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

Life Sci Alliance. 2020 Feb 10;3(3):e201900481. doi: 10.26508/lsa.201900481. Print 2020 Mar.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Biomarkers
  • Adenylate Kinase