Lycium barbarum polysaccharide alleviates DSS-induced chronic ulcerative colitis by restoring intestinal barrier function and modulating gut microbiota.

PURPOSE: This study examined the protective effects and mechanism of Lycium barbarum polysaccharides (LBP) in the context of intestinal barrier function and intestinal microbiota in mice with dextran sulfate sodium (DSS)-induced chronic ulcerative colitis (UC). METHODS: C57BL/6J male mice were assigned to a standard normal diet without DSS (control group), a normal diet with DSS (DSS group, 2% DSS given discontinuously for 3 weeks) or a normal diet supplemented with LBP (1% dry feed weight, LBP group, 2% DSS given discontinuously for 3 weeks) for a total of 8 weeks, at which point colonic tissues and caecal contents were collected. RESULTS: LBP exerted a significant effect against colitis by increasing body weight, colon length, DAI and histopathological scores. LBP inhibited proinflammatory cytokines (IL-1ß, IL-6, iNOS and TNF-α) expression, improved anti-inflammatory cytokine (IL-10) expression, promoted the expression of tight junction proteins (Occludin and ZO-1) via nuclear factor erythroid 2-related factor 2 (Nrf2) activation and decreased Claudin-2 expression to maintain the intestinal mucosal barrier. In addition, the abundances of some probiotics (Ruminococcaceae, Lactobacillus, Butyricicoccus, and Akkermansia) were decreased with DSS treatment but increased obviously with LBP treatment. And LBP reduced the abundance of conditional pathogens associated with UC (Mucispirillum and Sutterella). Furthermore, LBP improved the production of short-chain fatty acids (SCFAs), including acetic acid, propionic acid, butyric acid and isobutyric acid. CONCLUSION: LBP can alleviate DSS-induced UC by regulating inflammatory cytokines and tight junction proteins. Moreover, LBP promotes probiotics, suppresses conditional pathogens and increases SCFAs production, showing a strong prebiotic effect.

MiR-1-3p and MiR-124-3p Synergistically Damage the Intestinal Barrier in the Ageing Colon.

BACKGROUND AND AIMS: Disruption of the intestinal barrier of the digestive tract is a common pathophysiological change in the elderly, which may partly contribute to gut dysfunction and inflammatory bowel disease [IBD]. This study aimed to discover new interactive epigenetic regulation patterns involved in intestinal barrier dysfunction and colitis in elderly populations. METHODS: Intestinal barrier function and structure were evaluated in naturally ageing mice and elderly people. High-throughput analysis was performed on colonic tissues from humans and mice. The synergistic roles of miR-1-3p and miR-124-3p were identified using microRNA mimic/agomirs. Related genes were examined in biopsies of old IBD patients. RESULTS: A defective mucus barrier was observed before mucosal microstructural damage during ageing. Elevated miR-1-3p expression in the colons of older individuals impaired the mucus barrier by directly targeting T-synthase, similarly to the mechanism of miR-124-3p, which we reported previously. Importantly, the synergistic effect of a half dose of each microRNA supplement on T-synthase and CDK4/6 was stronger than that of a full dose of miR-1-3p or miR-124-3p alone, and mice co-treated with two microRNAs showed greater susceptibility to chemical-induced colitis than mice treated with either microRNA alone. These two microRNAs were up-expressed in old IBD patients. CONCLUSIONS: The slight increases in miR-1-3p and miR-124-3p expression with ageing may be important contributors to the breakdown of intestinal homeostasis by targeting divergent genes in different cells. These data reveal the potential ability of multiple microRNAs to exert synergistic effects to damage the intestinal barrier and promote inflammatory bowel disease development in elderly populations.

Elevated miR-124-3p in the aging colon disrupts mucus barrier and increases susceptibility to colitis by targeting T-synthase.

The risk of colitis and colorectal cancer increases markedly throughout adult life, endangering the health and lives of elderly individuals. Previous studies have proposed that bacterial translocation and infection are the main risk factors for these diseases. Therefore, in the present study, we aimed to identify the underlying mechanism by focusing on the mucus barrier function and mucin-type O-glycosylation. We evaluated alterations in the colon mucus layer in 2-, 16-, and 24-month-old mice and aged humans. Aged colons showed defective intestinal mucosal barrier and changed mucus properties. The miR-124-3p expression level was significantly increased in the aged distal colonic mucosa, which was accompanied by an increase in pathogens and bacterial translocation. Meanwhile, T-synthase, the rate-limiting enzyme in O-glycosylation, displayed an age-related decline in protein expression. Further experiments indicated that miR-124-3p modulated O-glycosylation by directly targeting T-synthase. Moreover, young mice overexpressing miR-124-3p exhibited abnormal glycosylation, early-onset, and more severe colitis. These data suggest that miR-124-3p predisposes to senile colitis by reducing T-synthase, and the miR-124-3p/T-synthase/O-glycans axis plays an essential role in maintaining the physiochemical properties of colonic mucus and intestinal homeostasis.