The stress polarity signaling (SPS) pathway serves as a marker and a target in the leaky gut barrier: implications in aging and cancer.

Abstract

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.

• Authors: Pradipta Ghosh, Lee Swanson, Ibrahim M Sayed, Yash Mittal, Blaze B Lim, Stella-Rita Ibeawuchi, Marc Foretz, Benoit Viollet, Debashis Sahoo, Soumita Das
• Journal: Life science alliance (Life Sci Alliance) Vol. 3 Issue 3 (03 2020) ISSN: 2575-1077 [Electronic] United States
• PMID: 32041849 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Ghosh et al.

Chemical References

• Biomarkers
• Adenylate Kinase

Topics

• Adenylate Kinase (metabolism)
• Adult
• Aging (metabolism)
• Animals
• Biomarkers (metabolism)
• Cell Culture Techniques (methods)
• Colon (metabolism)
• Colorectal Neoplasms (metabolism)
• Dysbiosis (immunology)
• Epithelium (immunology, metabolism)
• Female
• Gastrointestinal Microbiome (immunology)
• Humans
• Immune System (metabolism)
• Inflammation (metabolism)
• Intestinal Mucosa (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Signal Transduction
• Stress, Physiological (immunology, physiology)