Biology subjects

Trepka, K.

Publications and source records attributed to Trepka, K..

6 recordsLinked to original sources

bioRxiv2026

Female-enriched Eggerthella lenta drives neuroinflammation and IFN-γ via host receptor TLR2

Women are at increased risk of autoimmune diseases, including multiple sclerosis (MS); however, the degree to which sex differences in the gut microbiota impact autoimmunity remains largely unexplored. Our 27-cohort meta-analysis revealed 60 sex-associated gut bacterial species. Leveraging an independent clinical cohort, we demonstrate that female-enriched species significantly associate with MS status and clinical disability (EDSS). Top female-enriched species Eggerthella lenta drove disease in the experimental autoimmune encephalomyelitis (EAE) MS model, consistent with brain and gut lamina propria T cell infiltration and MS-associated T helper (Th) signatures. E. lenta induced intestinal Th1 and Th17 in healthy mice, independent of bacterial viability. Mechanistically, we demonstrate that TLR2 directly drives E. lenta-induced IFN-{gamma} production in Th cells and is necessary for exacerbation of EAE. Together, we identify a causal host-microbe axis contributing to sex differences in autoimmunity and provide a framework for evaluating sex as a biological variable in human microbiome research. HIGHLIGHTSO_LI27-cohort meta-analysis identifies a robust sex-signature in human gut microbiota. C_LIO_LIFemale-enriched species are associated with MS risk and severity. C_LIO_LIFemale-enriched Eggerthella lenta exacerbates the EAE model. C_LIO_LIE. lenta impacts neuroinflammation via toll-like receptor 2. C_LI

microbiology↗

bioRxiv2025

Gut bacterial lactate stimulates lung epithelial mitochondria and exacerbates acute lung injury

Acute respiratory distress syndrome (ARDS) is an often fatal critical illness where lung epithelial injury leads to intrapulmonary fluid accumulation. ARDS became widespread during the COVID-19 pandemic, motivating a renewed effort to understand the complex etiology of this disease. Rigorous prior work has implicated lung endothelial and epithelial injury in response to an insult such as bacterial infection; however, the impact of microorganisms found in other organs on ARDS remains unclear. Here, we use a combination of gnotobiotic mice, cell culture experiments, and re-analyses of a large metabolomics dataset from ARDS patients to reveal that gut bacteria impact lung cellular respiration by releasing metabolites that alter mitochondrial activity in lung epithelium. Colonization of germ-free mice with a complex gut microbiota stimulated lung mitochondrial gene expression. A single human gut bacterial species, Bifidobacterium adolescentis, was sufficient to replicate this effect, leading to a significant increase in mitochondrial membrane potential in lung epithelial cells. We then used genome sequencing and mass spectrometry to confirm that B. adolescentis produces L-lactate, which was sufficient to increase mitochondrial activity in lung epithelial cells. Finally, we found that serum lactate was significantly associated with disease severity in patients with ARDS from the Early Assessment of Renal and Lung Injury (EARLI) cohort. Together, these results emphasize the importance of more broadly characterizing the microbial etiology of ARDS and other lung diseases given the ability of gut bacterial metabolites to remotely control lung cellular respiration. Our discovery of a single bacteria-metabolite pair provides a proof-of-concept for systematically testing other microbial metabolites and a mechanistic biomarker that could be pursued in future clinical studies. Furthermore, our work adds to the growing literature linking the microbiome to mitochondrial function, raising intriguing questions as to the bidirectional communication between our endo- and ecto-symbionts.

molecular biology↗

bioRxiv2024

Expansion of a bacterial operon during cancer treatment ameliorates drug toxicity

Dose-limiting toxicities remain a major barrier to drug development and therapy, revealing the limited predictive power of human genetics. Herein, we demonstrate the utility of a more comprehensive approach to studying drug toxicity through longitudinal study of the human gut microbiome during colorectal cancer (CRC) treatment (NCT04054908) coupled to cell culture and mouse experiments. 16S rRNA gene sequencing revealed significant shifts in gut microbial community structure during oral fluoropyrimidine treatment across multiple patient cohorts, in mouse small and large intestinal contents, and in patient-derived ex vivo communities. Metagenomic sequencing revealed marked shifts in pyrimidine-related gene abundance during oral fluoropyrimidine treatment, including enrichment of the preTA operon, which is sufficient for the inactivation of active metabolite 5-fluorouracil (5-FU). preTA+ bacteria depleted 5-FU in gut microbiota grown ex vivo and the mouse distal gut. Germ-free and antibiotic-treated mice experienced increased fluoropyrimidine toxicity, which was rescued by colonization with the mouse gut microbiota, preTA+ E. coli, or preTA-high CRC patient stool. Finally, preTA abundance was negatively associated with fluoropyrimidine toxicity in patients. Together, these data support a causal, clinically relevant interaction between a human gut bacterial operon and the dose-limiting side effects of cancer treatment. Our approach is generalizable to other drugs, including cancer immunotherapies, and provides valuable insights into host-microbiome interactions in the context of disease. One Sentence Summary: Gut microbial enzymes can be used to predict and prevent anticancer drug toxicity.

systems biology↗

bioRxiv2022

Human gut Actinobacteria boost drug absorption by secreting P-glycoprotein ATPase inhibitors

Drug efflux transporters are a major determinant of drug efficacy and toxicity. A canonical example is P-glycoprotein (P-gp), an efflux transporter that controls the intestinal absorption of diverse compounds. Despite reports that P-gp expression depends on the microbiome, the mechanisms responsible and their physiological relevance remain unclear. Surprisingly, we found that the cardiac drug-metabolizing gut Actinobacterium Eggerthella lenta increases drug absorption in mice through post-translational inhibition of P-gp ATPase efflux activity. P-gp inhibition is conserved in the Eggerthellaceae family but absent in other Actinobacteria. Comparative genomics identified genes associated with P-gp inhibition. Finally, activity-guided biochemical fractionation coupled to metabolomics identified a cluster of isoflavonoids produced by E. lenta related to plant-derived P-gp inhibitors. These results highlight the unexpected overlap between diet- and microbiome-derived compounds, and the importance of considering the broader relevance of the gut microbiome for drug disposition beyond first-pass metabolism. One Sentence SummaryThe gut bacterium Eggerthella lenta secretes inhibitors of P-glycoprotein ATPase activity, accelerating drug absorption.

microbiology↗

bioRxiv2022

Systems biology illuminates alternative metabolic niches in the human gut microbiome

Human gut bacteria perform diverse metabolic functions with consequences for host health. The prevalent and disease-linked Actinobacterium Eggerthella lenta performs several unusual chemical transformations, but it does not metabolize sugars and its core growth strategy remains unclear. To obtain a comprehensive view of the metabolic network of E. lenta, we generated several complementary resources: defined culture media, metabolomics profiles of strain isolates, and a curated genome-scale metabolic reconstruction. Stable isotope-resolved metabolomics revealed that E. lenta uses acetate as a key carbon source while catabolizing arginine to generate ATP, traits which could be recapitulated in silico by our updated metabolic model. We compared these in vitro findings with metabolite shifts observed in E. lenta-colonized gnotobiotic mice, identifying shared signatures across environments and highlighting catabolism of the host signaling metabolite agmatine as an alternative energy pathway. Together, our results elucidate a distinctive metabolic niche filled by E. lenta in the gut ecosystem.

microbiology↗

bioRxiv2018

Modifying Reaction Diffusion: A Numerical Model for Turing Morphogenesis, Ben Jacob Patterns, and Cancer Growth

Building models of organismal growth enables predictions of natural variability and responses to perturbations. Complex systems such as animal pattern development and bacterial colonies can be modeled numerically using a reaction-diffusion system with relatively few factors and yield qualitatively accurate results, allowing exploration of different equilibrium and non-equilibrium solutions. Here, a discrete numerical reaction diffusion system is used to qualitatively reproduce both common animal patterns and Ben-Jacob bacterial growth.

biophysics↗