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.

 

It's interesting as an example of what's possible with enough understanding of the complex interactions in the body. ME can probably be treated or cured by the right chemical delivered to the right cells.