Resident microbiota activates regulatory cells that modulate intestinal inflammation and promote and maintain intestinal homeostasis. IL-10 is a key mediator of immune regulatory function. Our studies describe the functional importance and mechanisms by which gut microbiota and specific microbial components influence the development of intestinal IL-10–producing B cells. Using fecal transplant into germ-free (GF) Il10^+/EGFP reporter and Il10^–/– mice, we demonstrated that microbiota from specific pathogen–free mice primarily stimulated IL-10–producing colon-specific B cells and T regulatory 1 cells in ex-GF mice. IL-10 in turn downregulated microbiota-activated mucosal inflammatory cytokines. TLR2 and -9 ligands and enteric bacterial lysates preferentially induced IL-10 production and the regulatory capacity of intestinal B cells. Analysis of Il10^+/EGFP mice crossed with additional gene-deficient strains and B cell cotransfer studies demonstrated that microbiota-induced IL-10–producing intestinal B cells ameliorated chronic T cell–mediated colitis in a TLR2-, MyD88-, and PI3K-dependent fashion. In vitro studies implicated downstream signaling of PI3Kp110δ and AKT. These studies demonstrated that resident enteric bacteria activated intestinal IL-10–producing B cells through TLR2, MyD88, and PI3K pathways. These B cells reduced colonic T cell activation and maintained mucosal homeostasis in response to intestinal microbiota.

Short-chain fatty acids (SCFAs) play a pivotal role in maintaining intestinal homeostasis. We aimed to investigate the effects of SCFA supplementation on gut inflammation and microbiota composition in a murine colitis model. Mice were fed with sodium butyrate or a mixture of SCFAs in the drinking water for 2 weeks, followed by 2% dextran sulfate sodium (DSS) for 7 d. After euthanasia, mouse colons were extracted to examine histological findings. Flow cytometry of the mouse colon tissues was performed to assess T cell differentiation. Changes in gut microbiota were assessed by high-throughput sequencing of the mouse feces. There were no significant differences in weight change, colonic length, or histologic inflammation score between the DSS, butyrate, and SCFA mix groups. However, flow cytometry revealed that both the expression of CD4+Foxp3+ regulatory T cells and of IL-17-producing T cells were increased in the butyrate and SCFA mix groups. Microbial compositions of the butyrate and SCFA mix groups were significantly different from those of the control and DSS groups in principal coordinate analysis. Relative abundances of the phyla Verrucomicrobia and Proteobacteria, species Akkermansia muciniphila and Escherichia fergusonii were increased in the butyrate and SCFA mix groups. Genera Roseburia and Lactobacillus showed a negative correlation with the degree of colitis, whereas genera Escherichia and Mucispirillum showed a positive correlation. SCFA supplementation did not result in a significant reduction in colon inflammation, but it promoted both regulatory T cell and IL-17-producing T cell expression, and increased both protective and aggressive gut microbiota.

Youngouk Ro, Chang Soo Eun, Hyun Soo Kim, Ji Yeoun Kim, Young Jae Byun, Kyo-Sang Yoo, and Dong Soo Han. Gut and Liver 2016;10:581-6. https://doi.org/10.5009/gnl15324

Inflammatory bowel disease (IBD) refers to a group of disorders, including Crohn’s disease and ulcerative colitis, that exhibit similar but distinct manifestations. These diseases are characterized by refractory and chronic inflammation of the bowel. IBD is usually accompanied by severe symptoms. When a patient presents with suspected IBD, physicians encounter various challenges in terms of diagnosis and treatment. In addition, given such characteristics, the associated medical expenses gradually increase. Although IBD was formerly known as a disease of Western countries, the incidence and prevalence are increasing in Korea. Korean investigators have accumulated a great deal of knowledge about the regional characteristics and epidemiology of the disease, especially via well-organized, joint cohort studies. Against this background, this article describes the epidemiology of IBD in Korea compared to that in the West. In addition, an overview of the pathophysiology of the disease is provided, focusing on the latest results.

The gut microbiota has been implicated in the development of colitis-associated cancer (CAC). We investigated how the gut microbiota affects the development of CAC when the composition of the microbial community is altered by the administration of various antibiotics in a murine model. C57BL/6 mice were given intraperitoneal injection of 12.5 mg/kg azoxymethane (AOM), followed by two rounds of 2.0 % dextran sodium sulfate (DSS) exposure. Antibiotics, including ampicillin, neomycin, metronidazole, and/or vancomycin, were administered 14 days prior to AOM injection until the end of the experiment. High-throughput sequencing of mice feces was conducted to evaluate alterations of the gut microbiota. Tumorigenesis and inflammation were most markedly suppressed in the mice treated with an antibiotic cocktail therapy consisting of ampicillin, neomycin, metronidazole, and vancomycin. Individual antibiotic treatments had different effects on tumorigenesis and inflammation. Metronidazole attenuated both tumorigenesis and inflammation. Neomycin suppressed tumorigenesis but did not alleviate inflammation. Ampicillin and vancomycin did not significantly attenuate either tumorigenesis or inflammation. Antimicrobial therapy differentially altered the diversity and composition of the gut microbiota depending on antibiotic type. The phyla Proteobacteria and Tenericutes were positively correlated with tumor burden. Colon tumorigenesis was attenuated through various antibiotics in the AOM/DSS-induced CAC model. Individual antibiotics differentially altered the gut microbial composition and showed different effects on tumor suppression; however, the degree of tumor suppression was less pronounced than that relative to the antibiotic cocktail therapy, suggesting that the global gut microbial community plays an important role in the development of CAC.

Background/Aims: Infliximab (IFX) has proven effective as rescue therapy in steroid-refractory acute severe ulcerative colitis (ASUC), however, the long-term real-world data are scarce. Our study aimed to assess the long-term treatment outcomes of IFX in a real-life cohort.Methods: We established a multicenter retrospective cohort of hospitalized patients with ASUC, who met Truelove and Witt’s criteria and received intravenous corticosteroid (IVCS) or IFX during index hospitalization between 2006 and 2016 in 5 university hospitals in Korea. The cohort was systematically followed up until colectomy, death or last follow-up visit.Results: A total of 296 patients were followed up for a mean of 68.9 ± 44.0 months. During index hospitalization, 49 patients were treated with IFX; as rescue therapy for IVCS failure in 37 and as first-line medical therapy for ASUC in 12. All patients treated with IFX avoided colectomy during index hospitalization. The cumulative rates of rehospitalization and colectomy were 20.4% and 6.1% at 3 months and 39.6% and 18.8% at the end of follow-up, respectively. Patients treated with IFX presented with significantly shorter colectomy-free survival than IVCS responders (P= 0.04, log-rank test). Both cytomegalovirus colitis and Clostridioides difficile infection (CDI) were the significant predictors of colectomy in the overall study cohort (hazard ratios of 6.57 and 4.61, respectively). There were no fatalities.Conclusions: Our real-world cohort study demonstrated that IFX is an effective therapeutic option in Korean patients with ASUC, irrespective of IFX indication. Aggressive vigilance for cytomegalovirus colitis and CDI is warranted for hospitalized patients with ASUC.