Randy S. Longman

Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis

Rheumatoid arthritis (RA) is a prevalent systemic autoimmune disease, caused by a combination of genetic and environmental factors. Animal models suggest a role for intestinal bacteria in supporting the systemic immune response required for joint inflammation. Here we performed 16S sequencing on 114 stool samples from rheumatoid arthritis patients and controls, and shotgun sequencing on a subset of 44 such samples. We identified the presence of Prevotella copri as strongly correlated with disease in new-onset untreated rheumatoid arthritis (NORA) patients. Increases in Prevotella abundance correlated with a reduction in Bacteroides and a loss of reportedly beneficial microbes in NORA subjects. We also identified unique Prevotella genes that correlated with disease. Further, colonization of mice revealed the ability of P. copri to dominate the intestinal microbiota and resulted in an increased sensitivity to chemically induced colitis. This work identifies a potential role for P. copri in the pathogenesis of RA. DOI: http://dx.doi.org/10.7554/eLife.01202.001

Microbiota restricts trafficking of bacteria to mesenteric lymph nodes by CX 3 CR1 hi cells

The intestinal microbiota has a critical role in immune system and metabolic homeostasis, but it must be tolerated by the host to avoid inflammatory responses that can damage the epithelial barrier separating the host from the luminal contents. Breakdown of this regulation and the resulting inappropriate immune response to commensals are thought to lead to the development of inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis. We proposed that the intestinal immune system is instructed by the microbiota to limit responses to luminal antigens. Here we demonstrate in mice that, at steady state, the microbiota inhibits the transport of both commensal and pathogenic bacteria from the lumen to a key immune inductive site, the mesenteric lymph nodes (MLNs). However, in the absence of Myd88 or under conditions of antibiotic-induced dysbiosis, non-invasive bacteria were trafficked to the MLNs in a CCR7-dependent manner, and induced both T-cell responses and IgA production. Trafficking was carried out by CX3CR1hi mononuclear phagocytes, an intestinal-cell population previously reported to be non-migratory. These findings define a central role for commensals in regulating the migration to the MLNs of CX3CR1hi mononuclear phagocytes endowed with the ability to capture luminal bacteria, thereby compartmentalizing the intestinal immune response to avoid inflammation.

CX3CR1+ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22

Intestinal CX3CR1+ mononuclear phagocytes regulate ILC3 in vivo in response to colitis associated microbial signals.

Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring

Maternal immune activation (MIA) contributes to behavioural abnormalities associated with neurodevelopmental disorders in both primate and rodent offspring. In humans, epidemiological studies suggest that exposure of fetuses to maternal inflammation increases the likelihood of developing autism spectrum disorder. In pregnant mice, interleukin-17a (IL-17a) produced by T helper 17 (TH17) cells (CD4+ T helper effector cells involved in multiple inflammatory conditions) induces behavioural and cortical abnormalities in the offspring exposed to MIA. However, it is unclear whether other maternal factors are required to promote MIA-associated phenotypes. Moreover, the underlying mechanisms by which MIA leads to T cell activation with increased IL-17a in the maternal circulation are not well understood. Here we show that MIA phenotypes in offspring require maternal intestinal bacteria that promote TH17 cell differentiation. Pregnant mice that had been colonized with mouse commensal segmented filamentous bacteria or human commensal bacteria that induce intestinal TH17 cells were more likely to produce offspring with MIA-associated abnormalities. We also show that small intestine dendritic cells from pregnant, but not from non-pregnant, females secrete IL-1β, IL-23 and IL-6 and stimulate T cells to produce IL-17a upon exposure to MIA. Overall, our data suggest that defined gut commensal bacteria with a propensity to induce TH17 cells may increase the risk of neurodevelopmental disorders in the offspring of pregnant mothers undergoing immune system activation owing to infections or autoinflammatory syndromes.

Regulation of inflammation by microbiota interactions with the host.

The study of the intestinal microbiota has begun to shift from cataloging individual members of the commensal community to understanding their contributions to the physiology of the host organism in health and disease. Here, we review the effects of the microbiome on innate and adaptive immunological players from epithelial cells and antigen-presenting cells to innate lymphoid cells and regulatory T cells. We discuss recent studies that have identified diverse microbiota-derived bioactive molecules and their effects on inflammation within the intestine and distally at sites as anatomically remote as the brain. Finally, we highlight new insights into how the microbiome influences the host response to infection, vaccination and cancer, as well as susceptibility to autoimmune and neurodegenerative disorders.

IgA-coated E. coli enriched in Crohn's disease spondyloarthritis promote TH17-dependent inflammation.

IgA-reactive E. coli in Crohn’s disease–associated spondyloarthritis link mucosal immunity and systemic inflammation. Pathosymbiont perturbation of immune homeostasis The influence of the gut microbiome extends beyond the intestines and can modulate many host systems. A subset of Crohn’s disease patients also experience painful spondyloarthritis, and Viladomiu et al. discovered that the immune systems of these patients are more likely to recognize a certain kind of Escherichia coli. As colonization with this bacterium induced systemic TH17 immunity and worsened development of colitis and arthritis in mouse models, this pathosymbiont may be causing a systemic TH17-driven inflammation that leads to extraintestinal complications in Crohn’s disease patients, such as stiffness and spinal pain. Precise targeting of these types of bacteria or reversing the TH17 phenotype they induce could bring relief to patients. Peripheral spondyloarthritis (SpA) is a common extraintestinal manifestation in patients with active inflammatory bowel disease (IBD) characterized by inflammatory enthesitis, dactylitis, or synovitis of nonaxial joints. However, a mechanistic understanding of the link between intestinal inflammation and SpA has yet to emerge. We evaluated and functionally characterized the fecal microbiome of IBD patients with or without peripheral SpA. Coupling the sorting of immunoglobulin A (IgA)–coated microbiota with 16S ribosomal RNA–based analysis (IgA-seq) revealed a selective enrichment in IgA-coated Escherichia coli in patients with Crohn’s disease–associated SpA (CD-SpA) compared to CD alone. E. coli isolates from CD-SpA–derived IgA-coated bacteria were similar in genotype and phenotype to an adherent-invasive E. coli (AIEC) pathotype. In comparison to non-AIEC E. coli, colonization of germ-free mice with CD-SpA E. coli isolates induced T helper 17 cell (TH17) mucosal immunity, which required the virulence-associated metabolic enzyme propanediol dehydratase (pduC). Modeling the increase in mucosal and systemic TH17 immunity we observed in CD-SpA patients, colonization of interleukin-10–deficient or K/BxN mice with CD-SpA–derived E. coli lead to more severe colitis or inflammatory arthritis, respectively. Collectively, these data reveal the power of IgA-seq to identify immunoreactive resident pathosymbionts that link mucosal and systemic TH17-dependent inflammation and offer microbial and immunophenotype stratification of CD-SpA that may guide medical and biologic therapy.

Microbiota: Host Interactions in Mucosal Homeostasis and Systemic Autoimmunity

The vertebrate intestinal tract is colonized by hundreds of species of bacteria that must be compartmentalized and tolerated to prevent invasive growth and harmful inflammatory responses. Signaling initiated by commensal bacteria shapes antigen-specific mucosal and systemic adaptive immunity. A distinct type of effector CD4(+) T cells, Th17 cells, have a key role in coordinating the inflammatory immune responses that afford protection to pathogens at the mucosal interface. Balancing this powerful inflammatory response, regulatory T cells limit collateral damage and provide antigen-specific tolerance to both food and microbial antigens. Here, we discuss the implications for how the microbiota as a whole contributes to compartmentalization from the host and how individual constituents of the microbiota influence the functions and repertoire of effector T cells and organ-specific autoimmune disease.

The functional impact of the intestinal microbiome on mucosal immunity and systemic autoimmunity.

Purpose of reviewThis review will highlight recent advances functionally linking the gut microbiome with mucosal and systemic immune cell activation underlying autoimmunity. Recent findingsDynamic interactions between the gut microbiome and environmental cues (including diet and medicines) shape the effector potential of the microbial organ. Key bacteria and viruses have emerged that, in defined microenvironments, play a critical role in regulating effector lymphocyte functions. The coordinated interactions between these different microbial kingdoms — including bacteria, helminths, and viruses (termed transkingdom interactions) — play a key role in shaping immunity. Emerging strategies to identify immunologically relevant microbes with the potential to regulate immune cell functions both at mucosal sites and systemically will likely define diagnostic and therapeutic targets. SummaryThe microbiome constitutes a critical microbial organ with coordinated interactions that shape host immunity.

Vedolizumab and Infliximab Combination Therapy in the Treatment of Crohn’s Disease

To the Editor: A 43-year-old man diagnosed with ileocolic Crohn’s disease (CD) at 19 years of age was evaluated in our offi ce. His course was complicated by an ileocolic resection in 2009 and treatment failures with 6-mercaptopurine, methotrexate, adalimumab, and certolizumab. He received infl iximab for 4 years, currently at a dose of 5 mg/kg every 4 weeks, and delayed release mesalamine. At the time of his infl iximab infusion he reported increasing diarrheal episodes with associated blood. Sigmoidoscopy revealed moderateto severe-ulcerated mucosa and exudates ( Figure 1a ). Given ongoing symptoms vedolizumab was initiated and infl iximab was discontinued ~5 weeks aft er his last infusion. Repeat sigmoidoscopy, 4 days aft er receiving vedolizumab, revealed minimal colonic ulcerations and an improved vascular pattern ( Figure 1b ). He reported 2–3 formed bowel movements daily with less urgency. Approximately 7 weeks aft er his last infl iximab infusion, and 10 days aft er starting vedolizumab, he developed erythema nodosum (EN). He received his ferent MSA patterns was observed, probably owing to small sample size. Neither a signifi cant association was detected with no extra hepatic autoimmune disease. We studied aft erwards an independent control group with hypertransaminasemia (>2s.d.) by IIF ( n =123). We observed that 8% ( n =10) showed anti-MSA autoAb vs. the 1.43% described overall. Not previously described, anti-MSA autoAb were associated with a high prevalence of hypertransaminasemia in two independent cohorts. Th ese preliminary fi ndings point to the possibility to identify a subgroup of hepatopathy patients with up to 75% with a cholestatic profi le, with autoimmune alterations. Further studies with wider samples’ number and followup design should be performed to warrant the clinical relevance of our preliminary results.

Esophagitis dissecans superficialis

c t g w m h e a e A 59-year-old woman was evaluated for dysphagia and odynophagia. She had undergone double lung transplantation 3 months earlier for hypersensitivity pneumonitis complicated by respiratory failure. At the time of endoscopy, her immunosuppressive medications consisted of tacrolimus, azathioprine, and prednisone. In addition to her immunosuppression regimen, she was taking an oral bisphosphonate (risedronate). Before transplant, she experienced long-standing, mild reflux symptoms, but after transplant she developed ine