Biology subjects

Sandborn, W. J.

Publications and source records attributed to Sandborn, W. J..

6 recordsLinked to original sources

bioRxiv2026

Stromal state plasticity defines risk and therapeutic opportunity in recalcitrant inflammatory bowel disease

Inflammatory bowel diseases (IBD) remain a relapsing, treatment-refractory disorder marked by progressive tissue injury and inflammation despite expanding immune-targeted therapies. We established a prospective cohort integrating stromal biobanking, functional phenotyping, cross-cohort benchmarking, and outcome modeling to define disease-anchored cellular states. Colonic myofibroblasts from 34 individuals spanning health, ulcerative colitis, and Crohns disease resolved into two dominant states: inflammatory (IMFs) and quiescent (QMFs) myofibroblasts. QMF predominance forecasted remission, whereas IMF predominance increased the odds of worsening endoscopic severity despite therapy escalation during follow-up by [~]4.6-fold, linking early stromal biology to clinical outcomes. Unlike QMFs, IMFs exhibited a senescence-associated secretory phenotype that impaired epithelial stemness, barrier integrity, and innate immune fitness. State-guided prioritization identified EDNRB-antagonism as a high-confidence stromal intervention, reversing pathogenic phenotypes across orthogonal assays and species. Outcome simulation positioned stromal-state reversibility by EDNRB-antagonism as a precision axis, reducing odds of recalcitrance by [~]96.4% and reframing treatment resistance as a reversible stromal state. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=185 HEIGHT=200 SRC="FIGDIR/small/720931v2_ufig1.gif" ALT="Figure 1"> View larger version (88K): org.highwire.dtl.DTLVardef@3b2c50org.highwire.dtl.DTLVardef@da5400org.highwire.dtl.DTLVardef@1c100c1org.highwire.dtl.DTLVardef@1882e1_HPS_FORMAT_FIGEXP M_FIG C_FIG In this work, Tindle et al. identify reversible stromal states that govern remission vs. recalcitrant outcomes in IBD and nominate precision reprogramming of pathogenic myofibroblasts as a new therapeutic strategy.

physiology↗

bioRxiv2024

Pathogenic Bacteroides fragilis strains can emerge from gut-resident commensals

Bacteroides fragilis is a prominent member of the human gut microbiota, playing crucial roles in maintaining gut homeostasis and host health. Although it primarily functions as a beneficial commensal, B. fragilis can become pathogenic. To determine the genetic basis of its duality, we conducted a comparative genomic analysis of 813 B. fragilis strains, representing both commensal and pathogenic origins. Our findings reveal that pathogenic strains emerge across diverse phylogenetic lineages, due in part to rapid gene exchange and the adaptability of the accessory genome. We identified 16 phylogenetic groups, differentiated by genes associated with capsule composition, interspecies competition, and host interactions. A microbial genome-wide association study identified 44 genes linked to extra-intestinal survival and pathogenicity. These findings reveal how genomic diversity within commensal species can lead to the emergence of pathogenic traits, broadening our understanding of microbial evolution in the gut.

microbiology↗

bioRxiv2023

Pangenome comparison of Bacteroides fragilis genomospecies unveil genetic diversity and ecological insights

Bacteroides fragilis is a Gram-negative commensal bacterium commonly found in the human colon that differentiates into two genomospecies termed division I and II. We leverage a comprehensive collection of 694 B. fragilis whole genome sequences and report differential gene abundance to further support the recent proposal that divisions I and II represent separate species. In division I strains, we identify an increased abundance of genes related to complex carbohydrate degradation, colonization, and host niche occupancy, confirming the role of division I strains as gut commensals. In contrast, division II strains display an increased prevalence of plant cell wall degradation genes and exhibit a distinct geographic distribution, primarily originating from Asian countries, suggesting dietary influences. Notably, division II strains have an increased abundance of genes linked to virulence, survival in toxic conditions, and antimicrobial resistance, consistent with a higher incidence of these strains in bloodstream infections. This study provides new evidence supporting a recent proposal for classifying divisions I and II B. fragilis strains as distinct species, and our comparative genomic analysis reveals their niche-specific roles.

genomics↗

bioRxiv2021

Artificial Intelligence-rationalized balanced PPARα/γ dual agonism resets the dysregulated macrophage processes in inflammatory bowel disease

A computational platform, the Boolean network explorer (BoNE), has recently been developed to infuse AI-enhanced precision into drug discovery; it enables querying and navigating invariant Boolean Implication Networks of disease maps for prioritizing high-value targets. Here we used BoNE to query an Inflammatory Bowel Disease (IBD)-map and prioritize a therapeutic strategy that involves dual agonism of two nuclear receptors, PPAR/{gamma}. Balanced agonism of PPAR/{gamma} was predicted to modulate macrophage processes, ameliorate colitis in network-prioritized animal models, reset the gene expression network from disease to health, and achieve a favorable therapeutic index that tracked other FDA-approved targets. Predictions were validated using a balanced and potent PPAR/{gamma}-dual agonist (PAR5359) in two pre-clinical murine models, i.e., Citrobacter rodentium-induced infectious colitis and DSS-induced colitis. Using a combination of selective inhibitors and agonists, we show that balanced dual agonism promotes bacterial clearance more efficiently than individual agonists, both in vivo and in vitro. PPARa is required and its agonism is sufficient to induce the pro-inflammatory cytokines and cellular ROS, which are essential for bacterial clearance and immunity, whereas PPARg-agonism blunts these responses, delays microbial clearance and induces the anti-inflammatory cytokine, IL10; balanced dual agonism achieved controlled inflammation while protecting the gut barrier and reversal of the transcriptomic network. Furthermore, dual agonism reversed the defective bacterial clearance observed in PBMCs derived from IBD patients. These findings not only deliver a macrophage modulator for use as barrier-protective therapy in IBD, but also highlight the potential of BoNE to rationalize combination therapy.

bioinformatics↗

bioRxiv2019

Chemical Impacts of the Microbiome Across Scales Reveal Novel Conjugated Bile Acids

A mosaic of cross-phyla chemical interactions occurs between all metazoans and their microbiomes. In humans, the gut harbors the heaviest microbial load, but many organs, particularly those with a mucosal surface, associate with highly adapted and evolved microbial consortia1. The microbial residents within these organ systems are increasingly well characterized, yielding a good understanding of human microbiome composition, but we have yet to elucidate the full chemical impact the microbiome exerts on an animal and the breadth of the chemical diversity it contributes2. A number of molecular families are known to be shaped by the microbiome including short-chain fatty acids, indoles, aromatic amino acid metabolites, complex polysaccharides, and host lipids; such as sphingolipids and bile acids3-11. These metabolites profoundly affect host physiology and are being explored for their roles in both health and disease. Considering the diversity of the human microbiome, numbering over 40,000 operational taxonomic units12, a plethora of molecular diversity remains to be discovered. Here, we use unique mass spectrometry informatics approaches and data mapping onto a murine 3D-model13-15 to provide an untargeted assessment of the chemical diversity between germ-free (GF) and colonized mice (specific-pathogen free, SPF), and report the finding of novel bile acids produced by the microbiome in both mice and humans that have evaded characterization despite 170 years of research on bile acid chemistry16.

microbiology↗

bioRxiv2018

Dysregulation of the engulfment pathway in the gut fuels Inflammatory Bowel Disease

BACKGROUND & AIMSLuminal dysbiosis is ubiquitous in inflammatory bowel disease (IBD), but how the microbes trigger pro-inflammatory cascades in the epithelial and phagocytic cells remains unknown. Here we investigated the role of the microbial sensor ELMO1 (Engulfment and Cell Motility Protein-1) in sensing and responding to IBD-associated microbes in the gut epithelium and in macrophages.\n\nMETHODSA stem cell-based technique is used to grow enteroids from WT and ELMO1-/-mice and from colonic biopsies of patients with IBD and subsequently differentiate them into enteroid-derived monolayers (EDMs) that mimic the gut epithelium/Gut in a dish. EDMs infected with IBD-associated invasive E. coli-LF82 were analyzed for bacterial internalization, cytokine production and monocyte-recruitment when co-cultured with monocytes.\n\nRESULTSExpression of ELMO1 is elevated in the colonic epithelium and in the inflammatory infiltrates within the lamina propria in IBD, higher expression correlated with elevated expression of pro-inflammatory cytokines, MCP-1 and TNF-. ELMO1-/-murine EDMs displayed a significant reduction of bacterial internalization through epithelial tight junctions and in MCP-1 production compared to WT mice. MCP-1 that is released from the epithelium recruited monocytes. Once recruited, macrophages required ELMO1 to engulf the bacteria and propagate a robust pro-inflammatory cytokine storm (TNF-).\n\nCONCLUSIONSELMO1 couples microbial-sensing to inflammation in both phagocytic and non-phagocytic host cells; it is required for the production of MCP-1 in the epithelium and TNF- in macrophages. Findings raise the possibility that upregulation of epithelial ELMO1 and the epithelial ELMO1[->]MCP-1 axis may serve as an early biomarker and therapeutic target, respectively, in IBD and other disorders of inflammation.

cell biology↗