Lymphotoxin regulates commensal responses to enable diet-induced obesity

Abstract

The microbiota plays a critical, weight-promoting role in diet-induced obesity (DIO), but the pathways that cause the microbiota to induce weight gain are unknown. We report that mice deficient in lymphotoxin (LT), a key molecule in gut immunity, were resistant to DIO. Ltbr−/− mice differed in microbial community composition compared to their heterozygous littermates, including an overgrowth of segmented filamentous bacteria (SFB). Furthermore, cecal transplantation conferred leanness to germ-free recipients. Housing Ltbr−/− mice with their obese siblings rescued weight gain, demonstrating the communicability of the obese phenotype. Ltbr−/− animals lacked interleukin 23 (IL-23) and IL-22 that can regulate SFB. Mice deficient in these pathways also resisted DIO, demonstrating that intact mucosal immunity guides diet-induced changes to the microbiota to enable obesity.

Reciprocity in Microbiome and Immune System Interactions and its Implications in Disease and Health

“…Diet-induced obesity in mice is transferable from susceptible to resistant mice after co-housing of two groups of mice [109]. A High fat diet induces a LTβR dependent activation of the IL-23-IL-22 cytokine pathway in innate lymphoid cells to produce IL-22 [109], which is a key player in the process of diet-induced obesity and reduction of SFB colonization [109]. IL-22 driven production of the antibacterial peptide, RegIIIγ, limits the outgrowth of SFB in the gut [109].…”

“…Transfer of microbiota from mice with diet-induced obesity to germ-free recipient mice promotes fat deposition [108]. Lymphotoxin β receptor (LTβR) regulates the microbiota in the gut to induce obesity after intake of high fat diet [109], which indicates that both genetic background of host and composition of microbiota are involved in obesity. A hallmark of dietinduced obesity is the loss of diversity in microbial communities and lower frequency of SFB in the gut [109].…”

“…Lymphotoxin β receptor (LTβR) regulates the microbiota in the gut to induce obesity after intake of high fat diet [109], which indicates that both genetic background of host and composition of microbiota are involved in obesity. A hallmark of dietinduced obesity is the loss of diversity in microbial communities and lower frequency of SFB in the gut [109]. Diet-induced obesity in mice is transferable from susceptible to resistant mice after co-housing of two groups of mice [109].…”

“…A hallmark of dietinduced obesity is the loss of diversity in microbial communities and lower frequency of SFB in the gut [109]. Diet-induced obesity in mice is transferable from susceptible to resistant mice after co-housing of two groups of mice [109]. A High fat diet induces a LTβR dependent activation of the IL-23-IL-22 cytokine pathway in innate lymphoid cells to produce IL-22 [109], which is a key player in the process of diet-induced obesity and reduction of SFB colonization [109].…”

“…A High fat diet induces a LTβR dependent activation of the IL-23-IL-22 cytokine pathway in innate lymphoid cells to produce IL-22 [109], which is a key player in the process of diet-induced obesity and reduction of SFB colonization [109]. IL-22 driven production of the antibacterial peptide, RegIIIγ, limits the outgrowth of SFB in the gut [109]. Study of fecal microbial communities in twin individuals, being either lean or obese, has shown phylumlevel differences in the gut microbiota [110].…”