Biology subjects

Mishra, A. A.

Publications and source records attributed to Mishra, A. A..

4 recordsLinked to original sources

bioRxiv2025

Microbiota-derived short-chain fatty acids mediate Candida albicans gastrointestinal colonization resistance

The gut microbiota plays a critical role in constraining Candida albicans (Ca) colonization of the gastrointestinal (GI) tract, a key precursor to disseminated fungal infection in immunocompromised hosts. Depletion of commensal microbiota increases Ca burden and promotes dissemination, yet the mechanisms of microbiota-mediated Ca colonization resistance remain poorly defined. Here, we show that gut microbiota-derived short-chain fatty acids (SCFAs) directly inhibit Ca growth by impairing hexose uptake, disrupting central carbon metabolism, and inducing intracellular acidification. In vivo, SCFAs enhance Ca colonization resistance only in the presence of an intact gut microbiome, which is required to drive SCFA-induced taxonomic shifts that further augment resistance. Commensal microbiota lacking SCFA production exhibit diminished capacity to restrict Ca colonization, while prebiotic therapy that increases luminal SCFA levels enhances Ca clearance. These findings define a critical microbiota-metabolite mechanism underlying Ca colonization resistance and suggest strategies to modulate GI fungal burden and prevent invasive disease.

microbiology↗

bioRxiv2025

Identifying Optimal Machine Learning Approaches for Microbiome-Metabolomics Integration with Stable Feature Selection

Microbiome research is often limited by methodological inconsistencies that reduce reproducibility and functional insight. Traditional taxonomy-based profiling is limited by sparse data, variable resolution, and reliance on gDNA sequencing which provides only indirect links to microbial function. Multi-omics integration offers a framework for linking community composition to functional outputs, but progress has been hindered by the lack of standardized frameworks and inconsistent use of machine learning. In particular, feature selection stability, which is central to biomarker discovery and experimental validation, remains underexplored. Here, we systematically benchmarked three widely used algorithms (Elastic Net, Random Forest, XGBoost) across seven multi-omics integration strategies and single-omics models. Additionally, we evaluated the impact of transforming metabolomics and taxonomic abundance data. Using human gut microbiome datasets that integrate metagenomic taxonomic profiles with metabolomics, we evaluated models for 9 binary and 8 continuous outcomes across 20 train/test splits per dataset. We further assessed the effect of feature reduction on both predictive accuracy and feature selection stability. Nonlinear learners were most consistently competitive: continuous outcomes favored metabolomics-dominant models, whereas binary outcomes favored stacked multi-omics models. Random Forest and XGBoost also yielded greater feature selection stability, particularly for full dimensional metabolomics data. Together, these findings demonstrate how integration strategy, algorithm choice, and data preprocessing jointly shape predictive performance and feature selection reproducibility in multi-omics microbiome modeling.

bioinformatics↗

bioRxiv2024

The Sociodemographic and Lifestyle Correlates of Epigenetic Aging in a Nationally Representative U.S. Study of Younger Adults

ImportanceEpigenetic clocks represent molecular evidence of disease risk and aging processes and have been used to identify how social and lifestyle characteristics are associated with accelerated biological aging. However, most of this research is based on older adult samples who already have measurable chronic disease. ObjectiveTo investigate whether and how sociodemographic and lifestyle characteristics are related to biological aging in a younger adult sample across a wide array of epigenetic clock measures. DesignNationally representative prospective cohort study. SettingUnited States (U.S.). ParticipantsData come from the National Longitudinal Study of Adolescent to Adult Health, a national cohort of adolescents in grades 7-12 in U.S. in 1994 followed for 25 years over five interview waves. Our analytic sample includes participants followed-up through Wave V in 2016-18 who provided blood samples for DNA methylation (DNAm) testing (n=4237) at Wave V. ExposureSociodemographic (sex, race/ethnicity, immigrant status, socioeconomic status, geographic location) and lifestyle (obesity status, exercise, tobacco, and alcohol use) characteristics. Main OutcomeBiological aging assessed from blood DNAm using 16 epigenetic clocks when the cohort was aged 33-44 in Wave V. ResultsWhile there is considerable variation in the mean and distribution of epigenetic clock estimates and in the correlations among the clocks, we found sociodemographic and lifestyle factors are more often associated with biological aging in clocks trained to predict current or dynamic phenotypes (e.g., PhenoAge, GrimAge and DunedinPACE) as opposed to clocks trained to predict chronological age alone (e.g., Horvath). Consistent and strong associations of faster biological aging were found for those with lower levels of education and income, and those with severe obesity, no weekly exercise, and tobacco use. Conclusions and RelevanceOur study found important social and lifestyle factors associated with biological aging in a nationally representative cohort of younger-aged adults. These findings indicate that molecular processes underlying disease risk can be identified in adults entering midlife before disease is manifest and represent useful targets for interventions to reduce social inequalities in heathy aging and longevity. Key PointsO_ST_ABSQuestionC_ST_ABSAre epigenetic clocks, measures of biological aging developed mainly on older-adult samples, meaningful for younger adults and associated with sociodemographic and lifestyle characteristics in expected patterns found in prior aging research? FindingsSociodemographic and lifestyle factors were associated with biological aging in clocks trained to predict morbidity and mortality showing accelerated aging among those with lower levels of education and income, and those with severe obesity, no weekly exercise, and tobacco use. MeaningAge-related molecular processes can be identified in younger-aged adults before disease manifests and represent potential interventions to reduce social inequalities in heathy aging and longevity.

genomics↗

bioRxiv2021

Candida albicans Isolates 529L and CHN1 Exhibit Stable Colonization of the Murine Gastrointestinal Tract

Candida albicans is a pathobiont that colonizes multiple niches in the body including the gastrointestinal (GI) tract, but is also responsible for both mucosal and systemic infections. Despite its prevalence as a human commensal, the murine GI tract is generally refractory to colonization with the C. albicans reference isolate SC5314. Here, we identify two C. albicans isolates, 529L and CHN1, that stably colonize the murine GI tract in three different animal facilities under conditions where SC5314 is lost from this niche. Analysis of the bacterial microbiota did not show notable differences between mice colonized with the three C. albicans strains. We compared the genotypes and phenotypes of these three strains and identified thousands of SNPs and multiple phenotypic differences, including their ability to grow and filament in response to nutritional cues. Despite striking filamentation differences under laboratory conditions, however, analysis of cell morphology in the GI tract revealed that the three isolates exhibited similar filamentation properties in this in vivo niche. Notably, we found that SC5314 is more sensitive to the antimicrobial peptide CRAMP, and the use of CRAMP-deficient mice increased the ability of SC5314 to colonize the GI tract relative to CHN1 and 529L. These studies provide new insights into how strain-specific differences impact C. albicans traits in the host and advance CHN1 and 529L as relevant strains to study C. albicans pathobiology in its natural host niche. IMPORTANCEUnderstanding how fungi colonize the GI tract is increasingly recognized as highly relevant to human health. The animal models used to study Candida albicans commensalism commonly rely on altering the host microbiome (via antibiotic treatment or defined diets) to establish successful GI colonization by the C. albicans reference isolate SC5314. Here, we characterize two C. albicans isolates that can colonize the murine GI tract without antibiotic treatment and can therefore be used as tools for studying fungal commensalism. Importantly, experiments were replicated in three different animal facilities and utilized three different mouse strains. Differential colonization between fungal isolates was not associated with alterations in the bacterial microbiome but rather with distinct responses to CRAMP, a host antimicrobial peptide. This work emphasizes the importance of C. albicans intra-species variation as well as host anti-microbial defense mechanisms in defining commensal interactions.

microbiology↗