IgM-associated gut bacteria in obesity and type 2 diabetes in C57BL/6 mice and humans

Author:

Pearson James A.ORCID,Ding Heyuan,Hu Changyun,Peng Jian,Galuppo Brittany,Wong F. SusanORCID,Caprio SoniaORCID,Santoro Nicola,Wen LiORCID

Abstract

AbstractAims/hypothesisIgM is the primary antibody produced by B cells and we hypothesise that IgM antibodies to gut microbiota may play a role in immunometabolism in obesity and type 2 diabetes. To test our hypothesis, we used B6 mice deficient in activation-induced cytidine deaminase (Aid−/−[also known asAicda−/−]) which secrete only IgM antibodies, and human faecal samples.MethodsWe studied the immunometabolic effects and gut microbial changes in high-fat-diet-induced obesity (HFDIO) inAid−/−B6 mice compared with wild-type mice. To determine similarities between mice and humans, human stool samples were collected from children and adolescents who were obese with normal glucose tolerance (NGT), obese with glucose intolerance (IGT), or obese and newly diagnosed with type 2 diabetes, for faecal microbiota transplant (FMT) into germ-free (GF) B6 mice and we assessed IgM-bound bacteria and immune responses.ResultsCompared with wild-type mice,Aid−/−B6 mice developed exacerbated HFDIO due to abundant levels of IgM. FMT fromAid−/−B6 to GF B6 mice promoted greater weight gain in recipient mice compared with FMT using wild-type mouse faecal microbiota. Obese youth with type 2 diabetes had more IgM-bound gut bacteria. Using the stools from the obese youth with type 2 diabetes for FMT to GF B6 mice, we observed that the gut microbiota promoted body weight gain and impaired glucose tolerance in the recipient GF B6 mice. Importantly, some clinical features of these obese young individuals were mirrored in the GF B6 mice following FMT.Conclusions/interpretationOur results suggest that IgM-bound gut microbiota may play an important role in the immuno-pathogenesis of obesity and type 2 diabetes, and provide a novel link between IgM in obesity and type 2 diabetes in both mice and humans.Data availabilityThe 16s rRNA sequencing datasets supporting the current study have been deposited in the NCBI SRA public repository (https://www.ncbi.nlm.nih.gov/sra; accession no. SAMN18796639).Graphical abstract

Funder

National Institutes of Health

Medical Research Council

Juvenile Diabetes Research Foundation International

Diabetes Action Research and Education Foundation

European Foundation for the Study of Diabetes

Diabetes Research Connection

Publisher

Springer Science and Business Media LLC

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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