Biology subjects

Nirmalkar, K.

Publications and source records attributed to Nirmalkar, K..

4 recordsLinked to original sources

bioRxiv2025

Multi-omics Integration of Microbiota Transplant Therapy in Children with Autism Spectrum Disorders

BackgroundMicrobiota transplant therapy (MTT) is a promising avenue for the substantial improvement of gastrointestinal and behavioral symptoms in children with autism spectrum disorder (ASD). Previous work has demonstrated that microbiome and metabolite profiles of children with ASD become more similar to those of their typically developing (TD) peers following MTT. MethodsTo enhance a systems-level understanding of MTT in ASD children that extends beyond previously reported findings, we present a multi-omics analysis of an ASD cohort spanning 10 weeks and 2 years of follow-up after completion of MTT. We applied cutting-edge multi-omics approaches, including metagenomics, fecal and plasma metabolomics, and advanced statistical methods, including multimodal machine learning, differential network analysis, and causal mediation analysis, to extensively characterize molecular and biochemical responses before and after MTT, to identify key taxonomic, functional, and metabolite signatures associated with MTT treatment and ASD symptoms. ResultsUsing a combination of cross-sectional and longitudinal statistical analyses and integrative machine learning techniques, we identified key meta-omic features associated with MTT. Integrated multi-omics analysis revealed that children with ASD transition to distinct biological states following MTT, clearly separated from their pre-treatment states and from TD children, as demonstrated by robust group separation and strong classification performance. Several biological signals associated with the modulation of the gut microbiome after MTT were identified, including an increase of butyrate producers such as Faecalibacterium prausnitzii and Butyricimonas faecalis; decreased fecal sulfated primary bile acid, chenodeoxycholic acid sulfate; decreased secondary bile acid, glycolithocholate sulfate; and increased sarcosine and iminodiacetate in plasma after 10 weeks of MTT compared to baseline. Differential network analysis revealed hub species, including Prevotella copri, Ruminococcus callidus, and GGB9633 SGB15091, as differentially connected 2 years after completion of MTT compared to baseline. Mediation analysis uncovered several key players as mediators of symptoms, including Alistipes ihumii, Ruminococceae, amino acid biosynthesis, bile acids, long-chain fatty acids, and cysteine-glutathione disulfide, among others. ConclusionsThis study provides one of the first comprehensive analyses of multi-omic features underlying host-microbiome interactions associated with MTT in children with ASD. It offers further evidence that fusing data across diverse molecular modalities at pre- and post- treatment time points can illuminate the potential of MTT in neurodevelopmental disorders. These findings could advance microbiome-based immunomodulatory therapies and multi-omics strategies to restore gut microbiota in children with ASD, while aiding in the discovery of novel biomarkers predictive of treatment response.

systems biology↗

bioRxiv2025

A Sulfotransferase from a Gut Microbe Acts on Diverse Phenolic Sulfate Compounds, Including Acetaminophen Sulfate

Sulfonation is one of the two main phase II detoxification pathways in eukaryotes that transforms non-polar compounds into hydrophilic metabolites. Sulfotransferases catalyze these reactions by transferring a sulfo group from a donor to an acceptor molecule. Human cytosolic sulfotransferases use only 3-phosphoadenosine 5-phosphosulfate (PAPS) as a donor to sulfonate a variety of chemicals. Less understood are microbial aryl-sulfate sulfotransferases (ASSTs), which catalyze sulfo transfer reactions, without utilizing PAPS as a donor. Currently, the identity of physiological sulfo donor substrates remains unknown and sulfo acceptor substrates are underexplored. With this study, we aim to understand the potential contribution of a gut microbial enzyme to sulfonation chemistry by uncovering substrate preferences. Here, we show that a sulfotransferase (BvASST) from the prevalent gut microbe Bacteroides vulgatus (now Phocaeicola vulgatus) is a versatile catalyst that utilizes a wide range of phenolic molecules as substrates that are commonly encountered by the host. With this action, it has the ability to modulate concentrations of donor phenolic sulfates like acetaminophen sulfate, dopamine sulfate, p-coumaric acid sulfate, indoxyl sulfate, and p-cresol sulfate in vitro. Moreover, we report a large adaptability in the acceptor preferences with the evidence of sulfonation for many biologically relevant phenolic molecules including p-coumaric acid, p-cresol, dopamine, acetaminophen, tyramine, and 4-ethylphenol. These results suggest that such gut microbial enzymes may impact the detoxification of a variety of phenolic molecules in the host, which were previously thought to be solely detoxified via human sulfotransferases. However, further in vivo studies are necessary to understand potential contributions of ASSTs in host detoxification processes.

biochemistry↗

bioRxiv2024

Reanalysis of metabolomics data reveals that microbiota transfer therapy modulates important fecal and plasma metabolite profiles in children with autism spectrum disorders

While Autism Spectrum Disorder (ASD) is diagnosed through behavioral symptoms and psychometric evaluations, it has also been associated with distinct metabolomic patterns. A previous clinical trial of Microbiota Transplant Therapy (MTT) in children with ASD and gastrointestinal (GI) issues revealed significant differences in plasma metabolomics between children with ASD and their typically developing (TD) counterparts, which diminished after MTT. The objective of this study was to reanalyze the plasma and fecal samples using updated metabolomics libraries at Metabolon together with a comprehensive panel of statistical methods to provide deeper insights into ASD-related metabolic differences and the impact of MTT. Compared with the original analysis, the updated annotation identified substantially more annotated metabolites and uncovered additional plasma and fecal metabolic changes associated with MTT. The reanalysis highlighted specific metabolites whose relative peak intensities differed between the ASD and TD groups, as well as metabolites with significant changes following MTT. Several plasma metabolites, including sarcosine, iminodiacetate, caproate, and caprylate, initially showed significant differences between the ASD and TD groups but shifted to resemble TD levels after MTT. In fecal samples, p-cresol sulfate and sphingolipids emerged as metabolites with altered intensities following MTT. Multivariate Fishers Discriminant Analysis (FDA) with leave-one-out cross-validation revealed that a set of metabolites including p-cresol sulfate, hydroxyproline, and caprylate could robustly classify the ASD and TD cohorts before treatment. However, after treatment, the same FDA model could no longer distinguish the two groups, as FDA scores became similar to those of the TD cohort. These findings improve our understanding of ASD-associated metabolic alterations and demonstrate that reanalysis of existing untargeted metabolomics datasets using updated metabolite annotation resources and complementary statistical approaches can reveal biologically relevant metabolite changes that were not detected previously. Larger studies with placebo-controlled designs are needed to validate these findings, further define the underlying biochemical pathways, and evaluate their potential for developing personalized therapeutic strategies. IMPORTANCEReanalysis of existing untargeted metabolomics datasets using updated metabolite annotation resources and complementary statistical approaches can reveal biological insights that were not apparent in earlier analyses. By leveraging updated metabolomics libraries and expanded statistical analyses, we identified additional annotated metabolites and uncovered plasma and fecal metabolic changes associated with autism spectrum disorder (ASD) and Microbiota Transplant Therapy (MTT). Several metabolites, including sarcosine, caprylate, and p-cresol sulfate, distinguished children with ASD from typically developing (TD) controls at baseline and shifted toward TD-like profiles following MTT. These findings demonstrate the value of periodically reanalyzing legacy metabolomics datasets as annotation resources improve, providing a more comprehensive understanding of disease-associated metabolic alterations and therapeutic responses.

neuroscience↗

bioRxiv2023

Bimodal distribution of Candida albicans in children with Autism linked with ASD symptoms

The gastrointestinal (GI) tract harbors an intricate and remarkably diverse microbial ecosystem that profoundly impacts various aspects of health and pathophysiology. While bacteria overwhelmingly represent most of the GI microbiota, it is imperative to consider the presence and function of fungal constituents (i.e., mycobiota) within the GI ecosystem. The substantial incidence of GI disorders and associated manifestations in children diagnosed with autism spectrum disorder (ASD) suggests a plausible contributory role of the gut mycobiota. Our investigation aimed to elucidate the gut mycobiota in a cohort comprising 38 typically developing children (TD) and 40 children with ASD. Fecal samples were collected from all participants and autism severity and GI symptoms were assessed to unravel the potential implications of mycobiota alterations in the gut. We employed fungal internal transcribed spacer (ITS) gene amplicon sequencing to analyze the fungal composition and investigate their relationship with GI and autism symptoms. Among gut mycobiota, Saccharomyces cerevisiae was significantly lower (relative abundance) in ASD compared to TD children. Total Candida and C. albicans demonstrated a bimodal distribution among children with ASD. Children with ASD with elevated Autism Treatment Evaluation Checklist (ATEC) scores (a more severe diagnosis) displayed an increased abundance of C. albicans and a decreased abundance of S. cerevisiae. A significant positive correlation was observed between ATEC scores and GI symptoms and between ATEC scores and C. albicans. Our findings propose that a deficit of beneficial fungi, specifically S. cerevisiae, and an overgrowth of C. albicans may worsen autism severity in children with ASD. Future work employing more advanced techniques (i.e., shotgun metagenomics) is encouraged to advance understanding of the functional role of fungi/yeast, and their interplay between GI symptoms and autism severity in children with ASD.

microbiology↗