Biology subjects

Kyaw, T. S.

Publications and source records attributed to Kyaw, T. S..

7 recordsLinked to original sources

bioRxiv2026

Immune-Mediated Necrotic Cell Death Initiated by Stressed Cardiomyocytes is a Major Contributor to Cardiomyocyte Loss Following Myocardial Infarction

AimsPercutaneous coronary intervention has improved survival following myocardial infarction, yet strategies to further reduce infarct size are limited. This study investigates the role of cytotoxic {gamma}{delta}-T cells in ischemic cardiomyocyte death and potential therapeutic interventions to reduce infarct size. MethodsGenetic and pharmacological approaches were used to delete {gamma}{delta}-T cells and their specific proteins to assess their involvement in cardiomyocyte death using mouse models of permanent ligation (PL) and ischemia/reperfusion (IR). Results{gamma}{delta}-T cells accumulated in infarct zones within 6h post-PL, expressing IFN-{gamma}, TNF-, granzyme B, and perforin. Their deletion reduced infarct size by 73% (PL) and 64% (IR). They induced cardiomyocyte death via apoptosis, gasdermin E-dependent pyroptosis, and MLKL-dependent necroptosis; {gamma}{delta}-T cell depletion reduced apoptosis by 80% and pyroptosis by 38%, with perforin deletion yielding similar effects. Necroptosis, attributed to combined IFN-{gamma}/TNF- cytotoxicity, decreased by 67%. Cytoplasmic DNA (cDNA) in stressed cardiomyocytes activated the cGAS/STING pathway, inducing expression of chemoattractant MCP-1 and death signal RAE-1. These signals recruited and activated {gamma}{delta}-T cells, which then triggered the death of the stressed cardiomyocytes. STING inhibition suppressed these expressions, reducing {gamma}{delta}-T cell accumulation and infarct size. NKG2D-deficient {gamma}{delta}-T cells prevented activation and reduced infarct size. Administration of an anti-IFNAR antibody at PL onset markedly reduced infarct size. ConclusionEarly activation of cytotoxic {gamma}{delta}-T cells via cardiomyocyte stress signals contributes significantly to immunogenic cardiomyocyte death. Targeting the STING pathway and type I interferon signalling presents a promising therapeutic avenue to mitigate infarct size and improve outcomes.

immunology↗

bioRxiv2026

A widespread gut bacterial lineage distinguished by redox metabolism and phage defense

Genomic variation within gut microbial species can have consequences for host health and disease. However, for low abundance species, these variations can be difficult to capture by both culture-dependent and -independent approaches. Here, we focus on the prevalent but low abundance gut Actinomycetota Eggerthella lenta. We developed a selective media for sensitive and specific isolation of E. lenta from human stool. Genomes from 87 new E. lenta isolates were combined with prior high-quality assemblies, shedding light on within-species functional diversity. Phylogenetic analysis revealed a broadly distributed subclade, which we refer to as E. lenta Group B. This lineage was differentiated by its metabolic potential and bacteriophage defense, though mobile elements were shared broadly across the species. Notably, Group B was positively associated with intestinal inflammation in subjects with inflammatory bowel disease. Overall, these results emphasize the importance of bacterial population structure in host-microbiome interactions and provide a framework to study low-abundance gut taxa. HIGHLIGHTSO_LISelective media enables E. lenta isolation and reveals high prevalence in humans C_LIO_LIDiscovery of a distinctive lineage within E. lenta undergoing genome reduction C_LIO_LIE. lenta Group B has altered metabolism, phage defense, and disease associations C_LIO_LIA widespread conjugative plasmid could enable improved genetics C_LI

microbiology↗

bioRxiv2025

Shifts in the human gut microbiome during cancer chemotherapy are diet-dependent

Numerous studies have implicated both dietary intake and the human gut microbiome in colorectal cancer (CRC) treatment outcomes. However, little is known about how patients adjust their dietary intake during cancer chemotherapy or if these dietary changes contribute to treatment-associated alterations in the gut microbiome. We performed paired longitudinal diet and microbiome analysis during CRC treatment with oral fluoropyrimidines (NCT04054908) and validated key associations using cell culture assays. At each timepoint, diet was measured by averaging up to 3 consecutive days of 24-hour dietary records (NCI ASA24; 35 patients; 2.5{+/-}1.1 timepoints per patient), while microbiome composition was measured from stool (16S rRNA gene sequencing, metagenomics, qPCR; 40 patients; 5.6{+/-}1.4 timepoints per patient). Diet quality significantly decreased during chemotherapy. Carbohydrate and refined grain intake increased, accompanied by decreased consumption of fats, nuts and seeds, and fat-soluble micronutrients. Multiple individual dietary components were strongly linked to the gut microbiome. Decreases in theobromine intake correlated with decreases in overall microbial diversity and more gastrointestinal toxicities. Diet shifts partly explained changes in bacterial abundance during chemotherapy, including more severe depletion of Faecalibacterium prausnitzii in patients with decreased vitamin K1 intake. Changes in diet were correlated with multiple bacterial gene families involved in micronutrient metabolism and drug sensitivity. Increased copper intake was linked to decreased Fusobacterium nucleatum in patients and inhibited F. nucleatum in cell assays. Together, these data suggest that changes in diet during chemotherapy contribute to changes in gut bacterial diversity, taxonomic composition, and gene abundance. Our approach may generalize to other cancer therapies and emphasizes the need for collecting more robust dietary data in clinical microbiome studies.

microbiology↗

bioRxiv2025

Comprehensive Cross-Domain Taxonomic Classification of Microbiotas using Partitioned Amplification Multiplexed Amplicon Sequencing (PAMA-seq)

Microbial communities encompass diverse bacteria, archaea, and eukaryotes that play vital roles in ecosystems and host health. Comprehensive analysis of these communities requires accurate, quantitative, and cross-domain profiling, yet current sequencing methods--metagenome shotgun sequencing (MGS) and ribosomal RNA (rRNA) amplicon sequencing--struggle to achieve these goals in a single assay. MGS provides broad functional insights but suffers from high cost, computational burden, and reliance on incomplete reference databases. rRNA amplicon sequencing, while more taxonomically targeted, typically profiles either prokaryotes or eukaryotes separately, depending on the chosen primer sets, and thus lacks simultaneous cross-domain resolution. To address these limitations, we developed PAMA-seq, a droplet-digital multiplex PCR technique. PAMA-seq partitions DNA sample from microbial communities into nanoliter droplets, each containing a single template molecule, and independently amplifies both the 16S and 18S rRNA genes, resulting in uniform amplification efficiency and accurate quantification. We validated PAMA-seq on a synthetic microbial community, a stool sample from a patient with colorectal cancer, and a coastal seawater sample. The method provided stable, cross-domain taxonomic profiles at sequencing depths as low as 104 reads--one to two orders of magnitude fewer than comparable shotgun metagenomics approaches--while significantly reducing variability between replicates. By combining comprehensive domain coverage with low sequencing depth requirements, PAMA-seq offers an efficient, cost-effective, and scalable method for monitoring microbial communities across diverse ecosystems, from clinical samples to global marine environments.

microbiology↗

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↗

bioRxiv2020

Distinctive Gene and Protein Characteristics of Extremely Piezophilic Colwellia

BackgroundThe deep ocean is characterized by low temperatures, high hydrostatic pressures, and low concentrations of organic matter. While these conditions likely select for distinct genomic characteristics within prokaryotes, the attributes facilitating adaptation to the deep ocean are relatively unexplored. In this study, we compared the genomes of seven strains within the genus Colwellia, including some of the most piezophilic microbes known, to identify genomic features that enable life in the deep sea. ResultsSignificant differences were found to exist between piezophilic and non-piezophilic strains of Colwellia. Piezophilic Colwellia have a more basic and hydrophobic proteome. The piezophilic abyssal and hadal isolates have more genes involved in replication/recombination/repair, cell wall/membrane biogenesis, and cell motility. The characteristics of respiration, pilus generation, and membrane fluidity adjustment vary between the strains, with operons for a nuo dehydrogenase and a tad pilus only present in the piezophiles. In contrast, the piezosensitive members are unique in having the capacity for dissimilatory nitrite and TMAO reduction. A number of genes exist only within deep-sea adapted species, such as those encoding d-alanine-d-alanine ligase for peptidoglycan formation, alanine dehydrogenase for NADH/NAD+ homeostasis, and archaeal methyltransferase for tRNA modification. Many of these piezophile-specific genes are in variable regions of the genome near genomic islands, transposases, and toxin-antitoxin systems. ConclusionsWe identified a number of adaptations that may facilitate deep-sea radiation in members of the genus Colwellia, as well as in other piezophilic bacteria. An enrichment in more basic and hydrophobic amino acids could help piezophiles stabilize and limit water intrusion into proteins as a result of high pressure. Variations in genes associated with the membrane, including those involved in unsaturated fatty acid production and respiration, indicate that membrane-based adaptations are critical for coping with high pressure. The presence of many piezophile-specific genes near genomic islands highlights that adaptation to the deep ocean may be facilitated by horizontal gene transfer through transposases or other mobile elements. Some of these genes are amenable to further study in genetically tractable piezophilic and piezotolerant deep-sea microorganisms.

microbiology↗