Koji Atarashi

Th17 Cell Induction by Adhesion of Microbes to Intestinal Epithelial Cells

Intestinal Th17 cells are induced and accumulate in response to colonization with a subgroup of intestinal microbes such as segmented filamentous bacteria (SFB) and certain extracellular pathogens. Here, we show that adhesion of microbes to intestinal epithelial cells (ECs) is a critical cue for Th17 induction. Upon monocolonization of germ-free mice or rats with SFB indigenous to mice (M-SFB) or rats (R-SFB), M-SFB and R-SFB showed host-specific adhesion to small intestinal ECs, accompanied by host-specific induction of Th17 cells. Citrobacter rodentium and Escherichia coli O157 triggered similar Th17 responses, whereas adhesion-defective mutants of these microbes failed to do so. Moreover, a mixture of 20 bacterial strains, which were selected and isolated from fecal samples of a patient with ulcerative colitis on the basis of their ability to cause a robust induction of Th17 cells in the mouse colon, also exhibited EC-adhesive characteristics.

The microbiota regulates type 2 immunity through RORγt+ T cells

Gut microbes make T cells keep the peace Our guts harbor trillions of microbial inhabitants, some of which regulate the types of immune cells that are present in the gut. For instance, Clostridium species of bacteria induce a type of T cell that promotes tolerance between the host and its microbial contents. Ohnmacht et al. and Sefik et al. characterized a population of gut regulatory T cells in mice, which required gut microbiota to survive. Multiple bacterial species of the microbiota could induce transcription factor–expressing regulatory T cells that helped maintain immune homeostasis. Mice engineered to lack these transcription factors exhibited enhanced susceptibility to colonic inflammation and had elevated amounts of proinflammatory molecules associated with allergies (see the Perspective by Hegazy and Powrie). Science, this issue pp. 989 and 993 Microbes resident in the gut induce an immunoregulatory population of T cells that promote immune homeostasis. [Also see Perspective by Hegazy and Powrie] Changes to the symbiotic microbiota early in life, or the absence of it, can lead to exacerbated type 2 immunity and allergic inflammations. Although it is unclear how the microbiota regulates type 2 immunity, it is a strong inducer of proinflammatory T helper 17 (TH17) cells and regulatory T cells (Tregs) in the intestine. Here, we report that microbiota-induced Tregs express the nuclear hormone receptor RORγt and differentiate along a pathway that also leads to TH17 cells. In the absence of RORγt+ Tregs, TH2-driven defense against helminths is more efficient, whereas TH2-associated pathology is exacerbated. Thus, the microbiota regulates type 2 responses through the induction of type 3 RORγt+ Tregs and TH17 cells and acts as a key factor in balancing immune responses at mucosal surfaces.

Ectopic colonization of oral bacteria in the intestine drives TH1 cell induction and inflammation

Gut reasons to brush your teeth Some gut conditions, such as inflammatory bowel disease (IBD), ulcerative colitis, and Crohns disease (CD), are associated with imbalances in the gut microbe community. The causes of these intractable diseases have been difficult to discern. Atarashi et al. took samples from the mouths of IBD and CD patients and inoculated the extracted bacteria into germ-free mice (see the Perspective by Cao). Some of the inoculated mice showed strong proliferation of T helper 1 cells associated with the establishment of oral Klebsiella species in the colon. Klebsiella can be resistant to multiple antibiotics and are able to replace normal colon microbes after antibiotic therapy. Now we know that they probably originate from the mouth and could potentially contribute to bowel disease. Science, this issue p. 359; see also p. 308 The mouth may act as a reservoir for intestinal disease-causing bacteria. 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.

Clarithromycin expands CD11b+Gr-1+cells via the STAT3/Bv8 axis to ameliorate lethal endotoxic shock and post-influenza bacterial pneumonia

Macrolides are used to treat various inflammatory diseases owing to their immunomodulatory properties; however, little is known about their precise mechanism of action. In this study, we investigated the functional significance of the expansion of myeloid-derived suppressor cell (MDSC)-like CD11b+Gr-1+ cells in response to the macrolide antibiotic clarithromycin (CAM) in mouse models of shock and post-influenza pneumococcal pneumonia as well as in humans. Intraperitoneal administration of CAM markedly expanded splenic and lung CD11b+Gr-1+ cell populations in naïve mice. Notably, CAM pretreatment enhanced survival in a mouse model of lipopolysaccharide (LPS)-induced shock. In addition, adoptive transfer of CAM-treated CD11b+Gr-1+ cells protected mice against LPS-induced lethality via increased IL-10 expression. CAM also improved survival in post-influenza, CAM-resistant pneumococcal pneumonia, with improved lung pathology as well as decreased interferon (IFN)-γ and increased IL-10 levels. Adoptive transfer of CAM-treated CD11b+Gr-1+ cells protected mice from post-influenza pneumococcal pneumonia. Further analysis revealed that the CAM-induced CD11b+Gr-1+ cell expansion was dependent on STAT3-mediated Bv8 production and may be facilitated by the presence of gut commensal microbiota. Lastly, an analysis of peripheral blood obtained from healthy volunteers following oral CAM administration showed a trend toward the expansion of human MDSC-like cells (Lineage−HLA-DR−CD11b+CD33+) with increased arginase 1 mRNA expression. Thus, CAM promoted the expansion of a unique population of immunosuppressive CD11b+Gr-1+ cells essential for the immunomodulatory properties of macrolides.

Clinical impact of pre-transplant gut microbial diversity on outcomes of allogeneic hematopoietic stem cell transplantation

Post-transplant microbial diversity in the gastrointestinal tract is closely associated with clinical outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, little is known about the impact of the fecal microbiota before allo-HSCT. We analyzed fecal samples approximately 2xa0weeks before conditioning among 107 allo-HSCT recipients between 2013 and 2015. Microbial analysis was performed using 16S rRNA gene sequencing. Operational taxonomic unit-based microbial diversity was estimated by calculating the Shannon index. Patients were classified into three groups based on the diversity index: low (<2), intermediate (2, 3), and high (>3) diversity (18 (16.8%), 48 (44.9%), and 41 (38.3%) patients, respectively). There were no significant differences in the 20-month overall survival, cumulative incidence of relapse, and non-relapse mortality among three groups. The cumulative incidence of grade II to IV acute graft-versus-host disease (aGVHD) was similar among the three groups (low 55.6%; intermediate 35.4%; high 48.8%, pxa0=xa00.339, at day 100). Furthermore, we found no differences in the cumulative incidence of grade II to IV acute gastrointestinal GVHD among the three groups (low 38.9%; intermediate 21.3%; high 24.4%, pxa0=xa00.778, at day 100). Regarding the composition of microbiota before allo-HSCT, aGVHD patients showed a significantly higher abundance of phylum Firmicutes (pxa0<xa00.01) and a lower tendency for Bacteroidetes (pxa0=xa00.106) than non-aGVHD patients. Maintenance of Bacteroidetes throughout allo-HSCT may be a strategy to prevent aGVHD.

Control of Intestinal Regulatory T Cells by Human Commensal Bacteria

The human gut harbours diverse bacteria that play a fundamental role in our health and well-being. Recent studies have shown that the gut microbiota plays an important role in the development of the intestinal immune system, and that an altered microbiota composition is associated to some inflammatory diseases. Therefore, the microbiota is increasingly being recognised as a potential therapeutic target in several inflammatory disorders. Here, recent findings are presented on human microbiota-mediated colonic regulatory T (Treg) cell induction. We identified CD4+ FoxP3+ Treg cell-inducing bacteria derived from a healthy human fecal sample. These bacteria included 17 strains belonging to Clostridium cluster IV, XIVa, and XVIII. The 17 strains were found to increase markedly the number of colonic Treg cells and enhance their immunosuppressive capacity. Oral administration of the 17 strains to specific-pathogen–free mice resulted in significant attenuation of intestinal inflammation and allergic diarrhoea, suggesting that the isolated 17 strains may have therapeutic potential in the treatment of immune disorders.