Dysregulation of secondary bile acid metabolism precedes islet autoimmunity and type 1 diabetes

Santosh Lamichhane; Partho Sen; Alex M Dickens; Marina Amaral Alves; Taina Härkönen; Jarno Honkanen; Tommi Vatanen; Ramnik J Xavier; Tuulia Hyötyläinen; Mikael Knip; Matej Orešič

doi:10.1016/j.xcrm.2022.100762

Dysregulation of secondary bile acid metabolism precedes islet autoimmunity and type 1 diabetes

Cell Rep Med. 2022 Oct 18;3(10):100762. doi: 10.1016/j.xcrm.2022.100762. Epub 2022 Oct 3.

Authors

Affiliations

¹ Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland.
² Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; School of Medical Sciences, Örebro University, 702 81 Örebro, Sweden.
³ Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; Department of Chemistry, University of Turku, 20520 Turku, Finland.
⁴ Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; Walter Mors Institute of Research on Natural Products, Federal University of Rio de Janeiro, 21941-599 Rio de Janeiro, Brazil.
⁵ Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁶ The Liggins Institute, University of Auckland, Auckland, New Zealand; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁷ The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁸ School of Science and Technology, Örebro University, Örebro, Sweden.
⁹ Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland.
¹⁰ Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; School of Medical Sciences, Örebro University, 702 81 Örebro, Sweden. Electronic address: matej.oresic@oru.se.

Abstract

The gut microbiota is crucial in the regulation of bile acid (BA) metabolism. However, not much is known about the regulation of BAs during progression to type 1 diabetes (T1D). Here, we analyzed serum and stool BAs in longitudinal samples collected at 3, 6, 12, 18, 24, and 36 months of age from children who developed a single islet autoantibody (AAb) (P1Ab; n = 23) or multiple islet AAbs (P2Ab; n = 13) and controls (CTRs; n = 38) who remained AAb negative. We also analyzed the stool microbiome in a subgroup of these children. Factor analysis showed that age had the strongest impact on both BA and microbiome profiles. We found that at an early age, systemic BAs and microbial secondary BA pathways were altered in the P2Ab group compared with the P1Ab and CTR groups. Our findings thus suggest that dysregulated BA metabolism in early life may contribute to the risk and pathogenesis of T1D.

Keywords: bile acid; genome-scale metabolic modeling; gut microbiome; islet autoimmunity; lipid metabolism; lipidomics; metabolomics; microbial metabolism; type 1 diabetes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autoantibodies / analysis
Autoimmunity
Bile Acids and Salts
Child
Diabetes Mellitus, Type 1*
Humans
Islets of Langerhans* / chemistry

Substances

Autoantibodies
Bile Acids and Salts

Grants and funding

P30 DK043351/DK/NIDDK NIH HHS/United States