A Type 2 Immune Circuit in the Stomach Controls Mammalian Adaptation to Dietary Chitin

Ingestion of dietary fiber has been linked to decreased risk of metabolic disorders like obesity, and type 2 immune activation has been shown to promote metabolic homeostasis. Nevertheless, the relationship between fiber digestion, host immunity, and metabolism has not been well explored. The purpose of this study was to investigate how the digestion of a specific fiber, chitin (β−1,4-poly-N-acetylglucosamine), which is found in arthropods and fungi, affects immunity and metabolism in mammals.This study mainly used 8 to 12-week-old wild-type C57BL/6J versus knock-out mice. However, human gastrectomy samples from adults undergoing bariatric surgery were also used.Various genetically modified mice, including Red5, Yarg, and Smart13 reporter alleles, were used alongside wild-type and triple-knock-out strains. For germ-free experiments, embryos were transferred into germ-free isolator units. Mice were fed different diets, including control, chitin-enriched (up to 20%), high-fat, and combinations thereof. In vivo treatments involved cytokine injections and tamoxifen-induced gastric injury. Tissue preparation included detailed protocols for stomach, intestinal, lung, adipose tissues, and blood collection, followed by flow cytometry, biochemical, protein assays, and metabolic assessments.Mice fed with dietary chitin initially had increased gastric distension, ILC2 levels and ILC2-activated cytokines (IL-25 by tuft cells and IL-22 within epithelial cells), ILC2-activating neuropeptide neuromedin U (Nmu) levels, IL-5 and IL-13 producing ILC2s, and systemic eosinophilia. Triple-knockout mice without IL-25, IL-33, TSLPR, or tuft cells led to abolishment of ILC2-driven effects. A sustained diet of chitin led to increased number of activated ILC2 in adipose tissues and gastrointestinal remodeling events, including gastric epithelial proliferation, submucosal thickening, increased tuft cells, and induction of Chia1, the gene encoding acidic mammalian chitinase (AMCase) (enzyme evolutionarily linked to chitin consumption). Chitin-induced immune responses were independent of gut microbiota, as demonstrated in germ-free and antibiotic-treated mice. ILC-2 deficient mice fed chitin did not show increased stomach Chia1 expression. AMCase deficient mice had sustained stomach distention on a chitin-rich diet and increased levels of type 2 immune responses. Additionally, AMCase deficient mice who were fed a high fat diet plus chitin showed slower weight gain compared with wild type mice. However, both wild type and AMCase deficient mice fed a high fat diet plus chitin exhibited significant improvement in insulin sensitivity compared with mice not fed chitin.Mammals have evolved to metabolize the insoluble dietary fiber chitin. Chitin ingestion triggers gastric distention, neuropeptide release, and type 2 cytokine production by both tuft and innate lymphoid cells. This type 2 response ultimately drives gastrointestinal remodeling and increased chief cell production of AMCase, improving chitin digestion. Sustained chitin intake in mice lacking AMCase exhibits resistance to obesity and increased adipose ILC2 and eosinophils, which have been previously linked with metabolic homeostasis.Childhood obesity is a significant public health concern, where 1 in 6 people aged 1 to 17 years old are classified as obese, reaching epidemic levels. As such, numerous efforts are currently ongoing to for the treatment and prevention of pediatric obesity. Results from this study suggest that dietary fiber chitin ingestion can activate type 2 immune responses, which are associated with metabolic homeostasis and a resistance to obesity. Reduction in the gene responsible for chitin digestion has been associated with asthma in humans. The way mammals have evolutionarily adapted to chitin digestion underscore that diets rich in chitin from fungi and arthropods can contribute to overall metabolic and immune health and may be used as a possible obesity treatment target.