Bodogai, Monica and O'Connell, Jennifer and Kim, Ki and Kim, Yoo and Moritoh, Kanako and Chen, Chen and Gusev, Fedor and Vaughan, Kelli and Shulzhenko, Natalia and Mattison, Julie A. and Lee-Chang, Catalina and Chen, Weixuan and Carlson, Olga and Becker, Kevin G. and Gurung, Manoj and Morgun, Andrey and White, James and Meade, Theresa and Perdue, Kathy and Mack, Matthias and Ferrucci, Luigi and Trinchieri, Giorgio and de Cabo, Rafael and Rogaev, Evgeny and Egan, Josephine and Wu, Jiejun and Biragyn, Arya (2018) Commensal bacteria contribute to insulin resistance in aging by activating innate B1a cells. SCIENCE TRANSLATIONAL MEDICINE, 10 (467): eaat4271. ISSN 1946-6234, 1946-6242
Full text not available from this repository. (Request a copy)Abstract
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 Akkermansia muciniphila 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 A. muciniphila or the antibiotic enrofloxacin, which increased the abundance of A. muciniphila, 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CHAIN FATTY-ACIDS; BUTYRATE-PRODUCING BACTERIUM; AKKERMANSIA-MUCINIPHILA; ADIPOSE-TISSUE; B-CELLS; T-CELLS; SP NOV.; MICROBIOTA; GUT; INFLAMMATION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Abteilung für Nephrologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 10 Oct 2019 05:47 |
| Last Modified: | 10 Oct 2019 05:47 |
| URI: | https://pred.uni-regensburg.de/id/eprint/13539 |
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