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

Abstract

Radiotherapy or accidental exposure to high-dose radiation can cause severe damage to healthy organs. The gastrointestinal (GI) tract is a radiation-sensitive organ of the body. The intestinal barrier is the first line of defense in the GI tract, and consists of mucus secreted by goblet cells and a monolayer of epithelium. Intestinal stem cells (ISCs) help in barrier maintenance and intestinal function after injury by regulating efficient regeneration of the epithelium. The Wnt/β-catenin pathway plays a critical role in maintaining the intestinal epithelium and regulates ISC self-renewal. Metformin is the most widely used antidiabetic drug in clinical practice, and its anti-inflammatory, antioxidative, and antiapoptotic effects have also been widely studied. In this study, we investigated whether metformin alleviated radiation-induced enteropathy by focusing on its role in protecting the epithelial barrier. We found that metformin alleviated radiation-induced enteropathy, with increased villi length and crypt numbers, and restored the intestinal barrier function in the irradiated intestine. In a radiation-induced enteropathy mouse model, metformin treatment increased tight-junction expression in the epithelium and inhibited bacterial translocation to mesenteric lymph nodes. Metformin increased the number of ISCs from radiation toxicity and enhanced epithelial repair by activating Wnt/β-catenin signaling. These data suggested that metformin may be a potential therapeutic agent for radiation-induced enteropathy.

Combined Administration of Pravastatin and Metformin Attenuates Acute Radiation-Induced Intestinal Injury in Mouse and Minipig Models

“…Impaired intestinal stem cells by radiation retard epithelial cell proliferation and regeneration of the intestine [ 34 , 35 ]. In our previous study, we found that MF treatment promoted stem cell properties and increased epithelial proliferation [ 21 ]. Therefore, we assessed the epithelial proliferation capacity and intestinal stem cell ability in the combined PS and MF treatment under radiation exposure.…”

“…The protective effects of MF on radiation-induced GI damage have been previously reported [ 17 , 19 , 20 ]. We also identified the stem cell preservative effects of MF in a radiation-induced intestinal injury mouse model [ 21 ]. However, a single therapy with PS or MF did not show survival effects in lethal dose irradiation in our data.…”

“…The pathology of lethal GI tract damage is mainly involved in the depletion of the pool of intestinal stem cells, which impairs the regeneration of the villi-crypt structure and intestinal function [ 34 , 35 ]. MF was previously shown to mitigate radiation-induced enteropathy by promoting stem cell properties and epithelial proliferation in a mouse model and an ex vivo system [ 21 ]. In this study, we also identified that MF activated stem cell properties and alleviated radiation-induced intestinal injury in mice and minipig models.…”

“…Although many studies have confirmed that MF is effective for radiation-induced injury, most studies have focused on protective purposes rather than the mitigating effects. Nevertheless, in our previous study, we found that MF mitigated radiation-induced enteropathy by promoting stem cell properties [ 21 ].…”

Bacteroides fragilis strain ZY-312 promotes intestinal barrier integrity via upregulating the STAT3 pathway in a radiation-induced intestinal injury mouse model

“…At the bottom of crypts, intestinal stem cells (ISCs) differentiate into goblet cells and promote epithelial regeneration against radiation-induced intestinal injury ( 46 ). It has been reported that the mucus secreted from goblet cells performs an important role in radiation-induced intestinal injury ( 47 ). While at the top of crypts, the most important intercellular tight junction is mainly composed of claudin and ZO-1, which exert a vital role in sustaining cell polarity and the intestinal epithelial barrier ( 48 , 49 ).…”