Altered microbial bile acid metabolism exacerbates T cell-driven inflammation during graft-versus-host disease
A recent study, published in Nature Microbiology, has found that changes in bile acid (BA) composition and signaling might contribute to graft-versus-host disease (GVHD) pathogenesis, highlighting the potential of targeting BA pathways to modulate immune responses and improve allogeneic hematopoietic cell transplantation (allo-HCT) outcomes. BAs, cholesterol-derived molecules essential for gut physiology and immune response modulation, are synthesized in the liver and undergo extensive reabsorption and microbial transformation in the gut. These processes generate both host-derived and microbe-derived BAs, which activate various receptors affecting gut motility, barrier function, and T cell differentiation, particularly influencing T helper 17 and regulatory T cell activities through specific BA signaling pathways. The study further explores the role of BAs in the context of allo-HCT, a procedure often complicated by GVHD linked to microbiome diversity loss and altered BA metabolism.
The authors found significant alterations in the levels and composition of host-derived and microbe-derived BAs in mice with GVHD, showing a systemic remodeling of the BA pool alongside reduced microbial modification abilities. This alteration was linked to a decrease in bile salt hydrolase (BSH) gene abundance, suggesting a decline in microbial capacity to produce microbe-derived BAs in the context of GVHD. Moreover, transplantation of donor T cells not only induces GVHD but also affects various BA species, including those with known T cell modulatory functions, highlighting the extensive impact of GVHD on intestinal and systemic BA metabolism. Further investigations revealed that these shifts in the BA pool were associated with changes in microbial BA metabolism and host liver function, affecting overall BA homeostasis. The presence of T cell-driven inflammation was shown to modify both microbial and host BA metabolism pathways, indicated by alterations in gene expression related to BA synthesis and transport in the liver of GVHD mice.
Additionally, the study examined the role of farnesoid X receptor (FXR) signaling in donor T cells, suggesting that changes in BA metabolism during T cell-driven inflammation might influence the balance of FXR-activating and antagonizing BAs, thereby modulating T cell responses and potentially contributing to the pathophysiology of GVHD. Overall, this intricate interaction between the immune system, microbial metabolism, and host physiology highlights the complex nature of GVHD and highlights the potential for targeting BA pathways as a therapeutic strategy.
Reference:
Lindner, S., Miltiadous, O., Ramos, R.J.F. et al. Altered microbial bile acid metabolism exacerbates T cell-driven inflammation during graft-versus-host disease. Nat Microbiol 9, 614–630 (2024).