Oral histidine affects gut microbiota and MAIT cells improving glycemic control in type 2 diabetes patients
Moritz V. Warmbrunn,
Ilias Attaye,
Judith Aron-Wisnewsky,
Elena Rampanelli,
Eduard W.J. van der Vossen,
Youling Hao,
Annefleur Koopen,
Per-Olof Bergh,
Daniela Stols-Gonçalves,
Nadia Mohamed,
Marleen Kemper,
Xanthe Verdoes,
Koen Wortelboer,
Mark Davids,
Eugeni Belda,
Sébastien André,
Stanley Hazen,
Karine Clement,
Bert Groen,
Daniel H. van Raalte,
Hilde Herrema,
Fredrik Backhed,
Max Nieuwdorp
Affiliations
Moritz V. Warmbrunn
Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
Ilias Attaye
Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
Judith Aron-Wisnewsky
Assistante Publique Hôpitaux de Paris, Nutrition Department, Pitié-Salpêtrière Hospital, CRNH Ile de France, Paris, France
Elena Rampanelli
Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
Eduard W.J. van der Vossen
Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
Youling Hao
Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
Annefleur Koopen
Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
Per-Olof Bergh
Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska, Gothenburg, Sweden
Daniela Stols-Gonçalves
Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
Nadia Mohamed
Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
Marleen Kemper
Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
Xanthe Verdoes
Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
Koen Wortelboer
Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
Mark Davids
Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
Eugeni Belda
Assistante Publique Hôpitaux de Paris, Nutrition Department, Pitié-Salpêtrière Hospital, CRNH Ile de France, Paris, France
Sébastien André
Assistante Publique Hôpitaux de Paris, Nutrition Department, Pitié-Salpêtrière Hospital, CRNH Ile de France, Paris, France
Stanley Hazen
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
Karine Clement
Assistante Publique Hôpitaux de Paris, Nutrition Department, Pitié-Salpêtrière Hospital, CRNH Ile de France, Paris, France
Bert Groen
Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
Daniel H. van Raalte
Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
Hilde Herrema
Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
Fredrik Backhed
Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
Max Nieuwdorp
Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
Amino acids, metabolized by host cells as well as commensal gut bacteria, have signaling effects on host metabolism. Oral supplementation of the essential amino acid histidine has been shown to exert metabolic benefits. To investigate whether dietary histidine aids glycemic control, we performed a case-controlled parallel clinical intervention study in participants with type 2 diabetes (T2D) and healthy controls. Participants received oral histidine for seven weeks. After 2 weeks of histidine supplementation, the microbiome was depleted by antibiotics to determine the microbial contribution to histidine metabolism. We assessed glycemic control, immunophenotyping of peripheral blood mononucelar cells (PBMC), DNA methylation of PBMCs and fecal gut microbiota composition. Histidine improves several markers of glycemic control, including postprandial glucose levels with a concordant increase in the proportion of MAIT cells after two weeks of histidine supplementation. The increase in MAIT cells was associated with changes in gut microbial pathways such as riboflavin biosynthesis and epigenetic changes in the amino acid transporter SLC7A5. Associations between the microbiome and MAIT cells were replicated in the MetaCardis cohort. We propose a conceptual framework for how oral histidine may affect MAIT cells via altered gut microbiota composition and SLC7A5 expression in MAIT cells directly and thereby influencing glycemic control. Future studies should focus on the role of flavin biosynthesis intermediates and SLC7A5 modulation in MAIT cells to modulate glycemic control.
