Clarissa Campbell

Microbial dysbiosis is a hallmark of inflammatory bowel diseases (IBD); however, its drivers and impact on disease pathophysiology are poorly understood. Applying neural network-based feature attribution to metabolomics and metagenomics datasets from >5000 individuals, we identified epimerized host derived bile acids (BAs) produced by microbial hydroxysteroid dehydrogenases (HSDHs) as a novel hallmark of IBD-associated dysbiosis. Epimerized BAs reduce FXR activity in intestinal epithelial cells and dampen their production of FGF19, a negative feedback regulator of host-derived bile acid (HBA) production in the liver. Increased HBA levels drive colonic epithelial remodeling by impacting goblet cell maturation and select for HSDH-carrying bacteria that transform bactericidal HBA into less toxic, epimerized forms. Confirming the translational relevance of these findings, we demonstrated that high HBA levels limit fecal microbiota transplant engraftment and show that BA sequestering drugs support microbiome recovery in patients with high HBA levels. Together, we discover that elevated HBAs deplete BA-sensitive commensals and favor the growth of HSDH-encoding pathobionts that disrupt host BA feedback signaling, establishing a causal link between changes in microbial ecology and IBD pathophysiology.

Antiviral immunity profoundly impacts host metabolism, which can, in turn, modulate immune responses and influence disease pathology. The liver orchestrates systemic bile acid (BA) metabolism, a pathway disrupted in chronic liver diseases such as viral hepatitis. BAs are increasingly recognized for their immunomodulatory properties. Thus, improved understanding of the interplay between immunity and BA metabolism may reveal novel therapeutic avenues. Using lymphocytic choriomeningitis virus (LCMV) as a model, we investigated the interplay between chronic virus infection, BA metabolism, and immunity. Chronic LCMV infection increased BA levels and shifted circulating and liver BA composition toward host-derived, conjugated BAs. Hepatic BA transport and synthesis genes were broadly downregulated, in part depending on CD8 ⁺ T cells. Pharmacological inhibition of the main hepatic transporter of conjugated BAs, NTCP ( Slc10a1 ), increased hepatic damage, while combined genetic disruption of the BA transporters Slco1a1 , Slco1a4 , and Slco1b2 , responsible for the hepatic reuptake of unconjugated BA, reduced liver pathology and impaired antiviral CD8 ⁺ T cell responses. These findings reveal a reciprocal interplay between BA metabolism and CD8 ⁺ T cells, expanding our understanding of adaptive immunity in viral hepatitis. They also highlight how immunometabolic changes in liver disease may affect adaptive immune responses against infections.

Pulmonary fibrosis is an incurable disease that manifests with advanced age. Yet, how hematopoietic aging influences immune responses and fibrosis progression remains unclear. Using heterochronic bone marrow transplant mouse models, we found that an aged bone marrow exacerbates lung fibrosis irrespective of lung tissue age. Upon lung injury, there was an increased accumulation of monocyte-derived alveolar macrophages (Mo-AMs) driven by cell-intrinsic hematopoietic aging. These Mo-AMs exhibited an enhanced profibrotic profile and stalled maturation into a homeostatic, tissue-resident phenotype. This delay was shaped by cell-extrinsic environmental signals such as reduced pulmonary interleukin-10 (IL-10), perpetuating a profibrotic macrophage state. We identified regulatory T cells (T _regs ) as critical providers of IL-10 upon lung injury that promote Mo-AM maturation and attenuate fibrosis progression. Our study highlights the impact of an aging bone marrow on lung immune regulation and identifies T _reg -mediated IL-10 signaling as a promising target to mitigate fibrosis and promote tissue repair.

This year at JEM, we are highlighting women in science by sharing their stories and amplifying their voices. In this Viewpoint, we hear from a cross section of women, across multiple research fields, discussing their science and the process of setting up a lab as an independent researcher.

Microbial transformation of bile acids affects intestinal immune homoeostasis but its impact on inflammatory pathologies remains largely unknown. Using a mouse model of graft-versus-host disease (GVHD), we found that T cell-driven inflammation decreased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and reduced the levels of unconjugated and microbe-derived bile acids. Several microbe-derived bile acids attenuated farnesoid X receptor (FXR) activation, suggesting that loss of these metabolites during inflammation may increase FXR activity and exacerbate the course of disease. Indeed, mortality increased with pharmacological activation of FXR and decreased with its genetic ablation in donor T cells during mouse GVHD. Furthermore, patients with GVHD after allogeneic hematopoietic cell transplantation showed similar loss of BSH and the associated reduction in unconjugated and microbe-derived bile acids. In addition, the FXR antagonist ursodeoxycholic acid reduced the proliferation of human T cells and was associated with a lower risk of GVHD-related mortality in patients. We propose that dysbiosis and loss of microbe-derived bile acids during inflammation may be an important mechanism to amplify T cell-mediated diseases.

T cells increase cholesterol biosynthesis upon activation to generate substrates for cellular growth and proliferation. The ubiquitously expressed liver X receptor β (LXRβ) encoded by the Nr1h2 gene is a critical regulator of cholesterol homeostasis in mammalian cells; however, its cell-intrinsic role in T cell biology remains poorly understood. We report that ablation of LXRβ in T cells leads to spontaneous T cell activation and T lymphocytopenia. Unexpectedly, analysis of mixed bone marrow chimeric mice revealed a cell-autonomous survival defect that reduced the fitness of LXRβ-deficient effector T cells, suggesting that the heightened immune activation in mice harboring LXRβ-deficient T cells was due to impaired regulatory T (T reg) cell functionality. Indeed, we found that single-copy deletion of Nr1h2 in T reg cells disrupted activated T reg cell metabolism and fitness and resulted in early-onset fatal autoimmune disease. Our study demonstrated an indispensable requirement for T reg cell–intrinsic LXRβ function in immune homeostasis and provides a basis for immunological therapies through targeting of this receptor.