PT - JOURNAL ARTICLE AU - Pradipta Ghosh AU - Lee Swanson AU - Ibrahim M Sayed AU - Yash Mittal AU - Blaze B Lim AU - Stella-Rita Ibeawuchi AU - Marc Foretz AU - Benoit Viollet AU - Debashis Sahoo AU - Soumita Das TI - The stress polarity signaling (SPS) pathway serves as a marker and a target in the leaky gut barrier: implications in aging and cancer AID - 10.26508/lsa.201900481 DP - 2020 Mar 01 TA - Life Science Alliance PG - e201900481 VI - 3 IP - 3 4099 - https://www.life-science-alliance.org/content/3/3/e201900481.short 4100 - https://www.life-science-alliance.org/content/3/3/e201900481.full SO - Life Sci. Alliance2020 Mar 01; 3 AB - The gut barrier separates trillions of microbes from the largest immune system in the body; when compromised, a “leaky” gut barrier fuels systemic inflammation, which hastens the progression of chronic diseases. Strategies to detect and repair the leaky gut barrier remain urgent and unmet needs. Recently, a stress-polarity signaling (SPS) pathway has been described in which the metabolic sensor, AMP-kinase acts via its effector, GIV (also known as Girdin) to augment epithelial polarity exclusively under energetic stress and suppresses tumor formation. Using murine and human colon-derived organoids, and enteroid-derived monolayers (EDMs) that are exposed to stressors, we reveal that the SPS-pathway is active in the intestinal epithelium and requires a catalytically active AMP-kinase. Its pharmacologic augmentation resists stress-induced collapse of the epithelium when challenged with microbes or microbial products. In addition, the SPS-pathway is suppressed in the aging gut, and its reactivation in enteroid-derived monolayers reverses aging-associated inflammation and loss of barrier function. It is also silenced during progression of colorectal cancers. These findings reveal the importance of the SPS-pathway in the gut and highlights its therapeutic potential for treating gut barrier dysfunction in aging, cancer, and dysbiosis.