According to the World Health Organization, probiotics are defined as “live microorganisms which, when administered in adequate amounts, confer a health benefit on the host” (Mu et al., 2018). These probiotics, that have already been proven to exert a beneficial impact, include Saccharomyces boulardii, Lactobacillus spp., Bifidobacterium spp., Propionibacterium spp., Streptococcus spp., Bacillus spp., Enterococcus spp., and some specific strains of Escherichia colietc, in which Lactobacillus spp. is the most widely used in human nutrition (Kechagia et al., 2013; Markowiak and Slizewska, 2017).

Recently, numerous bodies of research demonstrated that probiotics are beneficial for various diseases, such as intestinal disorders, respiratory tract infections, vaginal diseases, and so on (Markowiak and Slizewska, 2017; Nami et al., 2018). With the development of the food and drug industries and the innovation of technology, an increasing number of emerging probiotic strains were developed and applied to different fields, including natural food preservatives, nutraceuticals, and so on (Nami et al., 2015, 2018). Some novel technologies can also enhance probiotic products' quality and sensory characteristics, which can contribute to the extensive application of probiotics (Kiani et al., 2021a,b).

Safety is also an essential issue during the process of investigating probiotics. An ocean of evidence indicated that the use of probiotics can cause some risks regarding systemic infections, deleterious metabolic activities, excessive immune stimulation in susceptible individuals, gastrointestinal side effects, and so on (Doron and Snydman, 2015). Some probiotic microorganisms can even transfer resistance genes to protect against antibiotics, which may be responsible for the development of the antibiotic resistance crisis (Daniali et al., 2020). Taken together, the application of probiotics is a double-edged sword. Before probiotics are used, we still need to carry out enough clinical trials and animal experiments to assess their benefits and harms.

Lactobacillus spp., which can be found in various food products, is one of the most widely used probiotics, and includes Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus bulgaricus, Lactobacillus casei, and Lactobacillus reuteri (L. reuteri) (Giraffa et al., 2010). Lactobacillus reuteri is a gut symbiont mainly colonized in the intestines of humans, rodents, pigs, and chickens (Oh et al., 2010; Walter et al., 2011; Rattanaprasert et al., 2019). Since first isolated in 1962, there have been a great number of studies conducted on L. reuteri to explore its functions and concrete mechanisms in different diseases, which cover gastrointestinal diseases, hypercholesterolemia, skin infection, allergic asthma, periodontitis, hand, foot, and mouth disease (HFMD), and so on (Prince et al., 2012; Ang et al., 2016; Giudice et al., 2016; Mu et al., 2018; Tachi et al., 2018; Theodoro et al., 2019; Wang et al., 2022). Among these, there is an increasingly prevalent trend that the investigations of L. reuteri in terms of intestinal diseases are becoming far and away the best area, which mainly concentrates on inflammatory bowel disease (IBD), colorectal cancer (CRC), children's functional bowel diseases, and so on.

Intestinal diseases, especially IBD, have become an increasing burden on the global healthcare system and society. The prevalence of IBD is expected to increase to 790 per 100,000 in 2025 (Morales et al., 2017). Of note, there will be over 1.5 million cases of IBD in China by 2025 (Kaplan, 2015). The increased use of biological therapies and the aging population will bring new challenges and complexities to public healthcare and society's economy (Kaplan, 2015). Moreover, IBD is one of the leading causes of CRC, which is the third most common cancer globally (Weitz et al., 2005; Keller et al., 2019). Although the incidence of CRC has decreased overall, it has been estimated that the incidence rates for colon and rectal cancers may increase by 90.0 and 124.2%, respectively, for patients between the ages of 20 and 34 by 2030 (Bailey et al., 2015). This phenomenon may be attributed to the fact that the pediatric overall prevalence of IBD has increased sharply (Ye et al., 2020). IBD, including ulcerative colitis (UC), and Crohn's disease (CD), is a type of chronic relapsing-remitting disease characterized by intestinal inflammation (Guo X. et al., 2021). Conventional treatment approaches include mesalazine, glucocorticoids, immunosuppressors, and so on. However, considering multiple investigations on gut microbiota and IBD (David et al., 2014; Jost et al., 2014; Thaiss et al., 2014; Ananthakrishnan, 2015), probiotics are expected to become an effective treatment for this disease. Notably, there is an abundance of studies on the fact that L. reuteri exhibits the following beneficial capacities: anti-inflammation, immune regulation, gut micro-ecology balance, gut barrier protection, metabolic control, and so on (Mu et al., 2018).

In this study, we comprehensively reviewed the literature concerning L. reuteri and its metabolites in the pathogenesis of several common intestinal diseases, which are illustrated in a separate section for a clearer understanding. Some basic introductions and future perspectives are also discussed in this review (Tables 1–3).

According to incomplete statistics, L. reuteri consists of dozens of strains that originated from different samples. In addition, each stain and its unique metabolite may play a distinct role in various intestinal diseases. It is well documented that L. reuteri plays multifaceted roles in regulating immune responses, modulating gut microbiota, boosting beneficial metabolites, protecting against oxidative stress, maintaining intestinal barrier (IEB) function and intestinal morphology, and so on (Yi et al., 2018b; Liu et al., 2019; Garg et al., 2020; Singh et al., 2021). In this study, we will list some representative strains to introduce concrete pathogenesis.

It is well established that histamine is beneficial to the intestine, whose synthesis and secretion require l-histidine decarboxylase and a l-histidine/histamine exchanger (Hemarajata et al., 2013; Spinler et al., 2014). The current study identified chloride channel (ClC)-family proton/chloride antiporters as a modulator in the process of histamine production (Hall et al., 2019). Lactobacillus reuteri 6475 is special among gut microbes due to it containing a complete chromosomal histidine decarboxylase (hdc) gene cluster (genes hdcA, hdcB, and hdcP) and thus having the genetic capacity to convert histidine to histamine (Spinler et al., 2014). Lactobacillus reuteri-derived histamine can suppress gut inflammation by activating type 2 histamine receptors (H2R) and restricting pro-inflammatory H1R (Schreiber et al., 2009; Preidis et al., 2012). One of the mechanisms can be attributed to the function of a soluble bacterial enzyme named diacylglycerol kinase (Dgk), secreted by the L. reuteri strain, which can diminish Protein Kinase C (PKC) phosphorylation and suppress the H1R signaling pathway in the intestinal epithelium (Ganesh et al., 2018). Lactobacillus reuteri 6475 was also related to folate metabolism, which was mediated by dihydrofolate synthase/folylpolyglutamate synthase type 2 (folC2). Notably, the folC2 mutant can yield diminished hdc gene cluster expression and thus reduced histamine production, hinting at a link between folate and histadine/histamine metabolism (Thomas et al., 2016). Tryptophan (Trp) metabolism is also essential for gut immune homeostasis. The Trp metabolites from L. reuteri are known as aryl hydrocarbon receptor (AhR) ligand—indole-3-aldehydes, which can contribute to activating the AhR-IL-22 axis and maintaining intestinal homeostasis (Zelante et al., 2013). Another experiment also disclosed that indole-activated AhR could reprogram intraepithelial CD4⁺ T cells into immunoregulatory T cells to perform regulatory functions (Cervantes-Barragan et al., 2017). Özçam et al. (2019) creatively identified a novel pathway by which L. reuteri activates AhR, which is independent of Trp metabolism, known as polyketide synthase (PKS) gene clusters in L. reuteri 2010 and R2lc.

As is well-known, the adhesive ability is significant for bacterial function in the intestines of the host. In vitro experiments showed that L. reuteri has the potential to enhance adhesion in HT-29 cells (Dudík et al., 2020). Given this, Gao et al. (2016) assessed the modulatory effects of two strains of L. reuteri—ZJ617 and ZJ615, with different adhesive abilities in in vivo experiments. Finally, the authors indicated that both of them can exert anti-inflammatory and anti-oxidative effects, plus metabolism regulation, including glucose and its derivatives, galactose, amino acid metabolism, biosynthesis of antibiotics, and mineral absorption (Gao et al., 2016). Furthermore, the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) protein of L. reuteri ZJ617 has been proven to work as an essential adhesion component in binding to the intestinal epithelial cells (Yang et al., 2020). In a harsh context, L. reuteri SH23 still retained its adhesive ability with the help of the Mub protein (Xu et al., 2021).

Maintaining the functions of the intestinal epithelium is a key point in protecting against bowel diseases. It was demonstrated that L. reuteri D8 has the ability to restore the epithelial damage caused by TNF by activating the Wnt/β-catenin pathway, thus stimulating the proliferation of the intestine, increasing the number of Paneth cells and increasing the expression of antimicrobial peptides (Wu et al., 2020). Lactobacillus reuteri 22 also was capable of promoting intestinal stem cell differentiation into goblet cells with increased mucin 2 (Muc-2) expression to ensure the functionality of the intestinal mucosal barrier (Xie et al., 2019). microRNAs (miRNAs) functioned as an agent during the anti-inflammatory course of L. reuteri I5007. It was able to maintain intestinal epithelial function by changing the miRNA expression of piglets, especially the PI3K-Akt and MAPK pathways, modulated by different signaling pathways (Wang Q. et al., 2020).

With the acceleration of industrialization and changes in diet, IBD has become an emerging global disease, the incidence of which has risen considerably over the past several decades, both in the Western world and in developing countries (Kaplan, 2015). It is common knowledge that the gut microbiota's roles in the development and course of IBD are significant and enlightening. Given this, probiotics have become a hot topic both in the fundamental research and clinical practice of IBD (Martyniak et al., 2021). Research on L. reuteri is thus increasingly important.

Colorectal cancer (CRC) ranks as the third most common type of cancer and the fourth leading cause of cancer-related deaths globally (Weitz et al., 2005). It is well-known that several risk factors have been associated with the occurrence and development of CRC, such as inflammatory bowel disease (IBD), age, and genetic, and environmental factors (Keller et al., 2019; Thanikachalam and Khan, 2019). Probiotic therapy has become a hotspot treatment for CRC (Ambalam et al., 2016; Fong et al., 2020). Researchers demonstrated that L. reuteri ATCC PTA 6475 had the ability to reduce the number and size of colon tumors, with the mechanism that administration of hdc⁺ L. reuteri led to hdc gene expression and histamine production in the gut to suppress chronic intestinal inflammation and colorectal tumorigenesis (Gao et al., 2017). In addition, the interaction between Sirt3 and L. reuteri was proven to be crucial in gut tumorigenesis (Zhang et al., 2018). The research conducted by Bell et al. (2022) acquired some convincing results. In vitro, the authors found fecal metabolites from wild-type mice and normal humans. Both can inhibit the proliferation of CRC cell lines but not repress the noncancerous cell line NCM460. Metabolomics finally identified reuterin as the most inhibitory compound. According to a previous study, we learned that reuterin was an antimicrobial produced by L. reuteri—an intermediate in glycerol metabolism to 1,3-Propanediol (Martín-Cabrejas et al., 2017; Asare et al., 2020; Zhang et al., 2020). In addition, reuterin at a dose of 25 μM could inhibit the growth of CRC cell lines (HCT116, SW480, RKO, and DLD1), but a higher concentration of reuterin (100 μM) had no effect on normal colon epithelial cells. In vivo, the authors concluded that L. reuteri was reduced in tumors compared with normal tissues.

Moreover, the authors confirmed this result by using public datasets and patient tissue samples. Based on metabolomics and gene-enriched analysis, it was found that L. reuteri growth was suppressed by the homocysteine degradative metabolites hydrogen sulfide and cystathionine. Lactobacillus reuteri growth could not be altered by supplementing with the antioxidant glutathione ethyl ester, which indicated that the oxidative stress pathway was not specific to L. reuteri. In a bid to explore the concrete mechanism, the authors treated an intestinal cell line with 100 μM reuterin for 24 h. With the help of metabolomics, transcriptomics, and proteomics, the authors observed upregulation of the nuclear factor erythroid 2–related factor 2 (NRF2), which played an essential role in the oxidative stress response. The most enriched pathway focuses on glutathione and glutamate metabolism. Quantification of oxidized L-glutathione confirmed the role reuterin played in oxidative stress. With the subsequent observation that acetylcysteine (NAC) inhibited the induction of NRF2-dependent oxidative stress genes, it was strongly confirmed that reuterin directly controls the redox balance of a cell in a glutathione (GSH)-dependent manner. Creatively, researchers found that sodium sulfide protected cells against reuterin-induced growth inhibition, along with the result that reuterin selectively bound to cysteine residues in numerous biological replicates, indicating the significantly different cysteine proteomics profile of reuterin. The NAD pathway was also involved in the oxidative stress process. Using RNA-sequencing analysis, the puromycin incorporation assay (SUnSET), and a cell inhibition experiment, the authors finally identified the inhibiting ribosomal assembly as an essential cytotoxic pathway of reuterin, in which YEATS2 target genes were found to be downregulated after treatment with reuterin.

Taken together, reuterin was capable of repressing colorectal cancer growth in vivo. This excellent study opened new avenues for researchers. Christina Watschinger and Alexander R. Moschen expressed their distinct opinions on this comprehensive research (Watschinger and Moschen, 2022). The authors further desired to determine how reuterin's selectivity is mediated and the mechanism by which reuterin accumulates in tumor cells outside the gut. All of these outstanding findings can contribute to enhancing the transformation from basic research to clinical application. Along with the experiments on living bacteria and their secrets, Kim et al. (2022) creatively reported the joint function of heat-killed L. reuteri MG5346 and L. casei MG4584 in human CRC. The authors ultimately demonstrated that both of these strains could play an antitumor role through the caspase-9-dependent apoptosis pathway (Figure 2).

Enterotoxigenic Escherichia coli (ETEC) is a leading cause of infectious diarrhea in humans and animals. In the study of Xie et al., the authors creatively developed a new type of L. reuteri—a bovine lactoferricin-lactoferrampin (LFCA)-encoding L. reuteri CO21 (LR-LFCA) and finally demonstrated that LR-LFCA can function in the following three aspects in a newborn ETEC-infected piglet intestine model: (1) it could enhance gut immune responses by improving intestinal barrier function and gut microbiota composition, (2) it was able to protect the gut from oxidative stress by activating the NRF2/HO-1 pathway, and (3) it had the ability to inhibit the NF-κB pathway to perform its anti-inflammatory effect (Xie et al., 2021). Further, Tkáčiková et al. (2020) found that the pretreatment of L. reuteri L26 Biocenol (CCM 8616)-derived bacterial exopolysaccharides (EPSs) can attenuate the overexpression of the genes induced by ETEC infection to suppress inflammatory responses. Human-derived L. reuteri strains (ATCC PTA 6475, DSM 17938, and 1563F), a rat strain (R2LC), and piglet-derived L. reuteri (HCM2 and LR1) were also able to reduce the detrimental effect of ETEC (Karimi et al., 2018; Wang et al., 2018; Yi et al., 2018a). Reuteran and Levan, two metabolites produced by L. reuteri TMW1.656 and L. reuteri LTH5794, respectively, can also reduce the colonization of weanling piglets by ETEC (Yang et al., 2015). As for enteropathogenic E. coli (EPEC), there was evidence suggesting that L. reuteri ATCC PTA 6475 and ATCC 53608 significantly inhibited EPEC by targeting either the epithelium or the mucus layer, depending on the strain's specialty (Walsham et al., 2016). Notably, L. reuteri ATCC PTA 6475 was also effective in suppressing enterohemorrhagic E. coli (EHEC) (Eaton et al., 2011). With respect to Salmonella infections, it was demonstrated that L. reuteri Lb11, isolated from the chicken intestinal tract, can effectively prevent the formation of an efflux pump, inhibiting the production of multidrug-resistant Salmonella enteritidis in eggs (Hai and Huang, 2021). Lactobacillus reuteri KUB-AC5 can also protect against Salmonella infection in chickens (Nakphaichit et al., 2019). Jiang P. et al. (2019) revealed that L. reuteri ATCC 55730 can prevent mice from acquiring Salmonella Typhimurium by activating macrophages to produce nitric oxide. A combination of a phage cocktail and L. reuteri was able to ameliorate mouse colitis caused by S. Typhimurium by improving the intestinal barrier and colonic pathological damage, in which the metabolites of L. reuteri-acetate and reuterin played important roles (Eaton et al., 2011). Remarkably, glycerol supplementation had the ability to enhance L. reuteri ATCC PTA 6475 's protective effect against S. Typhimurium colonization (De Weirdt et al., 2012). Lactobacillus reuteri CCM 8617 and SLZX19-12 were also shown to exert vital impacts on S. Typhimurium (Gancarčíková et al., 2019; Wu et al., 2022). In regard to virus infection, some investigations have already indicated that L. reuteri ATCC 23272 functions as a significant modulator in gnotobiotic pigs infected with human rotavirus, and L. reuteri L26 Biocenol™ plays an essential role in protecting against porcine circovirus type 2 (Azevedo et al., 2012; Karaffová et al., 2017).

A growing number of studies showed that intestinal diseases can cause mounting healthcare bills and economic burdens. It is well-documented that gut microbiota plays an increasingly essential role in the treatment and prognosis of gut diseases. Lactobacillus reuteri is a common and well-studied microbe. Extensive investigations have been conducted in this area. However, we still have numerous unanswered questions. As a gut symbiont, L. reuteri can be colonized in the intestine of humans, rodents, pigs, and chickens and can perform multiple actions, including regulating immune responses, modulating gut microbiota, boosting beneficial metabolites, protecting against oxidative stress, maintaining intestinal barrier (IEB) function and intestinal morphology, and so on (Yi et al., 2018b; Liu et al., 2019; Garg et al., 2020; Singh et al., 2021). In this review, we first elucidated the basic function of L. reuteri and its related metabolites. Next, we systematically interpreted its function in different intestinal diseases, such as inflammatory bowel disease, colorectal cancer, infection-associated bowel disease, and pediatric intestinal disorders. We also emphasized some vital molecules in association with the underlying mechanisms. Cumulatively, L. reuteri is potentially beneficial to intestinal diseases, which should be further investigated in a bid to obtain better clinical application and therapeutic effects.

Although an increasing number of research studies on L. reuteri are well-studied by current researchers, there are still some key issues that are in doubt. First, there is a substantial gap between basic research and clinical applications based on the present literature data, probably owing to the unspecific mechanisms and doubtful safety of this microbe. Safety is an important issue for the wide application of probiotics. Conducting standardized safety assessments and finding effective methods to control the side effects of probiotics may be the future research direction. In addition, the paradoxical results of clinical research also restrict the development of L. reuteri, which may be attributed to the fact that L. reuteri has many distinct strains, and each strain may have its own unique function, for better or worse.

We need to fully evaluate the clinical effect of each strain and the mechanism underlying it. These issues may be addressed with the improvement of industrialized probiotics and experimental techniques. At last, the development of multiple omics analyses, especially metabonomics, allows us to investigate the functions of L. reuteri's metabolites, which may help us thoroughly investigate this field. Based on this, researchers can develop metabolites-targeted probiotic products, contributing to the refinement management of the probiotic industry.

ZY, JC, and YL: writing—original draft and visualization. QM, HL, QY, WS, and XR: conceptualization. XC: conceptualization and writing—review, editing, and supervision. All authors contributed to the article and approved the submitted version.