Protection of beta cells against cytokine‐induced apoptosis by the gut microbial metabolite butyrate

Type 1 diabetes (T1D) is characterized by immune cell infiltration in the islets of Langerhans, leading to the destruction of insulin‐producing beta cells. This destruction is driven by secreted cytokines and cytotoxic T cells inducing apoptosis in beta cells. Butyrate, a metabolite produced by the gut microbiota, has been shown to have various health benefits, including anti‐inflammatory and anti‐diabetic effects. In this study, we investigated the potential protective effects of butyrate on cytokine‐induced apoptosis in beta cells and explored the underlying mechanisms. Insulin‐secreting INS‐1E cells and isolated mouse islets were treated with interleukin‐1beta (IL‐1β) or a combination of IL‐1β and interferon‐gamma (IFN‐γ) in the presence or absence of butyrate. We analyzed apoptosis, nitric oxide (NO) levels, expression of stress‐related genes, and immune cell migration. Our results demonstrated that butyrate significantly attenuated cytokine‐induced apoptosis in both INS‐1E cells and mouse islets, accompanied by a reduction in NO levels. Butyrate also decreased the expression of endoplasmic reticulum (ER) stress markers such as Chop , phosphorylated eIF2α and Atf4 , as well as some pro‐apoptotic genes including Dp5 and Puma . Butyrate reduced the cytokine‐induced expression of the chemokine genes Cxcl1 and Cxcl10 in mouse islets, as well as the chemotactic activity of THP‐1 monocytes toward conditioned media from IL‐1β‐exposed islets. In conclusion, these findings indicate that butyrate protects beta cells from cytokine‐induced apoptosis and ER stress, suggesting its potential as a therapeutic agent to prevent beta cell destruction in T1D.