Group X phospholipase A₂ links colonic lipid homeostasis to systemic metabolism via host-microbiota interaction

The gut microbiota influences physiological functions of the host, ranging from the maintenance of local gut homeostasis to systemic immunity and metabolism. Secreted phospholipase A₂ group X (sPLA₂-X) is abundantly expressed in colonic epithelial cells but is barely detectable in metabolic and immune tissues. Despite this distribution, sPLA₂-X-deficient (Pla2g10^-/-) mice displayed variable obesity-related phenotypes that were abrogated after treatment with antibiotics or cohousing with Pla2g10^+/+ mice, suggesting the involvement of the gut microbiota. Under housing conditions where Pla2g10^-/- mice showed aggravation of diet-induced obesity and insulin resistance, they displayed increased colonic inflammation and epithelial damage, reduced production of polyunsaturated fatty acids (PUFAs) and lysophospholipids, decreased abundance of several Clostridium species, and reduced levels of short-chain fatty acids (SCFAs). These obesity-related phenotypes in Pla2g10^-/- mice were reversed by dietary supplementation with ω3 PUFAs or SCFAs. Thus, colonic sPLA₂-X orchestrates ω3 PUFA-SCFA interplay via modulation of the gut microbiota, thereby secondarily affecting systemic metabolism.