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Benefits of L. Reuteri

Lactobacillus reuteri (L. reuteri) is a well-studied probiotic bacterium that can colonize a large number of mammals. In humans, L. reuteri is found in different body sites, including the gastrointestinal tract, urinary tract, skin, and breast milk. Several beneficial effects of L. reuteri have been noted. 

• L. reuteri can produce antimicrobial moleculesd due to its antimicrobial activity, L. reuteri is able to inhibit the colonization of pathogenic microbes and remodel the commensal microbiota composition in the host. 
• L. reuteri can benefit the host immune system. Some L. reuteri strains can reduce the production of pro-inflammatory cytokines while promoting regulatory T cell development and function. 
• L. reuteri has the ability to strengthen the intestinal barrier, the colonization of L. reuteri may decrease the microbial translocation from the gut lumen to the tissues. Direct supplementation or prebiotic modulation of L. reuteri may be an attractive preventive and/or therapeutic avenue against inflammatory diseases.
• Improve histamine response
• Prevent and attenuate colitis
• Production of vitamins including B 12
• Form EPS (exopolysaccharides)
•  Immune modulatory

Production of Metabolites With Health-Promoting Effect

The antimicrobial and immunomodulatory effects of L. reuteri strains are linked to their metabolite production profile such as Reuterin

Reuterin

Most L. reuteri strains of human and poultry lineage are able to produce and excrete reuterin, a well-known antimicrobial compound. Reuterin and other metabolites in L. Reuteri are anti bacterial, anti fungal and anti viral.

Histamine

A few strains of L. reuteri are able to convert the amino acid L-histidine, a dietary component, to the biogenic amine histamine. A human commensal bacterium, L. reuteri 6475 was used as the model strain for studying histamine in L. reuteri, L. reuteri 6475-derived histamine suppressed tumor necrosis factor (TNF) production from stimulated human monocytes. The same group of researchers also found that oral administration of hdc+ L. reuteri could effectively suppress intestinal inflammation in a trinitrobenzene sulfonic acid (TNBS)-induced mouse colitis model in 2015. Intraperitoneal injection of L. reuteri 6475 culture supernatant to TNBS-treated mice resulted in similar colitis attenuation. These results strongly indicate the involvement of L. reuteri metabolites, including histamine, in intestinal immunomodulation. Further investigations showed  reduced TNF inhibition in vitro and diminished anti-inflammatory function in vivo. Both the in vitro TNF suppression and the in vivo anti-colitis effects appear to be regulated by a gene named folC2. Inactivation of the gene resulted in diminished histamine production. Histamine production by L. reuteri is highly strain-dependent, and most studies have been focused on strains of human origin.

Production of Vitamins

Vitamins

There are 13 essential vitamins for humans due to the inability of the human body to synthesize them. Like many other Lactobacillus spp., several L. reuteri strains are able to produce different types of vitamins, including vitamin B12 (cobalamin) and B9 (folate). B12 is vital in reuterin production because the reduction of glycerol to 3-HPA requires a B12-dependent coenzyme. At least 4 L. reuteri strains with various origins have been found to produce B12. Among these strains, L. reuteri CRL1098 and L. reuteri JCM1112 are the most studied. In one study, the administration of L. reuteri CRL1098 together with a diet lacking vitamin B12 was shown to ameliorate pathologies in B12-deficient pregnant female mice and their offspring. This clearly points to the potential application of L. reuteri in treating B12 deficiency. In addition to B12, folate can also be synthesized by some specific L. reuteri strains, including L. reuteri 6475 and L. reuteri JCM1112.

Exopolysaccharide (EPS)

The EPS produced by L. reuteri is important for biofilm formation and adherence of L. reuteri to epithelial surfaces. EPS synthesized by L. reuteri is able to inhibit E. coli adhesion to epithelial cells in vitro. EPS-mediated blocking of adhesion also suppresses gene expression of pro-inflammatory cytokines that are induced by E. coli infection, including IL-1β and IL-6. Further in vivo experiments showed similar results in that EPS originated from L. reuteri prevented diarrhea in bacterial infection by reducing the adhesion of E. coli. In addition, EPS of L. reuteri origin has been reported to suppress the binding of enterotoxigenic E. coli to erythrocytes. EPS produced by rodent L. reuteri 100-23 was also demonstrated to induce Foxp3+ regulatory T (Treg) cells in the spleen. In contrast, an L. reuteri 100-23 strain with the ftf mutation that eliminates EPS production from L. reuteri did not induce splenic Treg cells. This suggests that EPS is required for the L. reuteri-mediated induction of Treg cells and indicates the potential of using wild-type L. reuteri 100-23 to treat Treg deficiency.

L. reuteri-Mediated Modulation of Host Microbiota

Emerging evidence suggests that the host microbiota and immune system interact to maintain tissue homeostasis in healthy individuals. Many diseases have been associated with perturbation of the microbiota, whereas restoration of the microbiota has been demonstrated to prevent or ameliorate several diseases. L. reuteri is able to influence the diversity, composition and metabolic function of the gut, oral, and vaginal microbiotas. These effects are largely strain-specific.

Gut Microbiota

Studies have shown the modulatory effects of L. reuteri on the microbiotas of rodents, piglets, and humans. One study assessed oral administration of a human-origin L. reuteri strain (DSM17938) to scurfy mice, which have gut microbial dysbiosis due to the foxp3 gene mutation. The results indicated that this strain of L. reuteri was able to prolong the lifespan of the mice and reduce multi-organ inflammation while remodeling the gut microbiota. Changes of gut microbiota included increases in the phylum Firmicutes and the genera Lactobacillus and Oscilospira. Notably, the disease-ameliorating effect of L. reuteri was attributed to the remodeled gut microbiota, though the community composition was still distinct from wild-type littermates. Further investigation showed that inosine production was enhanced by the gut microbiota upon L. reuteri administration. Through adenosine A2A receptor engagement, inosine can reduce Th1/Th2 cells and their associated cytokines. These results suggested that the L. reuteri – gut microbiota – inosine – adenosine A2A receptor axis serves as a potential therapeutic method for Treg-deficient disorders. Moreover, oral L. reuteri 6475 treatment led to a higher diversity of microbiota in both jejunum and ileum in an ovariectomy-induced bone loss mouse model. Specifically, there were more abundant Clostridiales but less Bacteriodales. However, whether or not the changed gut microbiota was directly associated with the prevention of bone loss requires further investigation. Furthermore, L. reuteri C10-2-1 has been shown to modulate the diversity of gut microbiota in the ileum of rats.

Compared to vaginally delivered infants, Cesarean (C)-section delivered infants display a higher abundance of Enterobacter but less Bifidobacterium in their gut microbiota. In one study, treating C-section babies with L. reuteri DSM 17938 from 2 weeks to 4 months of age modulated the development of gut microbiota toward the community pattern found in vaginally delivered infants. The gut microbiota structure of vaginally born infants remained unaltered upon L. reuteri supplementation. In another study, treating infants with the same L. reuteri strain resulted in decreased anaerobic Gram-negative and increased Gram-positive bacterial counts in gut microbiota, whereas the abundances of Enterobacteriaceae and Enterococci were largely lowered by L. reuteri treatment. The differences in infant age, duration of treatment, route of administration, and dosage may explain the differences in results from the two studies.

For human adults, L. reuteri NCIMB 30242 administered as delayed release capsules for 4 weeks was able to increase the ratio of Firmicutes to Bacteroidetes in healthy individuals. This strain of L. reuteri is known to be able to activate bile salt hydrolase and its effect in increasing circulating bile acid has been reported. The upregulation of circulating bile acid has been proposed as a reason for the modulated gut microbiota.

Oral Microbiota

The phyla Firmicutes, Bacteroidetes, Fusobacteria, Proteobacteria, and Actinobacteria are most abundant in the human oral microbiome. In a randomized controlled trial, 12 weeks of daily consumption of two L. reuteri strains – DSM 17938 and PTA 5289 led to a shift in oral microbiota composition, though the bacterial species richness was not altered. The alterations disappeared 4 weeks after the treatments were terminated, suggesting the fast turnover of the oral microbiome. 

Vaginal Microbiota

Lactobacilli dominate the vaginal bacterial community in healthy women. One study showed that only 14 days of oral L. reuteri RC-14 administration could restore the normal vaginal flora in postmenopausal women. The relative abundance of Lactobacilli is largely decreased in bacterial vaginosis patients.

Role of L. reuteri in Immunomodulation

Lactobacillus reuteri is able to increase free secretory IgA (sIgA) levels in rats. However, the up regulation of sIgA was eliminated in vitamin A-deficient rats, suggesting that L. reuteri functions in a vitamin A-dependent manner. Whether L. reuteri affects IgA levels by directly regulating B cells requires further investigations.

Many studies have shown that L. reuteri can induce anti-inflammatory Treg cells, which likely contributes to the beneficial effects of L. reuteri in a wide range of diseased and non-diseased conditions. The Treg-inducing property of L. reuteri is largely strain-dependent. However, the anti-inflammatory effect of L. reuteri does not always rely on the induction of Treg cells. A good example is L. reuteri-mediated suppression of Th1/Th2 responses in Treg-deficient mice. Certain L. reuteri strains are able to reduce the production of many pro-inflammatory cytokines. For example, L. reuteri GMNL-263 can reduce serum MCP-1, TNF, and IL-6 levels in mice fed with high fat diet. Similar effects were observed in mice treated with heat-killed GMNL-263. However, in some cases, the immunomodulatory effects of L. reuteri appear to rely on its metabolites, as the culture supernatant of L. reuteri BM36301 could reduce TNF production from human myeloid THP-1 cells. Tryptophan catabolites of L. reuteri have been recognized as ligands for aryl hydrocarbon receptor (AhR) which through activation L. reuteri can promote local IL-22 production from innate lymphoid cells. In addition, the derivatives of tryptophan generated by L. reuteri can induce the development of regulatory CD4+CD8αα+ double-positive intraepithelial lymphocytes in an AhR-dependent manner. Considering that AhR is ubiquitously expressed, L. reuteri and its metabolites may be able to influence many more types of immune cells beyond ILCs and T cells.

L. reuteri Attenuate Human Diseases

A growing body of evidences links microbiota and bacterial translocation with multiple diseases, including several autoimmune disorders. Due to its strong modulatory effects on host microbiota and immune responses with almost no safety concerns, L. reuteri is a good candidate for disease prevention and/or treatment. Indeed, the therapeutic potential of various L. reuteri strains has been studied in diverse diseases and the results are promising in many cases.

Early-Life Disorders

Taking advantage of the safety and tolerance of L. reuteri in infants and young children, a lot of efforts have been made to test the potential application of L. reuteri against disorders early in life. In general, the results are promising. L. reuteri has been demonstrated beneficial in the prevention and/or treatment of many conditions including diarrhea, functional abdominal pain, caries, atopic dermatitis, allergy, feeding intolerance, and regurgitation. Infant colic, for example, has been the major therapeutic target of L. reuteri. Infant colic is characterized by immoderate crying and affects 10–30% infants, the exact cause and efficient treatment of this condition have remained elusive. The clinical efficacy of L. reuteri DSM 17938 has been demonstrated as most of the clinical trials were successful. It is worth mentioning that L. reuteri is naturally contained in human breast milk, though inconsistencies exist among individuals. The presence of L. reuteri in milk may complicate the results of studies that involved breastfeeding. 

Systemic Lupus Erythematosus

The SLE is a multi-system autoimmune disease that involves both genetics and environment as the major disease causative factors. The role of gut microbiota in SLE development was suggested by recent studies, and probiotics have been proposed as potential immuno regulators in SLE. The study reported a significantly decreased level of Lactobacillaceae in lupus-prone MRL/lpr female mice compared to healthy control mice both before and after the disease initiated in MRL/lpr mice. Moreover, researchers found that treatment with retinoic acid improved kidney disease in MRL/lpr mice, and that the improvement of lupus symptoms was associated with restoration of Lactobacilli. This suggests a possible beneficial effect of Lactobacilli in lupus. They treated MRL/lpr mice with a mixture of five strains of Lactobacilli to determine their therapeutic benefit. As anticipated, increasing Lactobacilli in the gut improved renal function, reduced serum autoantibodies, and prolonged the survival of MRL/lpr mice. Interestingly, L. reuteri and an uncultured Lactobacillus sp. accounted for > 99% of the observed effects. It suggests a central role of L. reuteri in attenuating lupus nephritis. Furthermore, we found that MRL/lpr mice had a “leaky” gut during disease progression, whereas Lactobacillus treatment enhanced the intestinal barrier function in these mice and subsequently decreased metabolic endotoxemia. At the same time, the local and systemic pro- and anti-inflammatory network was rebalanced by Lactobacillus treatment. Specifically, IL-10 production was enhanced while the level of IL-6 was decreased systemically. Strikingly, the benefits of Lactobacilli were only observed in females and castrated males but not in intact males. Coincidently, the relative abundance of Lactobacilli in gut microbiota did not decrease as disease progressed in male MRL/lpr mice. Consistent with  observations, daily consumption of L. reuteri BM36301 significantly lowered serum TNF level in females but not in males. The high serum level of testosterone in males may have led to the difference in the response to L. reuteri. Together, these results suggest possible interaction between sex hormones and gut microbiota in autoimmune disease development. Further investigation of this link is required. In another lupus mouse model, NZB/W F1, the administration of two L. reuteri strains, together with one L. paracasei strain, was shown to be effective in ameliorating lupus hepatitis. Liver abnormalities, manifested as increased liver enzymes, portal inflammation and histopathological changes, have been observed in both lupus mouse models and SLE patients. In this study, the oral L. reuteri treatment largely mitigated hepatic apoptosis and inflammation, suggesting a protective function of L. reuteri against lupus-associated liver disease. The protection seems to rely on the capability of L. reuteri to increase antioxidant activity and reduce cytokines associated with more severe lupus, such as IL-6 and TNF. Interestingly, within these two L. reuteri strains, only GMNL-263 can significantly promote the differentiation of Treg cells, again emphasizing the uneven immunoregulatory abilities of different L. reuteri strains.

Obesity

The correlation between gut microbiota and obesity is well documented. The microbiota composition varies between lean and obese individuals, and a surprisingly high level of Lactobacillus spp. has been found in the microbiota of both obese adults and obese children. Among different Lactobacillus spp., L. reuteri was specifically described to be associated with obesity. The association was further established when vancomycin-resistant L. reuteri in gut microbiota was determined as a body weight gain predictor during vancomycin treatment. However, in a randomized, double-blind and placebo-controlled clinical trial, the administration of L. reuteri JBD301 for 12 weeks significantly reduced body weight in overweight adults. Moreover, supplementation of infant formula with L. reuteri did not increase weight gain in infants. These conflicting results indicate that L. reuteri may influence the development of obesity in a strain-dependent manner. 

Neurodevelopmental Disorder

Exposure to maternal obesity in utero increases the chance of neurodevelopmental disorders, such as autism spectrum disorder, in children. In a recent mouse study, maternal HFD (MHFD) was shown to induce social deficits in the offspring. The impaired social ability in GF mice was restored by fecal microbiota transplantation from offspring with maternal regular diet (MRD) but not MHFD, suggesting a potential role of microbiota in this process. Further analysis showed that the abundance of L. reuteri was reduced more than ninefold in the gut microbiome of MHFD vs. MRD offspring. The social defects in MHFD offspring were rescued by direct L. reuteri administration, suggesting an effect of L. reuteri in regulating neurodevelopment in MHFD mice. This regulatory function of L. reuteri was attributed to its capability to increase the level of oxytocin. The results of these studies suggest a potential application of L. reuteri in the treatment of patients who suffer from neurodevelopmental disorders.

Stressor Exposure and Enteric Infection

The composition of gut microbiota shift when the host is exposed to stressors. Analysis showed stressor-induced reductions in the families Porphyromonadaceae and Lactobacillaceae, especially in the genus Lactobacillus. The beneficial effect of L. reuteri on stressor exposure and subsequent enteric infection is not microbiota-dependent.

Conclusion

There has been a decrease in the abundance of L. reuteri in humans in the past few decades likely caused by the modern lifestyle (Antibiotic use, western diet, improved hygiene). Such decrease coincides with higher incidences of inflammatory diseases over the same period of time. While evidence is lacking to establish the correlation, it may be helpful to increase L. reuteri colonization and/or facilitate its probiotic functions as a new and relatively safe strategy against inflammatory diseases. In addition, through direct regulation or indirect modulation via the host microbiota, L. reuteri plays an impressive role in eliminating infections and attenuating both GI diseases and diseases in remote tissues. The safety and tolerance of L. reuteri has been proven by the numerous clinical studies. There are multiple L. reuteri strains with different host origins, and many of the probiotic functions of L. reuteri are strain-dependent. Therefore, it may be advantageous to combine different strains of L. reuteri to maximize their beneficial effects.

Source:

Role of Lactobacillus reuteri in Human Health and Diseases