IL-22 Restores Gut Homeostasis and Alleviates Diet-Induced MASLD

In recent years, the incidence of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) has significantly increased, closely related to the widespread consumption of high-energy diets rich in sugars and fats. MASLD is not only closely linked to metabolic diseases such as obesity, insulin resistance, and type 2 diabetes (T2D), but also involves an imbalance in the “gut-liver axis” and defects in specific immune signals. Consequently, researchers have been committed to finding effective treatments. In this paper, Peng Zhang et al. (2024) published a study titled “IL-22 Alleviates Diet-Induced MASLD by Restoring Homeostasis of Intestinal Epithelial Cells’ STAT3” in Cell Metabolism, exploring the mechanism of IL-22 in a diet-induced MASLD model, offering a new perspective for the treatment of this disease.

Research Background

The incidence of MASLD is closely linked to changes in modern dietary habits, particularly high-sugar and high-fat diets, leading to fat accumulation and inflammatory responses in the liver. This pathological process is called the “gut-liver axis,” where microbial metabolites and inflammatory mediators in the gut are transmitted to the liver through the portal vein, triggering inflammation and fibrosis. However, current drug options for MASLD are very limited, with only a few drugs like GLP-1 receptor agonists providing some aid, yet there are no effective treatments for more complex symptoms like liver fibrosis.

Interleukin-22 (IL-22) is an anti-microbial cytokine produced by innate immune cells (such as ILC3 cells) and Th17/22 cells, notable for its barrier-protective role. Research indicates that IL-22 plays a positive role in inhibiting lipid absorption and maintaining gut microbiota balance. However, high-sugar, high-fat diets inhibit the production of IL-22 in the intestine, thereby blocking its STAT3 signaling action on intestinal epithelial cells (IEC), leading to increased fat absorption and further promoting MASLD progression. Building on this foundation, Zhang’s team proposed that exogenous supplementation of the IL-22 signal via recombinant IL-22 protein (IL-22Fc) might effectively reverse diet-induced MASLD.

Research Methods

This research was completed collaboratively by scientists from various institutions, including the University of California, San Diego, and the University of Texas MD Anderson Cancer Center. They designed several experimental procedures, including constructing animal models, conducting histopathological analyses, and studying molecular signals, to thoroughly reveal the mechanism of IL-22 in the treatment of MASLD. The specific methods are as follows:

1. Model Construction: The research team used two different dietary models to simulate human diet-induced MASLD. One was a high-fat diet (HFD), where 60% of the calories came from fat, 25% from carbohydrates, and 15% from protein, along with a 30% fructose beverage; the other was a Western diet (WD), including 40.1% fat, 44.4% carbohydrates, and 0.2% cholesterol, also supplemented with 30% fructose.

2. Detection of IL-22 Signaling Pathway: Through IL-22Fc treatment, the team examined the activation of the IL-22 receptor (IL-22Ra1) and STAT3 phosphorylation signaling pathway in intestinal epithelial cells, and evaluated its therapeutic effects on MASLD. Furthermore, to validate the specific action of IL-22 signaling, they employed model mice with specific knockouts of the IL-22Ra1 gene to separately analyze the signal transduction in liver cells and IECs.

3. Analysis of Intestinal Absorption Function: By detecting the expression of fat and sugar absorption proteins (such as CD36, GLUT2, FATP2), the study explored how IL-22Fc reversed the enhancement of lipid and sugar absorption induced by a high-fat diet, using in vivo molecular analysis to further investigate changes in gut homeostasis and barrier integrity.

4. Study of Gut Microbial Diversity: Researchers performed 16S sequencing analysis to explore the impact of IL-22 on gut microbiota, further analyzing whether it alleviates MASLD by regulating the microbiome.

Research Results

This study obtained significant findings in multiple experimental steps, confirming the therapeutic effect of IL-22 on MASLD and elucidating its specific action mechanism:

1. Significant Alleviation of MASLD by IL-22: The study showed that exogenous supplementation of IL-22Fc significantly reduced liver fat accumulation, inflammation, and fibrosis in mice on HFD and WD diet models. IL-22Fc also significantly lowered serum insulin, endotoxin, and liver injury markers ALT and AST levels. Moreover, IL-22Fc treatment reduced food intake in mice and inhibited weight gain.

2. IL-22 Signaling Dependent on STAT3 Activation in Intestinal Epithelial Cells: Through using IL-22Ra1 or STAT3 knockout mouse models, the study found that the therapeutic effect of IL-22Fc mainly relies on IL-22’s action in intestinal epithelial cells (IEC), with no significant effect observed in liver cells. This indicates that IL-22’s therapeutic effect primarily occurs by regulating gut homeostasis rather than directly acting on the liver, thereby alleviating MASLD.

3. Inhibition of Intestinal Absorption Proteins: In the small intestine, IL-22Fc inhibited the expression of various lipid and sugar absorption-related proteins, including CD36, FATP2, GLUT2, by activating the STAT3 signal, thereby reducing the intestinal absorption of lipids and sugars and lowering liver lipid deposition.

4. Restoration of Gut Barrier Function and Microbial Diversity: IL-22Fc treatment restored the integrity of the gut barrier and improved the diversity of gut microbiota to some extent, significantly reducing gut permeability. This effect persisted even in germ-free mouse models, indicating that IL-22’s action in the gut is not entirely dependent on the presence of the microbiome.

5. IL-22Fc Inhibits Differentiation and Maturity of Intestinal Epithelial Cells: Single-cell RNA sequencing results showed that IL-22Fc reversed the excessive expansion of mature absorptive cells in the small intestine induced by HFD and promoted the expansion of intestinal epithelial progenitor cells, effectively restoring cellular homeostasis in the gut. This discovery further confirmed the critical role of IL-22Fc in maintaining gut homeostasis.

Conclusion and Significance

The findings of this study demonstrate the potential of IL-22Fc in treating MASLD. IL-22 alleviates liver fat deposition, inflammation, and fibrosis indirectly by restoring STAT3 signaling in intestinal epithelial cells, regulating lipid and sugar absorption, and restoring gut homeostasis. The discovery of this mechanism offers new therapeutic targets for MASLD, emphasizing restoring gut homeostasis as a strategy to alleviate liver lesions indirectly.

Highlights of the study include revealing the key role of the IL-22 signaling pathway in intestinal epithelial cells, confirming that the gut, rather than the liver, is the primary target of IL-22 treatment for MASLD, and proposing the potential role of restoring gut barrier and microbial diversity in treating MASLD. Exogenous supplementation of IL-22 is considered an effective therapeutic approach for MASLD with potential clinical application value.

Regarding future applications, the authors suggest that future research could explore the development of IEC-selective IL-22 receptor agonists, which may exhibit effects similar to GLP-1 receptor agonists in the treatment of obesity and MASLD. Additionally, future human studies will further verify whether IL-22 has similar effects on MASLD and obesity.

Limitations of the Study

Though the study confirmed the efficacy of IL-22 in mouse models, it has yet to be verified in humans and lacks the corresponding clinical samples to validate the impact of diet on IL-22 and IL-17a levels in humans. Moreover, the study did not explicitly reveal the specific mechanisms by which energy-intensive diets inhibit IL-22 and STAT3 signaling; hence, the therapeutic potential of IL-22 needs further exploration through more comprehensive studies.