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

James A Pearson; Heyuan Ding; Changyun Hu; Jian Peng; Brittany Galuppo; F Susan Wong; Sonia Caprio; Nicola Santoro; Li Wen

doi:10.1007/s00125-022-05711-8

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

Diabetologia. 2022 Aug;65(8):1398-1411. doi: 10.1007/s00125-022-05711-8. Epub 2022 May 19.

Authors

James A Pearson^{1

2}, Heyuan Ding^{3

4}, Changyun Hu^{3

5}, Jian Peng³, Brittany Galuppo⁶, F Susan Wong⁷, Sonia Caprio⁶, Nicola Santoro⁶, Li Wen⁸

Affiliations

¹ Section of Endocrinology, School of Medicine, Yale University, New Haven, CT, USA. pearsonj1@cardiff.ac.uk.
² Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK. pearsonj1@cardiff.ac.uk.
³ Section of Endocrinology, School of Medicine, Yale University, New Haven, CT, USA.
⁴ Department of Endocrinology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China.
⁵ Adept Therapeutics, Inc., Beverly, MA, USA.
⁶ Department of Pediatrics, School of Medicine, Yale University, New Haven, CT, USA.
⁷ Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.
⁸ Section of Endocrinology, School of Medicine, Yale University, New Haven, CT, USA. li.wen@yale.edu.

Abstract

Aims/hypothesis: IgM 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 as Aicda^-/-]) which secrete only IgM antibodies, and human faecal samples.

Methods: We studied the immunometabolic effects and gut microbial changes in high-fat-diet-induced obesity (HFDIO) in Aid^-/- 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.

Results: Compared with wild-type mice, Aid^-/- B6 mice developed exacerbated HFDIO due to abundant levels of IgM. FMT from Aid^-/- 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/interpretation: Our 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 availability: The 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).

Keywords: B cell; Gut bacteria; IgM; Obesity; Type 2 diabetes.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Adolescent
Animals
Bacteria / genetics
Child
Diabetes Mellitus, Type 2*
Diet, High-Fat
Humans
Immunoglobulin M
Mice
Mice, Inbred C57BL
Obesity / microbiology
RNA, Ribosomal, 16S / genetics
Weight Gain

Substances

Immunoglobulin M
RNA, Ribosomal, 16S

Abstract

Publication types

MeSH terms

Substances

Grants and funding