A microbiota-driven CCL25-CCR9 axis reprograms intestinal ILC2s in the distal small intestine to promote metabolic...

Metabolically unhealthy obesity is characterized by chronic inflammation and metabolic dysfunction; however, how intestinal immune organization shapes systemic metabolic outcomes remains unclear. We investigated whether region-specific intestinal immune remodeling contributes to obesity-associated metabolic dysfunction.

Human serum chemokine profiling was performed in patients with severe obesity before and after bariatric surgery. Diet-induced obesity models in male mice, microbiota manipulation, single-cell RNA sequencing, genetic and pharmacologic CCR9 perturbation, parabiosis, and adoptive transfer experiments were used to define mechanisms regulating intestinal innate lymphoid cells (ILCs).

Circulating CCL25 levels correlated with visceral adiposity in patients with severe obesity and declined following bariatric surgery. Segment-specific analyses demonstrated preferential upregulation of CCL25 and CCR9 in the distal small intestine under metabolic stress. In obese mice, microbiota-dependent induction of epithelial Ccl25 promoted CCR9-dependent accumulation of type 2 innate lymphoid cells (ILC2s) in the ileum, accompanied by reduced adipose-resident ILC2s. Small-intestinal ILC2s underwent selective inflammatory reprogramming toward an ILC1-like phenotype, whereas adipose tissue ILC2s remained comparatively stable. Genetic or pharmacologic disruption of CCR9 signaling reversed obesity-associated skewing of ILC2 distribution, suppressed intestinal inflammatory remodeling, preserved epithelial barrier integrity, and improved glucose homeostasis without affecting body weight, even in the absence of adaptive immunity. Parabiosis and adoptive transfer experiments further demonstrated that disruption of the CCL25-CCR9 axis redirected circulating ILC2s from the small intestine toward peripheral tissues.

These findings identify the distal small intestine as a microbiota-responsive immune trafficking checkpoint linking regional immune remodeling to systemic metabolic dysfunction and establish intestinal immune positioning pathways as potential therapeutic targets in metabolically unhealthy obesity.