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, Jaromír 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
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.