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Accumulating evidence indicates that gut microorganisms have a pathogenic role in autoimmune diseases, including in multiple sclerosis 1 . Studies of experimental autoimmune encephalomyelitis (an animal model of multiple sclerosis) 2 , 3 , as well as human studies 4 – 6 , have implicated gut microorganisms in the development or severity of multiple sclerosis. However, it remains unclear how gut microorganisms act on the inflammation of extra-intestinal tissues such as the spinal cord. Here we show that two distinct signals from gut microorganisms coordinately activate autoreactive T cells in the small intestine that respond specifically to myelin oligodendrocyte glycoprotein (MOG). After induction of experimental autoimmune encephalomyelitis in mice, MOG-specific CD4 + T cells are observed in the small intestine. Experiments using germ-free mice that were monocolonized with microorganisms from the small intestine demonstrated that a newly isolated strain in the family Erysipelotrichaceae acts similarly to an adjuvant to enhance the responses of T helper 17 cells. Shotgun sequencing of the contents of the small intestine revealed a strain of Lactobacillus reuteri that possesses peptides that potentially mimic MOG. Mice that were co-colonized with these two strains showed experimental autoimmune encephalomyelitis symptoms that were more severe than those of germ-free or monocolonized mice. These data suggest that the synergistic effects that result from the presence of these microorganisms should be considered in the pathogenicity of multiple sclerosis, and that further study of these microorganisms may lead to preventive strategies for this disease. Germ-free mice co-colonized with two bacterial strains from the small intestinal flora showed increased susceptibility to experimental autoimmune encephalomyelitis, implicating the synergistic effects of these microorganisms in this mouse model of multiple sclerosis.

The pathogenesis of multiple sclerosis (MS), an autoimmune disease affecting the brain and spinal cord, remains poorly understood. Patients with MS typically present with recurrent episodes of neurological dysfunctions such as blindness, paresis, and sensory disturbances. Studies on experimental autoimmune encephalomyelitis (EAE) animal models have led to a number of testable hypotheses including a hypothetical role of altered gut microbiota in the development of MS. To investigate whether gut microbiota in patients with MS is altered, we compared the gut microbiota of 20 Japanese patients with relapsing-remitting (RR) MS (MS20) with that of 40 healthy Japanese subjects (HC40) and an additional 18 healthy subjects (HC18). All the HC18 subjects repeatedly provided fecal samples over the course of months (158 samples in total). Analysis of the bacterial 16S ribosomal RNA (rRNA) gene by using a high-throughput culture-independent pyrosequencing method provided evidence of a moderate dysbiosis in the structure of gut microbiota in patients with MS. Furthermore, we found 21 species that showed significant differences in relative abundance between the MS20 and HC40 samples. On comparing MS samples to the 158 longitudinal HC18 samples, the differences were found to be reproducibly significant for most of the species. These taxa comprised primarily of clostridial species belonging to Clostridia clusters XIVa and IV and Bacteroidetes. The phylogenetic tree analysis revealed that none of the clostridial species that were significantly reduced in the gut microbiota of patients with MS overlapped with other spore-forming clostridial species capable of inducing colonic regulatory T cells (Treg), which prevent autoimmunity and allergies; this suggests that many of the clostridial species associated with MS might be distinct from those broadly associated with autoimmune conditions. Correcting the dysbiosis and altered gut microbiota might deserve consideration as a potential strategy for the prevention and treatment of MS.

Obesity is shown in a mouse model of liver cancer to strongly enhance tumorigenesis; a high fat diet alters the composition of intestinal bacteria, leading to more production of the metabolite DCA which, probably together with other factors, induces senescence and the secretion of various senescence-associated cytokines in hepatic stellate cells, thus promoting cancer. Bile acid metabolite links diet and cancer Epidemiological data have demonstrated a link between obesity and cancer. This study shows that in a mouse model of liver cancer, a high-fat diet strongly enhances tumorigenesis by provoking a senescence-associated secretory phenotype (SASP), a recently identified senescent phenotype associated with the secretion of various tumour-promoting factors. Antibiotic and other interventions show that the fatty diet altered the composition of intestinal bacteria leading to more production of deoxycholic acid (DCA), a by-product of microbial bile acid metabolism that is known to cause DNA damage. The authors suggest that DCA, acting with other as-yet unknown factors, induces senescence and the secretion of various senescence-associated cytokines in hepatic stellate cells. These cytokines in turn act to promote the development of liver cancer. These findings highlight the complex mechanistic links between diet, the microbiota and cancer and suggest novel therapeutic approaches. Obesity has become more prevalent in most developed countries over the past few decades, and is increasingly recognized as a major risk factor for several common types of cancer 1 . As the worldwide obesity epidemic has shown no signs of abating 2 , better understanding of the mechanisms underlying obesity-associated cancer is urgently needed. Although several events were proposed to be involved in obesity-associated cancer 1 , 3 , the exact molecular mechanisms that integrate these events have remained largely unclear. Here we show that senescence-associated secretory phenotype (SASP) 4 , 5 has crucial roles in promoting obesity-associated hepatocellular carcinoma (HCC) development in mice. Dietary or genetic obesity induces alterations of gut microbiota, thereby increasing the levels of deoxycholic acid (DCA), a gut bacterial metabolite known to cause DNA damage 6 . The enterohepatic circulation of DCA provokes SASP phenotype in hepatic stellate cells (HSCs) 7 , which in turn secretes various inflammatory and tumour-promoting factors in the liver, thus facilitating HCC development in mice after exposure to chemical carcinogen. Notably, blocking DCA production or reducing gut bacteria efficiently prevents HCC development in obese mice. Similar results were also observed in mice lacking an SASP inducer 8 or depleted of senescent HSCs, indicating that the DCA–SASP axis in HSCs has key roles in obesity-associated HCC development. Moreover, signs of SASP were also observed in the HSCs in the area of HCC arising in patients with non-alcoholic steatohepatitis 3 , indicating that a similar pathway may contribute to at least certain aspects of obesity-associated HCC development in humans as well. These findings provide valuable new insights into the development of obesity-associated cancer and open up new possibilities for its control.

Emerging evidence has suggested a potential impact of gut microbiota on the pathophysiology of heart failure (HF). However, it is still unknown whether HF is associated with dysbiosis in gut microbiota. We investigated the composition of gut microbiota in patients with HF to elucidate whether gut microbial dysbiosis is associated with HF. We performed 16S ribosomal RNA gene sequencing of fecal samples obtained from 12 HF patients and 12 age-matched healthy control (HC) subjects, and analyzed the differences in gut microbiota. We further compared the composition of gut microbiota of 12 HF patients younger than 60 years of age with that of 10 HF patients 60 years of age or older. The composition of gut microbial communities of HF patients was distinct from that of HC subjects in both unweighted and weighted UniFrac analyses. Eubacterium rectale and Dorea longicatena were less abundant in the gut microbiota of HF patients than in that of HC subjects. Compared to younger HF patients, older HF patients had diminished proportions of Bacteroidetes and larger quantities of Proteobacteria. The genus Faecalibacterium was depleted, while Lactobacillus was enriched in the gut microbiota of older HF patients. These results suggest that patients with HF harbor significantly altered gut microbiota, which varies further according to age. New concept of heart-gut axis has a great potential for breakthroughs in the development of novel diagnostic and therapeutic approach for HF.

Intestinal colonization by bacteria of oral origin has been correlated with several negative health outcomes, including inflammatory bowel disease. However, a causal role of oral bacteria ectopically colonizing the intestine remains unclear. Using gnotobiotic techniques, we show that strains of Klebsiella spp. isolated from the salivary microbiota are strong inducers of T helper 1 (TH1) cells when they colonize in the gut. These Klebsiella strains are resistant to multiple antibiotics, tend to colonize when the intestinal microbiota is dysbiotic, and elicit a severe gut inflammation in the context of a genetically susceptible host. Our findings suggest that the oral cavity may serve as a reservoir for potential intestinal pathobionts that can exacerbate intestinal disease.

This study identifies 17 strains of human-derived Clostridia capable of inducing the accumulation and functional maturation of regulatory T cells; it is suggested that these strains may be useful candidates for the future development of oral bacterial therapeutics to treat human inflammatory disorders. Bacterial cocktail settles the stomach Imbalances of the gut microbiota significantly contribute to inflammatory and allergic states, and therefore the manipulation of gut microbes holds promise for treating these immune disorders. This paper reports the isolation of 17 strains of human-derived Clostridia capable of stimulating the immune response by inducing the accumulation and functional maturation of regulatory T cells. Oral administration of a cocktail of these Clostridia attenuates disease in mouse models of colitis and allergic diarrhoea, suggesting that these strains may be candidates for the development of oral bacterial therapeutics to treat inflammatory disorders. Manipulation of the gut microbiota holds great promise for the treatment of inflammatory and allergic diseases 1 , 2 . Although numerous probiotic microorganisms have been identified 3 , there remains a compelling need to discover organisms that elicit more robust therapeutic responses, are compatible with the host, and can affect a specific arm of the host immune system in a well-controlled, physiological manner. Here we use a rational approach to isolate CD4 + FOXP3 + regulatory T (T reg )-cell-inducing bacterial strains from the human indigenous microbiota. Starting with a healthy human faecal sample, a sequence of selection steps was applied to obtain mice colonized with human microbiota enriched in T reg -cell-inducing species. From these mice, we isolated and selected 17 strains of bacteria on the basis of their high potency in enhancing T reg cell abundance and inducing important anti-inflammatory molecules—including interleukin-10 (IL-) and inducible T-cell co-stimulator (ICOS)—in T reg cells upon inoculation into germ-free mice. Genome sequencing revealed that the 17 strains fall within clusters IV, XIVa and XVIII of Clostridia, which lack prominent toxins and virulence factors. The 17 strains act as a community to provide bacterial antigens and a TGF-β-rich environment to help expansion and differentiation of T reg cells. Oral administration of the combination of 17 strains to adult mice attenuated disease in models of colitis and allergic diarrhoea. Use of the isolated strains may allow for tailored therapeutic manipulation of human immune disorders.

Protective effect of probiotic bacteria Bifidobacteria, sometimes used in yoghurts and other food products as 'probiotics', are natural inhabitants of the human gut and are known to protect us from infection. A possible mechanism for at least part of that protective action has now been found in the form of acetate. Oral application of a subtype of Bifidobacterium longum in mice seems to protect them from potentially fatal Escherichia coli O157:H7 by promoting host-defence mechanisms in epithelial cells. Bifidobacteria are natural inhabitants of the human gut and are known to provide protection from infection. It is now shown that certain features of bifidobacterial metabolism that ultimately lead to the production of acetate are involved in this effect. The human gut is colonized with a wide variety of microorganisms, including species, such as those belonging to the bacterial genus Bifidobacterium , that have beneficial effects on human physiology and pathology 1 , 2 , 3 . Among the most distinctive benefits of bifidobacteria are modulation of host defence responses and protection against infectious diseases 4 , 5 , 6 . Nevertheless, the molecular mechanisms underlying these effects have barely been elucidated. To investigate these mechanisms, we used mice associated with certain bifidobacterial strains and a simplified model of lethal infection with enterohaemorrhagic Escherichia coli O157:H7, together with an integrated ‘omics’ approach. Here we show that genes encoding an ATP-binding-cassette-type carbohydrate transporter present in certain bifidobacteria contribute to protecting mice against death induced by E. coli O157:H7. We found that this effect can be attributed, at least in part, to increased production of acetate and that translocation of the E. coli O157:H7 Shiga toxin from the gut lumen to the blood was inhibited. We propose that acetate produced by protective bifidobacteria improves intestinal defence mediated by epithelial cells and thereby protects the host against lethal infection.

Lactobacillus casei, L. paracasei, and L. rhamnosus form a closely related taxonomic group (Lactobacillus casei group) within the facultatively heterofermentative lactobacilli. Here, we report the complete genome sequences of L. paracasei JCM 8130 and L. casei ATCC 393, and the draft genome sequence of L. paracasei COM0101, all of which were isolated from daily products. Furthermore, we re-annotated the genome of L. rhamnosus ATCC 53103 (also known as L. rhamnosus GG), which we have previously reported. We confirmed that ATCC 393 is distinct from other strains previously described as L. paracasei. The core genome of 10 completely sequenced strains of the L. casei group comprised 1,682 protein-coding genes. Although extensive genome-wide synteny was found among the L. casei group, the genomes of ATCC 53103, JCM 8130, and ATCC 393 contained genomic islands compared with L. paracasei ATCC 334. Several genomic islands, including carbohydrate utilization gene clusters, were found at the same loci in the chromosomes of the L. casei group. The spaCBA pilus gene cluster, which was first identified in GG, was also found in other strains of the L. casei group, but several L. paracasei strains including COM0101 contained truncated spaC gene. ATCC 53103 encoded a higher number of proteins involved in carbohydrate utilization compared with intestinal lactobacilli, and extracellular adhesion proteins, several of which are absent in other strains of the L. casei group. In addition to previously fully sequenced L. rhamnosus and L. paracasei strains, the complete genome sequences of L. casei will provide valuable insights into the evolution of the L. casei group.

The objective of this study was to investigate comparatively the influence of proton-pump inhibitors (PPI) administration on three bacterial communities in the oral cavity, stomach, and colon along the alimentary tract. Forty-five subjects including 18 patients taking PPI were enrolled. Stimulated saliva, gastric fluid (GF), and feces were obtained from each subject for the microbiota analysis through bacterial 16S rRNA gene profiling using the pyrosequencing method. The species richness (alpha diversity) was similar among these three microbiota, whereas the interindividual diversity (beta diversity) was much higher in the fecal microbiota compared with that in the others. The UniFrac analysis indicated that the salivary and GF microbiota were similar to one another; however, both differed greatly from the fecal microbiota in the overall bacterial community structure. In the comparison between PPI-users and PPI-nonusers, a bacterial cell number increase of ~1,000 times was found in the GF of PPI-users using culturing methods, whereas the bacterial number and composition were nearly identical between the two groups using quantitative PCR and a similarity search based on 16S profiling. The beta diversity significantly increased in both the salivary and GF microbiota of PPI-users compared with PPI-nonusers. These results suggest that the GF microbiota has recently moved from the saliva. Bacterial overgrowth in the GF by PPI administration may be due to a lack of killing rather than proliferation of the bacteria in the acid-suppressed stomach. The biological significance of the increase in beta diversity by PPI administration remains unclear.

Primary sclerosing cholangitis (PSC) is a liver disease known for its frequent concurrence with inflammatory bowel disease. Dysbiosis of the gut microbiota in PSC was reported in several studies, but the microbiological features of the salivary microbiota in PSC have not been established. Here we compared the salivary microbial communities of 24 pediatric-onset PSC patients, 16 age-matched ulcerative colitis (UC) patients, and 24 healthy controls (HCs) by analyzing the bacterial 16S rRNA gene sequence data. The species-richness (α-diversity) showed no significant between-group differences, whereas the overall salivary microbiota structure (β-diversity) showed significant differences among the three groups. Taxonomic assignment revealed that the PSC salivary microbiota were characterized by significant decreases in the abundance of Rothia and Haemophilus compared to the HC group, and significantly decreased Haemophilus and increased Oribacterium compared to the UC group. By combining the genera selected by the random forest algorithm in machine learning, followed by confirmation with 10-fold cross-validation, we were able to distinguish the PSC group from the HC group with the area under the curve (AUC) of 0.7423, and from the UC group with the AUC of 0.8756. Our results indicate the potential of salivary microbiota as biomarkers for a noninvasive diagnosis of PSC.