Biology subjects

Sundrud, M. S.

Publications and source records attributed to Sundrud, M. S..

7 recordsLinked to original sources

bioRxiv2026

Ileitis abolishes tolerogenic functions of the enterohepatic bile acid pool

Bile acids (BAs) regulate lipid uptake, epithelial integrity, and immune responses in the gut. Hepatocytes synthesize primary BAs, which microbiota metabolize into secondary metabolites. Together, these species form a composite pool that circulates enterohepatically between the liver and intestines. Here, we show that immunoregulatory outputs of the enterohepatic BA pools involve competition between multiple BA species for individual nuclear receptors and are dependent on intestinal health. In healthy mice, the primary BA, tauro {beta} muricholic acid (t{beta}MCA) antagonized ROR{gamma}t-mediated Th17 function in the presence of two secondary BAs (tDCA, tLCA) which activated ROR{gamma}t. Conversely, ileitis in Crohns disease patients and Tnf{delta}ARE mice depleted primary BAs by reducing the number and function of BA transporting enterocytes. In mice, ileitis driven t{beta}MCA depletion enhanced tDCA and tLCA mediated ROR{gamma}t activation and supported Th17 cell function. Replenishing t{beta}MCA in Tnf{delta}ARE mice reestablished BA dependent Th17 cell regulation. Thus, intra pool competition underpins BA immunoregulatory functions and reveals new opportunities for precision Crohns disease therapy.

immunology↗

bioRxiv2026

Constitutive androstane receptor directs developing Th1 cells towards the Tr1 lineage

Constitutive androstane receptor (CAR; encoded by Nr1i3) is a nuclear xenobiotic receptor that mediates hepatic drug and bile acid metabolism. We previously identified CAR as also operating in CD4+ T helper (TH) cells, where CAR-dependent gene expression mitigates bile acid toxicity and promotes a Foxp3-IL-10+type 1 regulatory (Tr1)-like phenotype in the small intestine. Here, we show that CAR acts early and specifically during the priming of type 1 immune responses to stabilize Tr1 lineage commitment. CAR-dependent Tr1 cells formed during type 1 (Th1-associated) but not type 3 (Th17-associated) intestinal inflammation. In vitro, IL-27 upregulated CAR expression during naive TH cell activation, which contributed to Il10 induction. Single-cell analysis revealed that naive TH cells primed with IL-27 adopt a multipotent "Th1/Tr1 precursor" (THR1p) transcriptional state, which subsequently diverges into Th1 or Tr1 developmental trajectories. CAR transcriptional activity peaked in THR1p cells, upregulating Tr1 genes, including Il10, and repressing Th1 genes. Moreover, glucocorticoid receptor activation--which increases CAR expression in hepatocytes--synergized with IL-27 to augment both CAR expression and CAR-dependent Tr1 differentiation. Together, these results suggest that CAR acts in a lineage-biased manner to enforce Tr1-mediated immune tolerance during type 1 intestinal inflammation, and this pathway is amplified by glucocorticoids.

immunology↗

bioRxiv2026

Mucosal-associated invariant T cells support IL-15-dependent Treg response in skin injury and promote resolution of skin inflammation

Mucosal-associated invariant T (MAIT) cells are enriched at barrier sites, but their role in autoimmune skin inflammation remains unknown. Using cutaneous lupus as a model, we identify MAIT cells as protective regulators of skin inflammation and as critical upstream modulators of regulatory T cells (Treg). Topical MAIT cell activation with 5-OP-RU induced durable resolution of spontaneous skin lesions in MRL/lpr mice and suppressed TLR7-driven skin inflammation. MAIT cell activation selectively expanded and activated Treg populations in both healthy and lupus-like skin, while suppressing effector T cell cytokine production and cytotoxic programs. This MAIT-Treg axis was also activated in UV light-driven barrier injury in healthy murine and human skin, where MAIT cells were required for UV-elicited Treg expansion and function. In lupus-like skin, local MAIT cell activation restored the defective UVB-induced Treg response and limited CD8+ T cell expansion. Mechanistically, CCR2+ monocyte-derived antigen-presenting cells and IL-15 signaling were required for MAIT cell-driven Treg accumulation and therapeutic benefits of MAIT cells in inflamed skin. These studies identify a MAIT-IL-15-Treg axis that links barrier injury sensing to immune regulation, which is disrupted in cutaneous lupus, and nominate therapeutic MAIT cell activation as an unappreciated strategy for restoring immune homeostasis in inflamed skin.

immunology↗

bioRxiv2025

Profiling Bile Acids in the Stools of Humans and Animal Models of Cystic Fibrosis

Cystic fibrosis (CF) is associated with dysbiosis of the gut microbiome, alterations in intestinal mucus production, aberrant bile acid (BA) metabolism, fat malabsorption, and chronic inflammation. As little is known about BAs in CF, we performed both comprehensive and targeted BA profiling in stool of children with or without CF. Our results reveal that select BA species and metabolites are significantly different between children with CF (cwCF) and healthy controls. There is also a trend towards higher primary cBA and total BA levels for cwCF. Matched bacterial metagenomic analyses showed no change in alpha-diversity between groups in our small cohort, at odds with previous studies, whereas changes in relative abundance of Bacteroides (lower) and E. coli (increased) species is consistent with prior reports. A robust trend was noted toward reduced abundance of bsh gene families (Wilcox test, p = 0.052), a key rate-limiting enzyme required for bacterial synthesis of secondary BAs, in cwCF. Modest changes in both BAs and microbial BA metabolism-related gene abundances may be attributable to small sample sizes, but also suggest likely combination defects in both host and microbial BA metabolic pathways in cwCF. Importantly, although fecal BA profiles from both ferret and mouse CF models showed significant differences from human BA profiles, only the ferret model reproduced significant differences between CF and nonCF animals, highlighting ferrets as a potentially more appropriate model for studying BA in stool in the context of CF. Together, these results provide new insights into CF-related BA dysmetabolism in cwCF, and highlight limitations of CF animal models for BA functional studies. IMPORTANCEChanges in the abundance and/or composition of intestinal bile acids (BAs) may contribute to dysbiosis and altered gastrointestinal physiology in CF. Here, we report shifts in select fecal BA classes and species for children with CF (cwCF). Matched metagenomic analysis suggest possible defects in both host intestinal BA absorption and gut microbial BA metabolism. Additional analyses of mouse and ferret CF stool for BA composition suggest great care must be taken when interpreting BA functional studies using these animal models. Together, this work lays technical and conceptual foundations for interrogating BA-microbe interactions in cwCF.

microbiology↗

bioRxiv2024

Quantifying forms and functions of intestinal bile acid pools in mice

Bile acids (BAs) are gastrointestinal metabolites that serve dual functions in lipid absorption and cell signaling. BAs circulate actively between the liver and distal small intestine (i.e., ileum), yet the dynamics through which complex BA pools are absorbed in the ileum and interact with intestinal cells in vivo remain ill-defined. Through multi-site sampling of nearly 100 BA species in individual wild type mice, as well as mice lacking the ileal BA transporter, Asbt/Slc10a2, we calculate the ileal BA pool in fasting C57BL/6J mice to be [~]0.3 moles/g. Asbt-mediated transport accounts for [~]80% of this pool and amplifies size, whereas passive absorption explains the remaining [~]20%, and generates diversity. Accordingly, ileal BA pools in mice lacking Asbt are [~]5-fold smaller than in wild type controls, enriched in secondary BA species normally found in the colon, and elicit unique transcriptional responses in cultured ileal explants. This work quantitatively defines ileal BA pools in mice and reveals how BA dysmetabolism can impinge on intestinal physiology.

physiology↗

bioRxiv2024

Clonal Parabacteroides from Gut Microfistulous Tracts as Transmissible Cytotoxic Succinate-Commensal Model of Crohn's Disease Complications

Crohns disease (CD) has been traditionally viewed as a chronic inflammatory disease that cause gut wall thickening and complications, including fistulas, by mechanisms not understood. By focusing on Parabacteroides distasonis (presumed modern succinate-producing commensal probiotic), recovered from intestinal microfistulous tracts (cavernous fistulous micropathologies CavFT proposed as intermediate between mucosal fissures and fistulas) in two patients that required surgery to remove CD-damaged ilea, we demonstrate that such isolates exert pathogenic/pathobiont roles in mouse models of CD. Our isolates are clonally-related; potentially emerging as transmissible in the community and mice; proinflammatory and adapted to the ileum of germ-free mice prone to CD-like ileitis (SAMP1/YitFc) but not healthy mice (C57BL/6J), and cytotoxic/ATP-depleting to HoxB8-immortalized bone marrow derived myeloid cells from SAMP1/YitFc mice when concurrently exposed to succinate and extracts from CavFT-derived E. coli, but not to cells from healthy mice. With unique genomic features supporting recent genetic exchange with Bacteroides fragilis-BGF539, evidence of international presence in primarily human metagenome databases, these CavFT Pdis isolates could represent to a new opportunistic Parabacteroides species, or subspecies ( cavitamuralis) adapted to microfistulous niches in CD.

genomics↗

bioRxiv2020

Constitutive androstane receptor directs T cell adaptation to bile acids in the small intestine

Bile acids (BAs) are lipid emulsifying metabolites synthesized in hepatocytes and maintained in vivo through enterohepatic circulation between the liver and small intestine1. As detergents, BAs can cause toxicity and inflammation in enterohepatic tissues2. Nuclear receptors maintain BA homeostasis in hepatocytes and enterocytes3, but it is unclear how mucosal immune cells tolerate high BA concentrations in the small intestine lamina propria (siLP). We previously reported that CD4+ T effector (Teff) cells upregulate expression of the xenobiotic transporter MDR1/ABCB1 in the siLP to prevent BA toxicity and suppress Crohns disease-like small bowel inflammation4. Here, we identify the nuclear xenobiotic receptor, constitutive androstane receptor (CAR/NR1I3), as a regulator of MDR1 expression in T cells, and safeguard against BA toxicity and inflammation in the small intestine. CAR was activated and induced large-scale transcriptional reprograming in Teff cells infiltrating the siLP, but not the colon. CAR induced expression of detoxifying enzymes and transporters in siLP Teff cells, as in hepatocytes, but also the key anti-inflammatory cytokine, Il10. Accordingly, CAR-deficiency in T cells exacerbated, whereas pharmacologic CAR activation suppressed, BA-driven ileitis in T cell-reconstituted Rag-/- mice. These data suggest that CAR acts locally in small intestinal T cells to detoxify BAs and resolve inflammation. Activation of this program offers an unexpected strategy to treat small bowel Crohns disease, and provides evidence of lymphocyte sub-specialization within the small intestine.

immunology↗