Metformin Exerts Anti-inflammatory and Mucus Barrier Protective Effects by Enriching Akkermansia muciniphila in Mice With Ulcerative Colitis

Abstract

The present study aimed to determine if metformin exerts anti-inflammatory and mucus-protective effects via the gut microbiota. Metformin has extensive benefits including anti-inflammatory effects. Previous studies showed that metformin changed the gut microbiota composition and increases the number of goblet cells. Intestinal dysbiosis and goblet cell depletion are important features of ulcerative colitis (UC). The underlying mechanism and whether metformin can improve the mucus barrier in UC remain unclear. Metformin (400 mg/kg/day) was administered to mice with dextran sulfate sodium (DSS)-induced UC for 2 wk to investigate the effects of metformin on the intestinal mucus barrier. The gut microbiota was depleted, using antibiotics, to explore its role in the mucus-protecting effects of metformin. Akkermansia muciniphila (A. muciniphila), which was enriched in metformin-treated mice, was administered to mice to investigate the effects of the bacteria on UC and the mucus barrier. Metformin attenuated DSS-induced UC in mice, as evidenced by the alleviation of diarrhea, hematochezia, and the decrease in body weight. The expression of mucin2, a prominent mucus barrier protein, was increased in the metformin-treated group compared to the DSS-treated group. Furthermore, fecal 16S rRNA analysis showed that metformin treatment changed the gut microbiota composition by increasing the relative abundance of Lactobacillus and Akkermansia species while decreasing Erysipelatoclostridium at the genus level. Antibiotic treatment partly abolished the anti-inflammatory and mucus-protecting effects of metformin. Administration of A. muciniphila alleviated the colonic inflammation and mucus barrier disruption. Metformin alleviated DSS-induced UC in mice and protected against cell damage via affecting the gut microbiota, thereby providing a new mechanism for the therapeutic effect of metformin in patients with UC. This study also provides evidence that A. muciniphila as a probiotic has potential benefits for UC.

Metformin Protects the Intestinal Barrier by Activating Goblet Cell Maturation and Epithelial Proliferation in Radiation-Induced Enteropathy

“…However, we confirmed that metformin did not directly affect goblet cell maturation under radiation exposure. Others have reported that metformin alleviated DSS-induced colitis by increasing the levels of potential probiotics (e.g., Akkermansia muciniphila ) [ 38 ] and attenuated aging-related leaky gut by modulating the microbiome–goblet cell–mucin axis [ 36 ]. Therefore, metformin-induced goblet cell maturation in a mouse model may be related to microbiome alterations in the irradiated intestine.…”

Diet Supplementation with NUTRIOSE, a Resistant Dextrin, Increases the Abundance of Parabacteroides distasonis in the Human Gut

“…Several strategies to modulate gut microbiota currently exist and more are being developed. Fecal microbiota transplantation, [ 4 ] medication, [ 5 , 6 ] or whole‐diet modification [ 7 , 8 ] can all lead to significant changes in gut microbiota composition. However, implementing these strategies may be challenging or have adverse effects of their own.…”

Anti-Hyperglycemic Agents in the Adjuvant Treatment of Sepsis: Improving Intestinal Barrier Function

“…Ke et al have found that metformin restored intestinal barrier function by increasing the expression of mucin 2 in mice with ulcerative colitis induced by dextran sulfate sodium (DSS). 30 Myosin light-chain kinase (MLCK) is an enzyme activating the myosin light chain (MLC) and participating in cytoskeleton contraction and TJ regulation. Zhu et al have demonstrated that metformin stabilizes TJ proteins and improves intestinal barrier function by inhibiting the MLCK-MLC signaling pathway in Caco-2 cell monolayers.…”