Biology subjects

Loomba, R.

Publications and source records attributed to Loomba, R..

4 recordsLinked to original sources

bioRxiv2025

N-acetyl-phenylalanine induces hepatic steatosis in MASLD by disrupting ER-mitochondria calcium coupling and mitochondrial lipid oxidation

Background & AimsThe gut-liver axis and hepatic ER-mitochondria miscommunication (at contact sites called MAMs) are involved in the development of metabolic dysfunction-associated steatotic liver disease (MASLD). We investigated the role of circulating aromatic amino acids (AAA) derived from phenylalanine and tyrosine in MASLD potentially through MAM alterations. MethodsWe analyzed AAA metabolomic profiles in individuals with and without MASLD and validated findings in a biopsy-proven cohort. The pro-steatogenic effect of MASLD-associated AAAs was validated in vitro using lipid labeling, MAM structural/functional assays, and palmitate-induced respiration. In vivo effects were tested in mice fed with candidate AAAs, and MAM involvement was confirmed by expressing a specific organelle linker in vitro and in vivo. ResultsN-acetyl-phenylalanine (NAPA) was strongly associated with hepatic steatosis and correlated with specific gut microbes. In vitro, NAPA promoted lipid accumulation by impairing ER-mitochondria calcium exchange via a LAT1-dependent electrogenic mechanism, reducing mitochondrial lipid oxidation. Chronic NAPA administration in mice induced steatosis and MAM disruption. Notably, enhancing ER-mitochondria contacts with an organelle linker prevented NAPA-induced steatosis in vitro and in vivo. Additionally, other phenylalanine- and tyrosine-derived AAAs reproduced NAPAs effects, suggesting a class-dependent mechanism. ConclusionNAPA emerges as a MASLD-promoting metabolite, contributing to hepatic steatosis by disrupting ER-mitochondria calcium coupling and mitochondrial lipid oxidation. Lay SummaryThe gut-liver axis is a key component of the development of MASLD, and circulating gut-derived metabolites, notably AAAs derived from phenylalanine and tyrosine metabolism, have been associated with MASLD. However, the specific causal mechanisms of these AAA metabolites in MASLD development remain unexplored. Here, we identified NAPA, a gut microbiome linked metabolite elevated in MASLD patients, as a causal driver of hepatic steatosis both in vitro and in vivo. Mechanistically, NAPA alters ER-mitochondria calcium coupling leading to reduced mitochondrial lipid oxidation, highlighting a new mechanism with potential therapeutic implications. HIGHLIGHTS- Circulating NAPA levels are increased in MASLD patients and correlate with hepatic steatosis. - NAPA levels result from a complex host-microbiota interplay - NAPA induces lipid accumulation by dampening ER-mitochondria calcium coupling and mitochondrial lipid oxidation. - NAPA disrupts MAMs by a LAT1-mediated electrogenic mechanism. - Other Phe- and Tyr-mediated metabolites have the same pro-steatogenic effect than NAPA pointing to a class-dependent effect.

pathology↗

bioRxiv2020

Alterations in bile acid metabolizing gut microbiota and specific bile acid genes as a precision medicine to subclassify NAFLD

Background & AimsMultiple mechanisms for the gut microbiome contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD) have been implicated. Here, we aim to investigate the contribution and potential application for altered bile acid (BA) metabolizing microbe in NAFLD using whole metagenome sequencing (WMS) data. Methods86 well-characterized biopsy-proven NAFLD patients and 38 healthy controls were included in the discovery cohort. Assembly-based analysis was performed to identify BA-metabolizing microbes. Statistical tests, feature selection and microbial interaction analysis were integrated to identify microbial alterations and markers in NAFLD. An independent validation cohort was subjected to similar analyses. ResultsNAFLD microbiota exhibited decreased diversity and microbial interactions. We established a classifier model with 53 differential species exhibiting a robust diagnostic accuracy (AUC=0.97) for dectecting NAFLD. Next, 8 important differential pathway markers including secondary BA biosynthesis were identified. Specifically, increased abundance of 7-HSDH, baiA and baiB were detected in NAFLD. Further, 10 of 50 BA-metabolizing metagenome-assembled genomes (MAG)s, from Bacteroides ovatus and Eubacterium biforme, were dominant in NAFLD and interplayed as a synergetic ecological guild. Importantly, two subtypes of NAFLD patients were observed according to secondary BA metabolism potentials. Elevated capability for secondary BA biosynthesis was also observed in the validation cohort. ConclusionsWe identified novel bacterial BA-metabolizing genes and microbes that may contribute to NAFLD pathogenesis and serve as disease markers. Microbial differences in BA-metabolism and strain-specific differences among patients highlight the potential for precision medicine in NAFLD treatment.

pathology↗

bioRxiv2020

Identification of the keystone species in non-alcoholic fatty liver disease by causal inference and dynamic intervention modeling

ObjectiveKeystone species are required for the integrity and stability of an ecological community, and therefore, are potential intervention targets for microbiome related diseases. DesignHere we describe an algorithm for the identification of keystone species from cross-sectional microbiome data of non-alcoholic fatty liver disease (NAFLD) based on causal inference theories and dynamic intervention modeling (DIM). ResultsEight keystone species in the gut of NAFLD, represented by P. loveana, A. indistinctus and D. pneumosintes, were identified by our algorithm, which could efficiently restore the microbial composition of the NAFLD toward a normal gut microbiome with 92.3% recovery. These keystone species regulate intestinal amino acids metabolism and acid-base environment to promote the growth of the butyrate-producing Lachnospiraceae and Ruminococcaceae species. ConclusionOur method may benefit microbiome studies in the broad fields of medicine, environmental science and microbiology. SUMMARYWhat is already known about this subject? O_LINon-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disease whose pathogenesis remains unclear. C_LIO_LIDysbiosis in the gut microbiota affects the initiation and development of NAFLD, but the mechanisms is yet to be established. C_LIO_LIKeystone species represent excellent candidate targets for gut microbiome-based interventions, as they are defined as the species required for the integrity and stability of the ecological system. C_LI What are the new findings? O_LINAFLD showed significant dysbiosis in butyrate-producing Lachnospiraceae and Ruminococcaceae species. C_LIO_LIMicrobial interaction networks were constructed by the novel algorithm with causal inference. C_LIO_LIKeystone species were identified form microbial interaction networks through dynamic intervention modeling based on generalized Lotka-Volterra model. C_LIO_LIEight keystone species of NAFLD with the highest potential for restoring the microbial composition were identified. C_LI How might it impact on clinical practice in the foreseeable future? O_LIAn algorithm for the identification of keystone species from cross-sectional microbiome data based on causal inference theories and dynamic intervention modeling. C_LIO_LIEight keystone species in the gut of NAFLD, represented by P. loveana, A. indistinctus and D. pneumosintes, which could efficiently restore the microbial composition of the NAFLD toward a normal gut microbiome. C_LIO_LIOur method may benefit microbiome studies in the broad fields of medicine, environmental science and microbiology. C_LI

bioinformatics↗

bioRxiv2019

MASST: A Web-based Basic Mass Spectrometry Search Tool for Molecules to Search Public Data.

CorrespondenceWe introduce a web-enabled small-molecule mass spectrometry (MS) search engine. To date, no tool can query all the public small-molecule tandem MS data in metabolomics repositories, greatly limiting the utility of these resources in clinical, environmental and natural product applications. Therefore, we introduce a Mass Spectrometry Search Tool (MASST) (https://proteosafe-extensions.ucsd.edu/masst/), that enables the discovery of molecular relationships among accessible public metabolomics and natural product tandem mass spectrometry data (MS/MS).

bioinformatics↗