IL-22 resolves MASLD via enterocyte STAT3 restoration of diet-perturbed intestinal homeostasis (Zhang+, 2024)

IL-22 resolves MASLD via enterocyte STAT3 restoration of diet-perturbed intestinal homeostasis
Peng Zhang 1 , Junlai Liu 1 , Allen Lee 1 , Irene Tsaur 1 , Masafumi Ohira 1 , Vivian Duong 1 , Nicholas Vo 1 , Kosuke Watari 1 , Hua Su 1 , Ju Youn Kim 1 , Li Gu 1 , Mandy Zhu 1 , Shabnam Shalapour 2 , Mojgan Hosseini 3 , Gautam Bandyopadhyay 4 , Suling Zeng 5 , Cristina Llorente 5 , Haoqi Nina Zhao 6 , Santosh Lamichhane 7 , Siddharth Mohan 6 , Pieter C Dorrestein 6 , Jerrold M Olefsky 4 , Bernd Schnabl 5 , Pejman Soroosh 8 , Michael Karin 9
Affiliations

• PMID: 39317186
• DOI: 10.1016/j.cmet.2024.08.012

Abstract
The exponential rise in metabolic dysfunction-associated steatotic liver disease (MASLD) parallels the ever-increasing consumption of energy-dense diets, underscoring the need for effective MASLD-resolving drugs.

MASLD pathogenesis is linked to obesity, diabetes, "gut-liver axis" alterations, and defective interleukin-22 (IL-22) signaling. Although barrier-protective IL-22 blunts diet-induced metabolic alterations, inhibits lipid intake, and reverses microbial dysbiosis, obesogenic diets rapidly suppress its production by small intestine-localized innate lymphocytes.

This results in STAT3 inhibition in intestinal epithelial cells (IECs) and expansion of the absorptive enterocyte compartment. These MASLD-sustaining aberrations were reversed by administration of recombinant IL-22, which resolved hepatosteatosis, inflammation, fibrosis, and insulin resistance.

Exogenous IL-22 exerted its therapeutic effects through its IEC receptor, rather than hepatocytes, activating STAT3 and inhibiting WNT-β-catenin signaling to shrink the absorptive enterocyte compartment. By reversing diet-reinforced macronutrient absorption, the main source of liver lipids, IL-22 signaling restoration represents a potentially effective interception of dietary obesity and MASLD.

 

I'm sharing this because it's an example of a metabolic issue with a barrier component. And involves STAT singalling, which I know the stanford people are investigating. It's also quite hopeful because they seem to be onto a fix with IL-22.

The applicability of this to me/cfs is completely unknown to me, probably zero. I'd be interested in anyone's views.