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Commensal bacteria contribute to insulin resistance in aging by activating innate B1a cells.
- Source :
-
Science translational medicine [Sci Transl Med] 2018 Nov 14; Vol. 10 (467). - Publication Year :
- 2018
-
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 <superscript>+</superscript> 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 <superscript>+</superscript> monocytes when butyrate was decreased. Upon infiltration into the omentum, CCR2 <superscript>+</superscript> 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 <superscript>+</superscript> 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.<br /> (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Subjects :
- Animals
Bacteria drug effects
Butyrates pharmacology
Cell Line
Dysbiosis microbiology
Enrofloxacin pharmacology
Female
Gastrointestinal Microbiome drug effects
Macaca
Mice, Inbred C57BL
Monocytes drug effects
Monocytes metabolism
Omentum metabolism
Receptors, CCR2 metabolism
Aging immunology
Bacteria immunology
Immunity, Innate drug effects
Insulin Resistance
Subjects
Details
- Language :
- English
- ISSN :
- 1946-6242
- Volume :
- 10
- Issue :
- 467
- Database :
- MEDLINE
- Journal :
- Science translational medicine
- Publication Type :
- Academic Journal
- Accession number :
- 30429354
- Full Text :
- https://doi.org/10.1126/scitranslmed.aat4271