NLRP3 inflammasome is known to be involved in inflammatory bowel diseases. However, it is controversial whether it is pathogenic or beneficial. This study evaluated the roles of NLRP3 inflammasome in the pathogenesis of inflammatory bowel disease in IL-10^-/- mice and humans. NLRP3 inflammasome in colonic mucosa, macrophages, and colonic epithelial cells were analysed by western blotting. The NLRP3 inflammasome components were studied by sucrose density gradient fractionation, chemical cross-linking, and co-immunoprecipitation. The role of NLPR3 inflammasome in the pathogenesis of colitis was extensively evaluated in IL-10^-/- mice, using a specific NLPR3 inflammasome inhibitor glyburide. NLRP3 inflammasome was upregulated in colonic mucosa of both IL-10^-/- mice and Crohn’s patients. NLRP3 inflammasome activity in IL-10^-/- mice was elevated prior to colitis onset; it progressively increased as disease worsened and peaked as macroscopic disease emerged. NLRP3 inflammasome was found in both intestinal epithelial cells and colonic macrophages, as a large complex with a molecular weight of ≥ 360 kDa in size. In the absence of IL-10, NLRP3 inflammasome was spontaneously active and more robustly responsive when activated by LPS and nigericin. Glyburide markedly suppressed NLRP3 inflammasome expression/activation in IL-10^-/- mice, leading to not only alleviation of ongoing colitis but also prevention/delay of disease onset. Glyburide also effectively inhibited the release of proinflammatory cytokines/chemokines by mucosal explants from Crohn’s patients. Abnormal activation of NLRP3 inflammasome plays a major pathogenic role in the development of chronic colitis in IL-10^-/- mice and humans. Glyburide, an FDA-approved drug, may have great potential in the management of inflammatory bowel diseases.

The alterations induced in gut microbiota by tacrolimus may affect immune function and organ transplantation. Mice were treated with high‐dose tacrolimus for 14 days. The fecal microbiota were analyzed by pyrosequencing the 16S rRNA genes, and the effect on metabolism was predicted using the sequence data. The subgroups of T cells in the serum, gut‐associated lymphoid tissue, and draining lymph nodes were determined by flow cytometry. Tacrolimus treatment significantly altered the relative abundance of Allobaculum, Bacteroides, and Lactobacillus and CD4⁺CD25^hiFoxP3⁺ regulatory T cells in the colonic mucosa and the circulation. These were significantly increased after either tacrolimus treatment or treatment by fecal microbiota transfer from tacrolimus‐treated donors. Further, treatment with low‐dose tacrolimus plus fecal microbiota transfer from high‐dose tacrolimus–altered mice increased skin allograft survival rate in a skin transplantation model. Thus, high‐dose tacrolimus alters the compositions and taxa of the gut microbiota. Administration of these conditioned gut microbiota plus low‐dose tacrolimus resulted in regulation of colonic and systemic immune responses and an increased allograft survival rate. This study demonstrated a new strategy for controlling allograft rejection by combining an immunosuppressive agent with gut microbiome transplantation.

OBJECTIVES: Severe acute pancreatitis (SAP) is still a big challenge. Accumulated data showed that overexpression of cyclooxygenase-2 (COX-2) in acute pancreatitis and experimental pancreatitis could be attenuated with COX-2 inhibitors. This study was aimed to evaluate whether the occurrence of SAP could be prevented by selective COX-2 inhibitors. METHODS: A total of 190 patients with predicted SAP were randomized into convention group or convention plus COX-2 inhibitors (C+COX-2-Is) group. Besides conventional treatment to all patients in 2 groups, parecoxib (40 mg/d intravenous injection for 3 days) and celecoxib (200 mg oral or tube feeding twice daily for 7 days) were sequentially administrated to the patients in the C+COX-2-Is group. The primary outcome was predefined as the occurrence of SAP. The serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) for all of the patients were measured. RESULTS: The occurrence of SAP in the C+COX-2-Is group was decreased 47.08% compared with the convention group, 21.05% (20/95) vs 39.78% (37/93), P = 0.005. A reduction of late local complications was also shown in the C+COX-2-Is group, 18.95% (18/93) vs 34.41% (32/95), P = 0.016. The serum levels of IL-6 and TNF-α were significantly lower in the C+COX-2-Is group than those in the convention group, P < 0.05. Parecoxib relieved abdominal pain more rapidly and decreased the consumption of meperidine. An incremental reduction of cost for 1% decrease of SAP occurrence was RMB475. DISCUSSION: Sequential administration of parecoxib and celecoxib in patients with predicted SAP obtained about half-reduction of SAP occurrence through decreasing serum levels of TNF-α and IL-6. This regimen presented good cost-effectiveness.

Approximately, 33.6% of nondiabetic solid organ transplantation recipients who received tacrolimus developed hyperglycemia. Whether the tacrolimus‐induced gut microbiota is involved in the regulation of hyperglycemia has not been reported. Hyperglycemia was observed in a tacrolimus‐treated mouse model, with reduction in taxonomic abundance of butyrate‐producing bacteria and decreased butyric acid concentration in the cecum. This tacrolimus‐induced glucose metabolic disorder was caused by the gut microbiota, as confirmed by a broad‐spectrum antibiotic model. Furthermore, oral supplementation with butyrate, whether for remedy or prevention, significantly increased the butyric acid content in the cecum and arrested hyperglycemia through regulation of glucose‐regulating hormones, including GLP‐1, PYY and insulin, in serum. The butyrate‐GRP43‐GLP‐1 pathway in the intestine crypts may involve in the pathogenesis of normalization of hyperglycemia caused by the tacrolimus. Therefore, tacrolimus affects glucose metabolism through the butyrate‐associated GLP‐1 pathway in the gut, and oral supplementation with butyrate provides new insights for the prevention and treatment of tacrolimus‐induced hyperglycemia in transplant recipients.

The effect of low‐FODMAPs diet on irritable bowel syndrome (IBS) in Western China has not been reported. We aimed to investigate the effect of low‐FODMAPs diet on IBS patients in the area and whether low‐FODMAPs diet‐induced alterations of microbiota could be improved through probiotics. IBS patients were randomized to the control group, low‐FODMAPs diet group, probiotics group, or combined group. IBS Symptom Severity Score questionnaire (IBS‐SSS) and IBS Quality of Life Score questionnaire (IBS‐QOL) were completed at baseline, 2 and 4 weeks to evaluate the severity of symptoms. Fresh feces were collected for analyses of gut microbiota and short‐chain fatty acids at baseline and 4 weeks after intervention. Seventy‐three patients were included in the per protocol analysis. After intervention, there was significant improvement in IBS‐SSS in the low‐FODMAPs group (37.5%, 44.2%), probiotics group (51.4%, 62.0%), and combined group (34.1%, 40.4%) at both 2 weeks and 4 weeks, compared with the baseline (p < .05). In the low‐FODMAPs group, the abundance of several microbiota (Lachnoclostridium, Enterococcus, etc.) was significantly decreased. Furthermore, after the supplementation of probiotics in the combined group, the abundance of Genus_Ruminococcus, Coprococcus, Acidaminococcus, Ruminiclostridium, Akkermansia, Eggerthella, and Oxalobacter was significantly increased, which was associated with the improvements of symptoms score in the Pearson correlation analysis. Our study confirmed the effectiveness and safety of short‐term low‐FODMAPs diet in IBS symptoms based on the Chinese diet in Western China. The combination of low‐FODMAPs and probiotics plays a beneficial role in gut microbiota in IBS.