Biology subjects

Bhatt, A. P.

Publications and source records attributed to Bhatt, A. P..

6 recordsLinked to original sources

bioRxiv2026

Fatty Acid Oxidation Suppression Reprograms Fibroblasts in Fibrostenotic Crohns Disease

Fibrostenotic complications represent a major cause of morbidity in Crohns disease (CD), yet the cellular mechanisms that drive intestinal fibrosis independent of active inflammation remain poorly understood. Here, we identify impaired fatty acid oxidation (FAO) as a defining metabolic feature of fibroblasts in fibrostenotic CD. Untargeted lipidomics of non-inflamed colonic tissue from CD patients demonstrated enrichment of triacylglycerols and long-chain acylcarnitines, suggesting altered lipid utilization. Across three independent RNA-sequencing cohorts, including treatment-naive pediatric ileal biopsies, FAO genes (CPT1A, CPT2, SLC25A20) were selectively downregulated in patients with or destined to develop fibrostenotic disease. Single-cell RNA-sequencing localized these transcriptional alterations specifically to fibroblasts within strictured ileum. Primary fibroblasts derived from fibrostenotic CD exhibited increased neutral lipid accumulation, impaired mitochondrial fatty acid trafficking, and diminished responsiveness to PPAR{gamma}-mediated suppression of TGF{beta}-induced myofibroblast activation. Together, these findings demonstrate that FAO impairment is a conserved, fibroblast-specific metabolic program associated with intestinal fibrosis in CD and suggest that metabolic modulation of stromal cells represents a potential therapeutic strategy for fibrostenotic disease.

genomics↗

bioRxiv2025

Commercially Purchased and In-House Bred C57BL/6 Mice with Different Gut Microbiota Exhibit Distinct Indomethacin-Induced Toxicities

Non-steroidal anti-inflammatory drug (NSAID)-induced toxicities are a significant clinical problem, yet the factors influencing these outcomes remain incompletely understood. Here, we investigated the impact of mouse vendor on indomethacin-induced injury using C57BL/6 mice from different breeding facilities (in-house "Tar Heel" and commercial Charles River). We found that Tar Heel mice exhibited significantly enhanced susceptibility to indomethacin toxicity, characterized by greater body weight loss, increased ileal ulceration, elevated fecal lipocalin-2 levels, and higher goblet cell numbers in ileum compared to Charles River mice. Importantly, whole genome metagenomic analysis revealed distinct baseline gut microbiomes between the two types of mice. Notably, Tar Heel mice showed higher abundances of {beta}-glucuronidase (GUS)-producing bacteria, particularly those expressing Loop-1 GUS enzymes, and elevated levels of mucolytic enzyme-encoding bacteria. These differences suggest that enhanced indomethacin toxicity observed in Tar Heel mice may be related to functional changes in their gut microbiome, which may predispose to an exaggerated response to NSAID exposure. Together, our findings demonstrate that vendor-specific differences significantly influence NSAID-induced intestinal toxicity and highlight the importance of considering mouse sources and gut microbial compositions in experimental design. Moreover, we highlight potential functional roles that gut microbes play in host-indomethacin interactions.

microbiology↗

bioRxiv2025

Sex-Dependent Responses in Mice to Indomethacin-Induced Injury and Gut Microbiome-Targeted Alleviation

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used widely but produce gastrointestinal (GI) toxicities in both short- and long-term users. Previous studies have shown that the intestinal microbiota play an important role in gut damage and that gut microbial {beta}-glucuronidase (GUS) inhibitors can alleviate NSAID-induced injury in male mice by blocking the GI reactivation of NSAID-glucuronides. Here, in both male and female C57BL/6 mice, we examine the effects of indomethacin alone and with the GUS inhibitor UNC10201652. Oral delivery of 5 mg/kg body weight indomethacin over five days decreased body weight, induced colonic and hepatic inflammatory cytokine gene expression, and enlarged the spleens of both male and female mice. However, sex-specific inflammatory responses to indomethacin were observed, with males demonstrating more colonic injury while females presented greater splenic and hepatic toxic responses. Females also showed a unique indomethacin-induced bloom of fecal Verrucomicrobia as measured by 16S rRNA metagenomic sequencing. UNC10201652 alleviated aspects of these indomethacin-induced toxicities, including features of the male-specific colonic damage and the female-specific compositional changes and spleen and liver toxicities. Thus, GI and non-GI tissues in male and female mice respond distinctly to indomethacin-induced damage. These findings advance our understanding of how sex impacts systemic responses to xenobiotic exposure and may lead to improved therapeutic outcomes with these widely used drugs.

biochemistry↗

bioRxiv2024

Giardia Antagonizes Beneficial Functions of Indigenous and Therapeutic Intestinal Bacteria during Malnutrition

Undernutrition in children commonly disrupts the structure and function of the small intestinal microbial community, leading to enteropathies, compromised metabolic health, and impaired growth and development. The mechanisms by which diet and microbes mediate the balance between commensal and pathogenic intestinal flora remain elusive. In a murine model of undernutrition, we investigated the direct interactions Giardia lamblia, a prevalent small intestinal pathogen, on indigenous microbiota and specifically on Lactobacillus strains known for their mucosal and growth homeostatic properties. Our research reveals that Giardia colonization shifts the balance of lactic acid bacteria, causing a relative decrease in Lactobacillus spp. and an increase in Bifidobacterium spp. This alteration corresponds with a decrease in multiple indicators of mucosal and nutritional homeostasis. Additionally, protein-deficient conditions coupled with Giardia infection exacerbate the rise of primary bile acids and susceptibility to bile acid-induced intestinal barrier damage. In epithelial cell monolayers, Lactobacillus spp. mitigated bile acid-induced permeability, showing strain-dependent protective effects. In vivo, L. plantarum, either alone or within a Lactobacillus spp consortium, facilitated growth in protein-deficient mice, an effect attenuated by Giardia, despite not inhibiting Lactobacillus colonization. These results highlight Giardias potential role as a disruptor of probiotic functional activity, underscoring the imperative for further research into the complex interactions between parasites and bacteria under conditions of nutritional deficiency.

microbiology↗

bioRxiv2024

Mouse Adaptation of Human Inflammatory Bowel Diseases Microbiota Enhances Colonization Efficiency and Alters Microbiome Aggressiveness Depending on Recipient Colonic Inflammatory Environment

Understanding the cause vs consequence relationship of gut inflammation and microbial dysbiosis in inflammatory bowel diseases (IBD) requires a reproducible mouse model of human-microbiota-driven experimental colitis. Our study demonstrated that human fecal microbiota transplant (FMT) transfer efficiency is an underappreciated source of experimental variability in human microbiota associated (HMA) mice. Pooled human IBD patient fecal microbiota engrafted germ-free (GF) mice with low amplicon sequence variant (ASV)-level transfer efficiency, resulting in high recipient-to-recipient variation of microbiota composition and colitis severity in HMA Il-10-/- mice. In contrast, mouse-to-mouse transfer of mouse-adapted human IBD patient microbiota transferred with high efficiency and low compositional variability resulting in highly consistent and reproducible colitis phenotypes in recipient Il-10-/- mice. Human-to-mouse FMT caused a population bottleneck with reassembly of microbiota composition that was host inflammatory environment specific. Mouse-adaptation in the inflamed Il-10-/-host reassembled a more aggressive microbiota that induced more severe colitis in serial transplant to Il-10-/- mice than the distinct microbiota reassembled in non-inflamed WT hosts. Our findings support a model of IBD pathogenesis in which host inflammation promotes aggressive resident bacteria, which further drives a feed-forward process of dysbiosis exacerbated gut inflammation. This model implies that effective management of IBD requires treating both the dysregulated host immune response and aggressive inflammation-driven microbiota. We propose that our mouse-adapted human microbiota model is an optimized, reproducible, and rigorous system to study human microbiome-driven disease phenotypes, which may be generalized to mouse models of other human microbiota-modulated diseases, including metabolic syndrome/obesity, diabetes, autoimmune diseases, and cancer.

microbiology↗

bioRxiv2021

A proximal-to-distal survey of healthy adult human small intestine and colon epithelium by single-cell transcriptomics

Background and AimsSingle-cell transcriptomics offer unprecedented resolution of tissue function at the cellular level, yet studies analyzing healthy adult human small intestine and colon are sparse. Here, we present single-cell transcriptomics covering the duodenum, jejunum, ileum, and ascending, transverse, and descending colon from 3 humans. Methods12,590 single epithelial cells from three independently processed organ donors were evaluated for organ-specific lineage biomarkers, differentially regulated genes, receptors, and drug targets. Analyses focused on intrinsic cell properties and capacity for response to extrinsic signals along the gut axis across different humans. ResultCells were assigned to 25 epithelial lineage clusters. Human intestinal stem cells (ISCs) are not specifically marked by many murine ISC markers. Lysozyme expression is not unique to human Paneth cells (PCs), and PCs lack expression of expected niche-factors. BEST4+ cells express NPY and show maturational differences between SI and colon. Tuft cells possess a broad ability to interact with the innate and adaptive immune systems through previously unreported receptors. Some classes of mucins, hormones, cell-junction, and nutrient absorption genes show unappreciated regional expression differences across lineages. Differential expression of receptors and drug targets across lineages reveals biological variation and potential for variegated responses. ConclusionsOur study identifies novel lineage marker genes; covers regional differences; shows important differences between mouse and human gut epithelium; and reveals insight into how the epithelium responds to the environment and drugs. This comprehensive cell atlas of the healthy adult human intestinal epithelium resolves likely functional differences across anatomical regions along the gastrointestinal tract and advances our understanding of human intestinal physiology.

physiology↗