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Sci Transl Med. 2018 Nov 14;10(467). pii: eaat4271. doi: 10.1126/scitranslmed.aat4271.

Commensal bacteria contribute to insulin resistance in aging by activating innate B1a cells.

Author information

1
Immunoregulation Section, National Institute on Aging, Baltimore, MD 21224, USA.
2
Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD 21224, USA.
3
Department of Genomics and Human Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.
4
Nonhuman Primate Core Facility, National Institute on Aging, Baltimore, MD 21224, USA.
5
College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA.
6
Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01604, USA.
7
Janssen Research & Development, San Diego, CA 92121, USA.
8
Laboratory of Genetics, National Institute on Aging, Baltimore, MD 21224, USA.
9
College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA.
10
Resphera Biosciences, Baltimore, MD 21231, USA.
11
Comparative Medicine Section, National Institute on Aging, Baltimore, MD 21224, USA.
12
Department of Nephrology, Universitätsklinikum Regensburg, Regensburg 93001-93059, Germany.
13
Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD 21224, USA.
14
Cancer Inflammation Program, National Cancer Institute, Frederick, MD 21701, USA.
15
Center for Genetics and Genetic Technologies, Faculty of Biology, Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia.
16
Immunoregulation Section, National Institute on Aging, Baltimore, MD 21224, USA. biragyna@mail.nih.gov.

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.

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