Background: Previous studies implicated matrix metalloproteinases (MMPs), such as MMP-7, in inflammatory bowel diseases (IBD) by showing increased activity during inflammation of the gut. However, the pathophysiological roles of MMP-7 have not been clearly elucidated.Methods: The expression of MMP-7 was assessed in colonic biopsies of patients with ulcerative colitis (UC), in rodents with experimental colitis, and in cell-based assays with cytokines. Wild-type and MMP-7-null mice treated with dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid were used for determining the pro-inflammatory function(s) of MMP-7 in vivo.Results: MMP-7 was highly expressed in patients with UC and in rodents with experimental colitis. IL-1β, IL-4, IL-13, TNFα, or lipopolysaccharide enhanced MMP-7 expression in human colonic epithelial cells, rat colonic smooth muscle cells, and THP-1-derived macrophages. Active MMP-7 degraded tight junction protein Claudin-7 in epithelial cells, cleaved recombinant Claudin-7 in cell-free system, and increased Caco-2 monolayer permeability. Immunostaining of colon biopsies revealed up-regulation of MMP-7 and reduction of Claudin-7 in UC patients. Compared to wild-type mice, Mmp7^-/- mice had significantly less inflammation in the colon upon DSS insult. DSS-induced alterations in junction proteins were mitigated in Mmp7^-/- mice, suggesting that MMP-7 disrupts the intestinal barrier. MMP-7 antibody significantly ameliorated colonic inflammation and Claudin-7 reduction in 2 different rodent models of colitis.Summary: MMP-7 impairs intestinal epithelial barrier by cleavage of Claudin-7, and thus aggravating inflammation. These studies uncovered Claudin-7 as a novel substrate of MMP-7 in the intestinal epithelium and reinforced MMP-7 as a potential therapeutic target for IBD.

This study aims to elucidate the relationships between gut microbiota, bile acid metabolism, and psychological comorbidity in Crohn's disease (CD). We profiled the fecal microbiota composition and quantified the bile acid pool of 39 CD patients and 14 healthy controls using 16S rRNA gene sequencing and liquid chromatography–tandem mass spectrometry, respectively. Significant reductions in the secondary bile acids, LCA and DCA, were found in both the feces and serum samples of CD patients, while the concentration of 7‐DHCA was particularly higher in the serum of CD patients with psychological disorders. The fecal levels of HDCA and 12‐DHCA of the CD patients were inversely correlated with their Self‐Rated Depression Scale (SDS) scores, whereas the serum level of 7‐DHCA was positively correlated with the SDS scores. In addition, the fecal levels of TDCA, TLCA, and TβMCA showed a positive correlation with the Self‐Rated Anxiety Scale (SAS) scores. The fecal microbiota biodiversity was particularly declined in CD patients with psychological disorders. An enrichment of Ruminococcus gnavus in CD patients may cause psychological disorders by affecting the microbiota–gut–brain axis via its ability to degrade the gut barrier, regulate the tryptophan–kynurenine metabolism, and modulate bile acid metabolism. In addition, the overabundant Enterobacteriaceae and Lachnospiraceae in CD patients may contribute to psychological comorbidity via dysregulating their bile acids metabolism. Taken together, changes in the gut microbiota composition may cooperate with alterations in the bile acid metabolism that are involved in the development of psychological disorders in CD.

Background: A low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols diet (LFD) is claimed to improve functional gastrointestinal symptoms (FGSs). However, the role of LFD in inflammatory bowel disease (IBD) patients with FGSs remains unclear. Objective: To systematically assess the efficacy of LFD in IBD patients with FGSs. Methods: Six databases were searched from inception to 1 January 2022. Data were synthesized as the relative risk of symptoms improvement and normal stool consistency, mean difference of Bristol Stool Form Scale (BSFS), Short IBD Questionnaire (SIBDQ), IBS Quality of Life (IBS-QoL), Harvey-Bradshaw index (HBi), Mayo score, and fecal calprotectin (FC). Risk of bias was assessed based on study types. A funnel plot and Egger’s test were used to analyze publication bias. Results: This review screened and included nine eligible studies, including four randomized controlled trials (RCTs) and five before–after studies, involving a total of 446 participants (351 patients with LFD vs. 95 controls). LFD alleviated overall FGSs (RR: 0.47, 95% CI: 0.33–0.66, p = 0.0000) and obtained higher SIBDQ scores (MD = 11.24, 95% CI 6.61 to 15.87, p = 0.0000) and lower HBi score of Crohn’s disease (MD = −1.09, 95% CI −1.77 to −0.42, p = 0.002). However, there were no statistically significant differences in normal stool consistency, BSFS, IBS-QoL, Mayo score of ulcerative colitis, and FC. No publication bias was found. Conclusions: LFD provides a benefit in FGSs and QoL but not for improving stool consistency and mucosal inflammation in IBD patients. Further well-designed RCTs are needed to develop the optimal LFD strategy for IBD.

Cholangiocytes play a crucial role in bile formation. Cholangiocyte injury causes cholestasis, including primary biliary cholangitis (PBC). However, the etiology of PBC remains unclear despite being characterized as an autoimmune disease. Using single-cell RNA sequencing (scRNA-seq), fluorescence-activated-cell-sorting, multiplex immunofluorescence (IF) and RNAscope analyses, we identified unique DUOX2⁺ACE2⁺ small cholangiocytes in human and mouse livers. Their selective decrease in PBC patients was associated with the severity of disease. Moreover, proteomics, scRNA-seq, and qPCR analyses indicated that polymeric immunoglobulin receptor (pIgR) was highly expressed in DUOX2⁺ACE2⁺ cholangiocytes. Serum anti-pIgR autoantibody levels were significantly increased in PBC patients, regardless of positive and negative AMA-M2. Spatial transcriptomics and multiplex IF revealed that CD27⁺ memory B and plasma cells accumulated in the hepatic portal tracts of PBC patients. Collectively, DUOX2⁺ACE2⁺ small cholangiocytes are pathogenic targets in PBC, and preservation of DUOX2⁺ACE2⁺ cholangiocytes and targeting anti-pIgR autoantibodies may be valuable strategies for therapeutic interventions in PBC.