TitleCommensal bacteria contribute to insulin resistance in aging by activating innate B1a cells.
Publication TypeJournal Article
Year of Publication2018
AuthorsBodogai, M, O'Connell, J, Kim, K, Kim, Y, Moritoh, K, Chen, C, Gusev, F, Vaughan, K, Shulzhenko, N, Mattison, JA, Lee-Chang, C, Chen, W, Carlson, O, Becker, KG, Gurung, M, Morgun, A, White, J, Meade, T, Perdue, K, Mack, M, Ferrucci, L, Trinchieri, G, de Cabo, R, Rogaev, E, Egan, J, Wu, J, Biragyn, A
JournalSci Transl Med
Date Published2018 11 14
KeywordsAging, Animals, Bacteria, Butyrates, Cell Line, Dysbiosis, Enrofloxacin, Female, Gastrointestinal Microbiome, Immunity, Innate, Insulin Resistance, Macaca, Mice, Inbred C57BL, Monocytes, Omentum, Receptors, CCR2

Aging in humans is associated with increased hyperglycemia and insulin resistance (collectively termed IR) and dysregulation of the immune system. However, the causative factors underlying their association remain unknown. Here, using "healthy" aged mice and macaques, we found that IR was induced by activated innate 4-1BBL B1a cells. These cells (also known as 4BL cells) accumulated in aging in response to changes in gut commensals and a decrease in beneficial metabolites such as butyrate. We found evidence suggesting that loss of the commensal bacterium impaired intestinal integrity, causing leakage of bacterial products such as endotoxin, which activated CCR2 monocytes when butyrate was decreased. Upon infiltration into the omentum, CCR2 monocytes converted B1a cells into 4BL cells, which, in turn, induced IR by expressing 4-1BBL, presumably to trigger 4-1BB receptor signaling as in obesity-induced metabolic disorders. This pathway and IR were reversible, as supplementation with either or the antibiotic enrofloxacin, which increased the abundance of , restored normal insulin response in aged mice and macaques. In addition, treatment with butyrate or antibodies that depleted CCR2 monocytes or 4BL cells had the same effect on IR. These results underscore the pathological function of B1a cells and suggest that the microbiome-monocyte-B cell axis could potentially be targeted to reverse age-associated IR.

Alternate JournalSci Transl Med
PubMed ID30429354
PubMed Central IDPMC6445267
Grant ListR01 AG054712 / AG / NIA NIH HHS / United States
R01 DK103761 / DK / NIDDK NIH HHS / United States
Z99 AG999999 / / Intramural NIH HHS / United States