Levels of circulating bile acids and type 2 diabetes are associated in silico with changes in polyamine synthesis and amino acid metabolism of the gut bacterial community

Background: The interplay between bile acids (BAs), metabolic diseases and the gut microbiome has gained importance in recent years, with a variety of studies investigating their relationship with diverging results. By addressing the systemic functional implications of the gut microbiome, our study complements the existing literature, providing a broader context for understanding the host-microbiome axis.

Methods: Levels of nine BAs were measured in a cohort of 492 subjects. We calculated a BA weighted score (BWS) based on strength of association between BAs and type 2 diabetes (T2D). Gut community metabolism (GCM) was predicted in silico from 16s data using the GapSeq workflow and parsimonious flux balance analysis. We then analyzed GCM for its relation to the BWS by univariate tests and regression models, focusing on microbial metabolic pathway abundance, cross-feeding between bacterial species, and bacterial metabolite production.

Results: We identified 184 nominally differentially abundant pathways related to BWS, 18 of which remained significant after adjusting for multiple testing. A noteworthy finding was the significant increase in the microbial spermidine biosynthesis pathway associated with higher BWS, independent of weight (beta=0.95, p=0.003). Putrescine, a spermidine precursor molecule, was the top metabolite in cross-feeding related to the BWS (p=0.006), followed by eight amino acids.

Conclusion: While many studies claim that changes in the gut microbiome in relation to diabetes are mostly negative, the up-regulation of the microbial spermidine production in relation to the BWS found in our study might suggest also beneficial/compensatory effects of altered microbial communities in diabetic subjects, especially since spermidine has recently been shown to suppress diabetes onset and progression by modulating RIPK1-mediated cell death and inflammation ([1]). From our point of view, this aspect should be addressed in future translational and/or mechanistic studies.

Publikationsverlauf

Artikel online veröffentlicht:
28. Mai 2025

• Literatur

• 1 Zhang T, Fu W, Zhang H, Li J, Xing B, Cai Y, Zhang M, Liu X, Qi C, Qian L, Hu X, Zhu H, Yang S, Zhang M, Liu J, Li G, Li Y, Xiang R, Qi Z, Hu J, Li Y, Zou C, Wang Q, Jin X, Pang R, Li P, Liu J, Zhang Y, Wang Z, Zhu ZJ, Shan B, Yuan J.. Spermidine mediates acetylhypusination of RIPK1 to suppress diabetes onset and progression. Nat Cell Biol 2024; 26: 2099-2114 Epub 2024 Nov 7 39511379