelial integrity (Armstrong et al., 2022).

More recently, Ansari and collaborators investigated the benefits of Lactobacillus sp. probiotics in improving vaginal dysbiosis and facilitating the colonization in asymptomatic women. This study included 36 patients who received a combination of L. acidophilus, L. rhamnosus, and L. reuteri and revealed that oral administration of these probiotics improved vaginal dysbiosis in asymptomatic women (Ansari et al., 2023). A recent randomized, double-blind trial (ISRCTN34840624, BioMed Central) conceptualized by Mandar and collaborators investigated the impact of the vaginal probiotic capsules containing L. crispatus strains in 182 patients with BV and vulvovaginal candidiasis (VVC). The study highlighted the benefits of vaginal capsules in improving the signs, symptoms, and amount of discharge and itching/irritation in BV and VVC patients (Mandar et al., 2023). Another clinical trial (KCT0005881, Clinical Research Information Service, the Republic of Korea) was conducted to evaluate the effectiveness of a complex of five strains of probiotic candidates in restoring vaginal health in 76 reproductive-aged women. The consequent analyses confirmed the increment of L. plantarum, concomitant with inhibiting harmful bacteria such as Mobiluncus spp., Gardnerella vaginalis, and Atopobium vaginae. This clinical trial demonstrated that this probiotic complex can be used for treating BV, as it improves the vaginal microbiota (Park et al., 2023).

Preterm birth (PTB) is a significant global challenge and ranks second leading cause of neonatal mortality (Keelan and Newnham, 2017). Research has highlighted a robust connection between BV and PTB. Consumption of Lactobacillus sp. during both early and late pregnancy has been shown to reduce the incidence of PTB-related infections, inflammation, and even conditions like pre-eclampsia (Zheng et al., 2019). A notable characteristic of healthy female reproductive tracts is the predominance of a less diverse community of Lactobacillus sp. (Madhivanan et al., 2015). In contrast, a highly diverse vaginal microbiome is associated with BV and serves as a primary risk factor for PTB and the acquisition of pelvic inflammatory disease (Holdcroft et al., 2023).

Probiotics have emerged as promising agents in the fight against cancer, showing their potential in laboratory experiments (in vitro) and animal studies (in vivo). Various probiotic strains have exhibited their ability to combat different types of cancer. Lactobacillus strains (L. paracasei SR4, L. casei SR1, and L. casei SR2) have demonstrated anticancer effects against cervical cancer cells (HeLa) by increasing the expression of apoptotic genes like BAX, BAD, caspase-8, caspase-3, and caspase-9 while reducing the activity of the anti-apoptotic BCl-2 gene (Riaz Rajoka et al., 2018). Studies have revealed that a compound produced by Enterococcus thailandicus possesses significant anticancer properties, particularly against liver cancer cells (HepG2). Yogurt fortified with probiotics has demonstrated the ability to hinder the development of colon tumors induced by 1,2-dimethylhydrazine in laboratory mice (BALB/c mice), suggesting its potential as an anticancer dietary option. An aqueous extract of Bifidobacterium sp. has been shown to induce apoptosis in non-small cell lung cancer cells, effectively inhibiting the invasive behavior of cancer cells (Ahn et al., 2020). Various mixtures of probiotics, including L. casei-01, combined with dairy beverages, have demonstrated antiproliferative and apoptotic effects on human prostate cell lines (Rosa et al., 2020).

Bacillus Calmette-Guerin (BCG) has long been employed as preventive immunotherapy for recurrent superficial bladder cancer (Guallar-Garrido and Julián, 2020). Additionally, regular lactic acid bacteria consumption is considered a preventative measure against bladder cancer (Andolfi et al., 2020). Probiotics enhance the expression of junctional molecules, thereby preserving the integrity of the intestinal barrier. They also contribute to the production of IgA and short-chain fatty acids, which impede the adherence and proliferation of pathogens (Engevik and Versalovic, 2017).

Moreover, L. plantarum releases polysaccharides with recognized antitumor properties. These polysaccharides act by downregulating the expression of MAPK mRNA and upregulating PTEN (Asoudeh-Fard et al., 2017). Research on L. lactis strains has revealed their capacity to secrete IL-10 and INF-β, as well as express antioxidants that mitigate the generation of reactive oxygen species (ROS) and reduce colonic damage in animal models (Zhao et al., 2023).

A recent randomized clinical trial conducted by Liu and colleagues confirmed that the perioperative use of probiotic supplements can reduce postoperative infections, improve short-term clinical outcomes, and alleviate common inflammatory symptoms in patients with gastric cancer receiving neoadjuvant chemotherapy (Liu G. et al., 2022; Liu Y. et al., 2022).

The incidence of oral cancer is closely linked to changes in the oral and intestinal microbiota. Variations in the levels of essential vitamins and nutrients can trigger the production of inflammatory cytokines, leading to various pathological conditions (Kany et al., 2019). Certain microbes, including F. nucleatum, P. gingivalis, and P. intermedia, have strong associations with the initiation and progression of oral cancer (Atanasova and Yilmaz, 2014). Among the microbial species extensively studied in this context are Actinomyces sp., Clostridium sp., Enterobacteriaceae sp., Fusobacterium sp., Haemophilus sp., Prevotella sp., Veillonella sp., and Streptococcus sp. These microorganisms exhibit a robust correlation with precancerous oral lesions and the development of oral cancer (Hu et al., 2016).

Inflammation of the oral mucosa is a frequently encountered condition known as oral mucositis (OM). OM presents with symptoms such as redness (erythema), ulceration, pain, difficulty swallowing (dysphagia), and nutritional deficiencies. This condition is a common consequence in individuals undergoing radiotherapy and chemotherapy. It is primarily attributed to several factors, including the detrimental effects of reactive oxygen species leading to the death of basal stem cells, DNA damage, and inflammatory cytokines synthesis (Lalla et al., 2014).

L. rhamnosus GG (LGG) is a naturally occurring gut commensal bacterium known for its anti-inflammatory properties and has been a pioneer in oncology research (Banna et al., 2017). LGG maintains the equilibrium of the intestinal mucosa by neutralizing harmful pathogens and toxins, effectively preventing breaches in the mucosal barrier through a high-affinity binding system (Okumura and Takeda, 2018). One of its key mechanisms involves regulating the production of IgA (Wang et al., 2017). LGG is also recognized for producing increased levels of geniposide, an anticancer molecule, and its potential as a beneficial adjuvant during cancer treatment. Studies have indicated that LGG, through its probiotic action, can protect epithelial stem cells from radiation-induced damage and reduce their apoptosis. It modulates cyclooxygenase-2 and stimulates the release of prostaglandin E2 (PGE2) (Desai et al., 2018). Furthermore, LGG plays a role in immune system modulation by secreting various cytokines, including IL-6, IL-10, IL-1β, TNF-α, IL-12, and p40. These actions help reduce inflammation, regulate epithelial function, and maintain intestinal mucosa integrity (Andrews et al., 2018). In the context of cancer treatment, L. brevis CD2 lozenges have been found to reduce the occurrence of oral mucositis in patients undergoing high-dose chemotherapy (Sharma et al., 2017). Additionally, L. brevis lozenges have shown benefits in reducing oral ulcers in individuals with recurrent aphthous stomatitis (Abruzzo et al., 2020). These findings underscore the potential of probiotics such as LGG and L. brevis in alleviating oral mucosal problems and promoting overall health.

Recently, a meta-analysis conducted by Frey-Furtado and colleagues examined nine articles to evaluate the therapeutic effectiveness of probiotics in managing oral mucositis. Among these studies, four clinical trials reported a decrease in the severity of oral mucositis by using specific strains of bacteria, including Lactobacillus (L. casei and L. brevis CD2) and B. clausii UBBC07. Preclinical studies revealed the positive effects of L. lactis, L. reuteri, and S. salivarius K12 in reducing the severity of oral mucositis and the size of ulcers (Frey-Furtado et al., 2023). Moreover, two distinct meta-analyses conducted by research teams from Taiwan and China, encompassing a total of 19 randomized clinical trials, investigated the potential of probiotics in preventing oral mucositis induced by cancer therapy and in managing the occurrence of chemotherapy-induced diarrhea and oral mucositis. Both studies revealed the effectiveness of probiotics in preventing and alleviating cancer therapy-induced oral mucositis and addressing adverse reactions associated with chemotherapy (Feng et al., 2022; Liu G. et al., 2022; Liu Y. et al., 2022).

Numerous studies have highlighted a significant connection between gut microbiota and iron deficiency. Furthermore, research has illuminated the reciprocal relationship between iron deficiency and the composition of gut microbiota, as well as the beneficial impact of probiotic bacteria on enhancing iron absorption (Sandberg et al., 2018; Hadadi et al., 2021).

Folic acid, a water-soluble B vitamin crucial for addressing and managing anemia, is derived from probiotic bacteria, including L. lactis, L. cremoris, B. pseudocatenulatum, Candida famata, B. adolescentis, Candida glabrata, Candida guilliermondii, S. cerevisiae, Yarrowia lipolytica, and Pichia glucozyma. These bacteria are harnessed to enhance the intestinal absorption of folic acids. In addition, P. denitrificans and P. shermanii have found utility in treating vitamin B12 deficiency. Lactic acid-fermented foods are instrumental in increasing iron absorption and are employed in managing anemic patients. They help optimize the pH of the digestive tract and activate the enzyme phytase, which plays a role in nutrient absorption. Furthermore, a combination of probiotic bacteria has been incorporated into food to treat megaloblastic anemia. These probiotics promote colonic fermentation and counteract the adverse effects of antibiotics (Ohtani et al., 2014).

Numerous studies have shed light on the positive effects of probiotics, particularly Lactiplantibacillus plantarum 299v, in addressing iron deficiency anemia and enhancing non-heme iron absorption. A study among Caucasian Europeans revealed that L. plantarum 299v had a beneficial impact in preventing iron deficiency anemia and improving the absorption of non-heme iron (Vonderheid et al., 2019). Korcok and collaborators investigated the role of L. plantarum 299v, sucrosomal iron, and vitamin C in preventing and treating iron deficiency, administering vitamin C and iron to one group. In contrast, the second group received additional L. plantarum. The results showed that the second group had higher iron blood levels due to increased iron absorption, highlighting the additive effect of L. plantarum 299v (Korcok et al., 2018). Adiki and colleagues demonstrated that using L. plantarum 299v with pear millet enhanced iron absorption. Interestingly, they noted that the increased dose of probiotics did not directly influence hemoglobin and hematocrit levels (Adiki et al., 2019). In individuals with an increased need for iron supplementation, Hoppe and colleagues reported that adding L. plantarum 299v to a meal improved iron bioavailability (Hoppe et al., 2017). In a double-blind clinical trial involving patients undergoing hemodialysis, probiotic supplementation containing L. acidophilus, B. bifidum, B. lactis, and B. longum led to a significant increase in serum hemoglobin levels compared to the placebo group (Haghighat et al., 2021). A recent randomized placebo-controlled study among athletes found that daily high-protein concentrated pro-yogurt enriched with whey protein isolates significantly increased hemoglobin levels. The study suggested that probiotics in concentrated yogurt, alongside enhanced iron bioavailability through mineral binding, can positively influence iron status and help improve athletic anemia and performance (Gomaa et al., 2022).

Obesity is a significant risk factor for various health conditions, including hypertension, coronary heart disease, and type II diabetes. Multiple factors contribute to obesity, including dietary choices, physical activity levels, age, genetics, and developmental stage (Leon Aguilera et al., 2022). In recent times, a novel approach to managing and reducing obesity has emerged through the use of probiotic bacteria. Probiotics have demonstrated their potential to reduce weight gain and combat obesity effectively, regulating food intake and promoting prolonged feelings of satiety, reducing fat deposition in the body, enhancing energy metabolism, and increasing insulin sensitivity (Daniali et al., 2020).

Research into the use of probiotics for managing obesity has yielded several significant findings from various studies. A comprehensive meta-analysis of 105 trials involving 6,826 obese patients concluded that probiotics moderately improved body mass index (BMI) and weight, resulting in a 3–5% reduction. However, there was no statistically significant impact on parameters such as glycated hemoglobin, cholesterol, triglycerides, insulin resistance, or liver function. Notably, in overweight (but not obese) individuals, probiotics, especially strains like bifidobacteria (B. breve, B. longum), S. salivarius subsp. thermophilus, and lactobacilli (L. acidophilus, L. casei, L. delbrueckii), brought about improvements in waist circumference, body fat mass, visceral adipose tissue mass, BMI, and body weight (Koutnikova et al., 2019). In another meta-analysis focusing on women with polycystic ovary syndrome (PCOS), probiotic supplementation was found to have a positive impact. It improved BMI, weight, insulin levels, triglycerides, and low-density lipoprotein (VLDL) cholesterol levels. However, it did not significantly affect dehydroepiandrosterone sulfate levels or total LDL and HDL cholesterol levels (Tabrizi et al., 2022). A comprehensive review encompassing thirty-three randomized clinical trials involving individuals with overweight and obesity revealed that approximately 30% of the trials reported reductions in body weight and BMI, while 50% showed significant reductions in waist circumference and total fat mass (Guedes et al., 2023). In a PROSPERO meta-analysis comprising eleven randomized controlled trials involving morbidly obese patients undergoing bariatric surgery, probiotics demonstrated beneficial effects. The pooled analysis indicated that probiotics could help regulate triglycerides, reduce weight, and influence dietary intake, particularly carbohydrates and fiber. The findings suggested that probiotics might delay the progression of liver function impairment, improve lipid metabolism, and reduce weight and food intake (Wang et al., 2023b).

Moreover, the microbiota administration from a healthy individual to an obese person can alter the composition of the recipient’s microbial flora. Recent studies have revealed that probiotics play a role in reducing serum cholesterol levels through mechanisms involving the production of short-chain fatty acids and the conjugation of bile salts (Jia et al., 2023; Momin et al., 2023).

The global pandemic caused by coronavirus disease 2019 (COVID-19) has tragically impacted countless lives. Despite the widespread adoption of rigorous public health measures such as social distancing, personal care, mask mandates, and lockdowns, the virus continues to proliferate, escalating infections and fatalities worldwide. The primary culprit behind this disease is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which distinguishes itself from previously identified coronaviruses. Consequently, existing antiviral treatments have demonstrated limited effectiveness (Singh and Rao, 2021). In this context, natural products like probiotics and their derivatives are being investigated for their potential contributions to pandemic prevention, treatment, and overall management, extending to post-pandemic periods and other severe infections (Brahma et al., 2022; Banerjee et al., 2023).

Currently, no direct evidence suggests that probiotics can directly inhibit coronaviruses. However, research has shown that certain probiotic strains have inhibitory effects on various viruses, as reviewed by multiple researchers (Olaimat et al., 2020; Tiwari et al., 2020; Singh and Rao, 2021). For example, in an animal study, L. plantarum was found to effectively reduce the proliferation of the influenza A (IFV) virus in the lungs in a dose-dependent manner. This probiotic also strengthened the Th1 immune response and increased the production of secretory IgA, contributing to the elimination of IFV from the lungs (Kawashima et al., 2011). This suggests that probiotic consumption can help reduce viral loads and enhance immune responses, which is particularly important during the pandemic. Bacteriocidins produced by S. salivarius 24 SMB have been shown to inhibit the common respiratory pathogen S. pneumoniae (Santagati et al., 2012). Additionally, L. rhamnosus, alone or in combination with B. animalis subsp. lactis Bb-12 has been found to reduce upper respiratory infections in children. It modulates the immune system and reduces nasal colonization with S. aureus and S. pneumoniae in adults. S. salivarius K12 has effectively reduced the incidence of infectious episodes in pharynx-tonsillar infections caused by group A beta-hemolytic streptococci and in children with otitis media. It has also been shown to prevent the recurrence of tonsillitis and pharyngitis (Di Pierro et al., 2016).

While limited data is available, specific probiotic strains such as L. gasseri SBT2055, L. rhamnosus CRL1505, B. bifidum, and B. subtilis warrant further exploration for their potential roles in managing COVID-19. Moreover, probiotic bacteria exhibit antioxidant capabilities, which are especially pertinent for COVID-19 management due to the critical role of redox homeostasis in curbing disease progression (Starosila et al., 2017; Singh and Rao, 2021).

Similar to other coronaviruses, SARS-CoV-2 employs the angiotensin-converting enzyme 2 (ACE2) for cellular entry and relies on the transmembrane protease serine 2 precursor (TMPRSS2) for priming and replication within the host (Ahlawat et al., 2020; Hoffmann et al., 2020)(Figure 4). This has suggested that ACE inhibitors could have a role in COVID-19 management (Meng et al., 2020). Notably, certain probiotics, especially lactic acid bacteria, are known to produce bioactive peptides that function as ACE inhibitors (Kim et al., 2021; Bhattacharya et al., 2022). Additionally, the lung-gut axis and its interplay with microbiota, in conjunction with probiotics, have been proposed for investigating COVID-19 management, building on prior work by Ahlawat et al. (2020).

Hence, there is a need to delve into the potential of probiotics and their derivatives, individually and in combinations, which exhibit promising activities that could be harnessed in the future (Singh and Rao, 2021).

Two recent meta-analyses suggest that probiotics may positively impact the overall symptoms experienced by individuals with COVID-19. Specifically, the results showed that probiotics have the potential to restore equilibrium in the intestinal microbiota, decrease the duration of diarrhea, enhance respiratory symptoms such as cough and dyspnea, and reduce the length of hospitalization (Tian et al., 2023; Zhu et al., 2023).

The potential application of microbiome or probiotic therapy holds promise as an emerging therapeutic approach due to its foundation on the multifactorial mechanism of action exhibited by beneficial bacteria in combating respiratory viral diseases (De Boeck et al., 2022). This adjuvant is characterized by its immunomodulatory properties, including the capacity to stimulate interferon production, mitigate excessive immune responses, and inhibit cytokine storms, thereby preventing pathological inflammatory states through immune response modulation (Nayebi et al., 2021). Other studies on different probiotic formulas investigated a throat spray containing specific antiviral lactobacilli. These studies suggest that this formula can decrease nasopharynx viral loads and alleviate acute symptoms (De Boeck et al., 2022). The administration of oral probiotic formula based on Lactiplantibacillus plantarum strains and Pediococcus acidilactici shows a reduced nasopharyngeal viral load, lung infiltrates, and digestive and non-digestive symptoms duration. The observed effect of the therapy resulted in an elevation of specific IgM and IgG antibodies targeting SARS-CoV2. This finding implies that the intervention may predominantly influence the gut-lung axis through communication with the host’s immune system rather than altering the colonic microbiota (Gutierrez-Castrellon et al., 2022). However, studies based on the microbiome analysis confirmed that the abundance of Lactobacillus rhamnosus was notably higher in individuals who were administered probiotics with L. rhamnosus GG strain compared to those who received a placebo (Tang et al., 2021; Wischmeyer et al., 2022).

Age-related immune response modifications make the elderly substantially more susceptible to COVID-19. Vaccination is crucial in mitigating the severity and fatality rates among older adults. However, it is important to note that age-related deficiencies in immune response might result in diminished levels of protection following vaccination when compared to younger cohorts. Probiotic supplements have been recognized as a supplementary measure to enhance immune function and improve the particular immune responses to vaccines in the aged demographic. The administration of Loigolactobacillus coryniformis K8 has shown promising effects, such as increasing the IgA response in correlation with the activation of TGF-β, a key signaling molecule involved in immune regulation and tolerance. Furthermore, the positive immune response induced by K8, as evidenced by the enhanced response to the BNT162b2 mRNA COVID-19 vaccine, suggests that individuals who receive this probiotic may have a more robust immune response if they are exposed to the live virus in the case of infection. This finding underscores the potential benefits of probiotics like K8 in strengthening the body’s defenses against viral threats, including COVID-19 (Fernández-Ferreiro et al., 2022).