Microbiome-derived bile acid signatures in early life and their association with islet autoimmunity

Santosh Lamichhane; Alex M. Dickens; Tanja Buchacher; Tianai Lou; Vincent Charron-Lamoureux; Roosa Kattelus; Pragya Karmacharya; Lucas Pinto da Silva; Matilda Kråkström; Omid Rasool; Partho Sen; Corinn Walker; Abubaker Patan; Emily C. Gentry; Simone Zuffa; Aron Arzoomand; Tadepally Lakshmikanth; Jaromir Mikeš; Aman Mebrahtu; Tommi Vatanen; Manuela Raffatellu; Karsten Zengler; Tuulia Hyötyläinen; Ramnik J. Xavier; Petter Brodin; Riitta Lahesmaa; Pieter C. Dorrestein; Mikael Knip; Matej Orešič

doi:10.1038/s41467-025-66619-6

Microbiome-derived bile acid signatures in early life and their association with islet autoimmunity

Santosh Lamichhane^*
, Alex M. Dickens
, Tanja Buchacher
, Tianai Lou
, Vincent Charron-Lamoureux
, Roosa Kattelus
, Pragya Karmacharya
, Lucas Pinto da Silva
, Matilda Kråkström
, Omid Rasool
, Partho Sen
, Corinn Walker
, Abubaker Patan
, Emily C. Gentry
, Simone Zuffa
, Aron Arzoomand
, Tadepally Lakshmikanth
, Jaromir Mikeš
, Aman Mebrahtu
, Tommi Vatanen

Manuela Raffatellu, Karsten Zengler, Tuulia Hyötyläinen, Ramnik J. Xavier, Petter Brodin, Riitta Lahesmaa, Pieter C. Dorrestein, Mikael Knip^*, Matej Orešič^*

^*Korresponderande författare för detta arbete

Åbo biovetenskapscentrum

Forskningsoutput: Tidskriftsbidrag › Artikel › Vetenskaplig › Peer review

7 Citeringar (Scopus)

15 Nedladdningar (Pure)

Sammanfattning

Emerging studies reveal that gut microbes can conjugate diverse amino acids to bile acids, known as microbially conjugated bile acids. However, their regulation and health effects remain unclear. Here, we analyzed early-life microbially conjugated bile acid patterns and their link to islet autoimmunity. We quantified 110 microbial bile acids in 303 stool samples collected longitudinally (3–36 months) from children who developed one or more islet autoantibodies and controls who remained autoantibody-negative. We identified distinct age-dependent trajectories of these bile acid amidates and correlated them with gut microbiome composition. We found that altered levels of ursodeoxycholic and deoxycholic acid conjugates were linked to islet autoimmunity as well as modulated monocyte activation in response to immunostimulatory lipopolysaccharide and Th17/Treg cell balance. These findings suggest that microbially conjugated bile acids influence immune development and type 1 diabetes risk.

Originalspråk	Engelska
Artikelnummer	38
Tidskrift	Nature Communications
Volym	17
Nummer	1
DOI	https://doi.org/10.1038/s41467-025-66619-6
Status	Publicerad - dec. 2026
MoE-publikationstyp	A1 Tidskriftsartikel-refererad

Finansiering

This study was supported by the “Inflammation in human early life: targeting impacts on life-course health” (INITIALISE) consortium funded by the Horizon Europe Program of the European Union under Grant Agreement 101094099 (to M.O.), the Research Council of Finland funding (no. 363417 to S.L.; grants no. 331793 and 329277 to R.L.), the Research Council of Finland project grant (grant no. 333981 to M.O.), and the Novo Nordisk Foundation (grant no. NNF20OC0063971 to T.H. and M.O. and grant no. NNF19OC0057218 to R.L). Further support was received from the Swedish Research Council (grant no. 2016-05176 to T.H. and M.O.), the Sigrid Jusélius Foundation, the Jane and Aatos Erkko Foundation (to R.L.), Formas (grant no. 2019-00869 to T.H. and M.O.), and the Medical Research Funds, Helsinki University Hospital (to M.K.). Further support was received by the InFLAMES Flagship Programme of the Academy of Finland (grant no. 337530). We further acknowledge support by NICHD, P50HD106463, and NIDDK R01DK136117, U24DK133658 (to P.C.D.). RJX is funded by NIH (DK 43351, AI172147) and the Center for Microbiome Informatics and Therapeutics. Mass spectrometric analysis was performed at the Turku Metabolomics Centre with the support of Biocenter Finland. The DIABIMMUNE study was supported by the European Union Seventh Framework Programme FP7/2007-2013 under grant agreement number 202063 (to M.K. and R.L.), Breakthrough T1D (formerly Juvenile Diabetes Research Foundation) grants 17-2011-529 and 17-2014-305 to R.L., and the Academy of Finland Centre of Excellence in Molecular Systems Immunology and Physiology Research grant Decision number 250114, 2012–2017 (to M.O., R.L., and M.K.). We thank all voluntary blood donors and personnel of Turku University Hospital, Department of Obstetrics and Gynecology, Maternity Ward (Hospital District of Southwest Finland) for the umbilical cord blood collection. We acknowledge Marjo Hakkarainen (Turku Bioscience Center, University of Turku) and Sarita Heinonen for her excellent technical assistance. We thank Denys Mavrynsky and Tuomas Karskela for the synthesis of pure UDCA conjugates. We also acknowledge Mauricio Caraballo (Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego) and Nicole Avalon (Scripps Institution of Oceanography) for their assistance with the experimental setup for metabolomics and compound purification. Open access funding provided by Örebro University.

Nyckelord

Metabolomics
Type 1 diabetes

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10.1038/s41467-025-66619-6Licens: CC BY

s41467-025-66619-6Slutlig publicerad version, 2,17 MBLicens: CC BY

https://urn.fi/URN:NBN:fi-fe2026050136899

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Lamichhane, S., Dickens, A. M., Buchacher, T., Lou, T., Charron-Lamoureux, V., Kattelus, R., Karmacharya, P., da Silva, L. P., Kråkström, M., Rasool, O., Sen, P., Walker, C., Patan, A., Gentry, E. C., Zuffa, S., Arzoomand, A., Lakshmikanth, T., Mikeš, J., Mebrahtu, A., ... Orešič, M. (2026). Microbiome-derived bile acid signatures in early life and their association with islet autoimmunity. Nature Communications, 17(1), Artikel 38. https://doi.org/10.1038/s41467-025-66619-6

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title = "Microbiome-derived bile acid signatures in early life and their association with islet autoimmunity",

abstract = "Emerging studies reveal that gut microbes can conjugate diverse amino acids to bile acids, known as microbially conjugated bile acids. However, their regulation and health effects remain unclear. Here, we analyzed early-life microbially conjugated bile acid patterns and their link to islet autoimmunity. We quantified 110 microbial bile acids in 303 stool samples collected longitudinally (3–36 months) from children who developed one or more islet autoantibodies and controls who remained autoantibody-negative. We identified distinct age-dependent trajectories of these bile acid amidates and correlated them with gut microbiome composition. We found that altered levels of ursodeoxycholic and deoxycholic acid conjugates were linked to islet autoimmunity as well as modulated monocyte activation in response to immunostimulatory lipopolysaccharide and Th17/Treg cell balance. These findings suggest that microbially conjugated bile acids influence immune development and type 1 diabetes risk.",

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Lamichhane, S, Dickens, AM, Buchacher, T, Lou, T, Charron-Lamoureux, V, Kattelus, R, Karmacharya, P, da Silva, LP, Kråkström, M, Rasool, O, Sen, P, Walker, C, Patan, A, Gentry, EC, Zuffa, S, Arzoomand, A, Lakshmikanth, T, Mikeš, J, Mebrahtu, A, Vatanen, T, Raffatellu, M, Zengler, K, Hyötyläinen, T, Xavier, RJ, Brodin, P, Lahesmaa, R, Dorrestein, PC, Knip, M & Orešič, M 2026, 'Microbiome-derived bile acid signatures in early life and their association with islet autoimmunity', Nature Communications, vol. 17, nr. 1, 38. https://doi.org/10.1038/s41467-025-66619-6

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AU - Lamichhane, Santosh

AU - Dickens, Alex M.

AU - Buchacher, Tanja

AU - Lou, Tianai

AU - Charron-Lamoureux, Vincent

AU - Kattelus, Roosa

AU - Karmacharya, Pragya

AU - da Silva, Lucas Pinto

AU - Kråkström, Matilda

AU - Rasool, Omid

AU - Sen, Partho

AU - Walker, Corinn

AU - Patan, Abubaker

AU - Gentry, Emily C.

AU - Zuffa, Simone

AU - Arzoomand, Aron

AU - Lakshmikanth, Tadepally

AU - Mikeš, Jaromir

AU - Mebrahtu, Aman

AU - Vatanen, Tommi

AU - Raffatellu, Manuela

AU - Zengler, Karsten

AU - Hyötyläinen, Tuulia

AU - Xavier, Ramnik J.

AU - Brodin, Petter

AU - Lahesmaa, Riitta

AU - Dorrestein, Pieter C.

AU - Knip, Mikael

AU - Orešič, Matej

PY - 2026/12

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N2 - Emerging studies reveal that gut microbes can conjugate diverse amino acids to bile acids, known as microbially conjugated bile acids. However, their regulation and health effects remain unclear. Here, we analyzed early-life microbially conjugated bile acid patterns and their link to islet autoimmunity. We quantified 110 microbial bile acids in 303 stool samples collected longitudinally (3–36 months) from children who developed one or more islet autoantibodies and controls who remained autoantibody-negative. We identified distinct age-dependent trajectories of these bile acid amidates and correlated them with gut microbiome composition. We found that altered levels of ursodeoxycholic and deoxycholic acid conjugates were linked to islet autoimmunity as well as modulated monocyte activation in response to immunostimulatory lipopolysaccharide and Th17/Treg cell balance. These findings suggest that microbially conjugated bile acids influence immune development and type 1 diabetes risk.

AB - Emerging studies reveal that gut microbes can conjugate diverse amino acids to bile acids, known as microbially conjugated bile acids. However, their regulation and health effects remain unclear. Here, we analyzed early-life microbially conjugated bile acid patterns and their link to islet autoimmunity. We quantified 110 microbial bile acids in 303 stool samples collected longitudinally (3–36 months) from children who developed one or more islet autoantibodies and controls who remained autoantibody-negative. We identified distinct age-dependent trajectories of these bile acid amidates and correlated them with gut microbiome composition. We found that altered levels of ursodeoxycholic and deoxycholic acid conjugates were linked to islet autoimmunity as well as modulated monocyte activation in response to immunostimulatory lipopolysaccharide and Th17/Treg cell balance. These findings suggest that microbially conjugated bile acids influence immune development and type 1 diabetes risk.

KW - Metabolomics

KW - Type 1 diabetes

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DO - 10.1038/s41467-025-66619-6

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SN - 2041-1723

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ER -

Microbiome-derived bile acid signatures in early life and their association with islet autoimmunity

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