Biology subjects

DeLeon, O.

Publications and source records attributed to DeLeon, O..

3 recordsLinked to original sources

bioRxiv2023

Imbalanced gut microbiota predicts and drives the progression of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in a fast-food diet mouse model

Nonalcoholic fatty liver disease (NAFLD) is multifactorial in nature, affecting over a billion people worldwide. The gut microbiome has emerged as an associative factor in NAFLD, yet mechanistic contributions are unclear. Here, we show fast food (FF) diets containing high fat, added cholesterol, and fructose/glucose drinking water differentially impact short- vs. long-term NAFLD severity and progression in conventionally-raised, but not germ-free mice. Correlation and machine learning analyses independently demonstrate FF diets induce early and specific gut microbiota changes that are predictive of NAFLD indicators, with corresponding microbial community instability relative to control-fed mice. Shotgun metagenomics showed FF diets containing high cholesterol elevate fecal pro-inflammatory effectors over time, relating to a reshaping of host hepatic metabolic and inflammatory transcriptomes. FF diet-induced gut dysbiosis precedes onset and is highly predictive of NAFLD outcomes, providing potential insights into microbially-based pathogenesis and therapeutics. HighlightsO_LIGerm-free mice are protected from fast-food diet-induced NAFLD. C_LIO_LIFast-food diets rapidly shift gut microbiota composition and function. C_LIO_LIIncreasing dietary cholesterol exacerbates hepatic inflammation only in SPF mice. C_LIO_LIFast-food diet-induced gut dysbiosis precedes and predicts late-stage NAFLD severity. C_LI

physiology↗

bioRxiv2022

Gut Microbes and the Liver Circadian Clock Partition Glucose and Lipid Metabolism

Circadian rhythms govern glucose homeostasis, and their dysregulation leads to complex metabolic diseases. Gut microbes also exhibit diurnal rhythms that influence host circadian networks and metabolic processes, yet underlying mechanisms remain elusive. Here, we show hierarchical, bi-directional communication between the liver circadian clock, gut microbes, and glucose homeostasis in mice. The liver clock, but not the forebrain clock, requires gut microbes to drive glucose clearance and gluconeogenesis. Liver clock dysfunctionality expands proportions and abundances of oscillating microbial features by two-fold relative to controls. The liver clock is the primary driver of differential and rhythmic hepatic expression of glucose and fatty acid metabolic pathways. Absent the liver clock, gut microbes provide secondary cues that dampen these rhythms, resulting in reduced utilization of lipids as fuel relative to carbohydrates. Together, the liver clock transduces signals from gut microbes necessary to regulate glucose and lipid metabolism and meet energy demands over 24 hours. HighlightsThe liver circadian clock is autonomous from the central clock in metabolic regulation Liver clock and gut microbes interact to direct hepatic glucose and lipid metabolism Reciprocating host-microbe interactions drive rhythmic hepatic transcription Perturbed liver Bmal1 results in chaotic downstream oscillators and metabolism

physiology↗

bioRxiv2022

Dynamic genetic adaptation of Bacteroides thetaiotaomicron murine gut colonization

To understand how a bacterium ultimately succeeds or fails in adapting to a new environment, it is essential to assess the temporal dynamics of its fitness over the course of colonization. The mammalian gut, into which exogenous microorganisms are regularly introduced, represents a biologically and clinically relevant system to explore microbial adaptational processes. In this study, we introduce a human-derived commensal organism, Bacteroides thetaiotaomicron, into the guts of germ-free mice to 1) determine whether the genetic requirements for colonization shift over time and, if so, 2) characterize the biological functions required for microbial survival at different points of colonization. The results of a high-throughput functional genetics assay (BarSeq), transcriptomics, and metabolomics converge on several conclusions. First, adaptation to the host gut occurs in distinct stages. We observed drastic changes in gene usage during the first week, shifting from high expression of amino acid biosynthesis to polysaccharide utilization genes. These changes were sustained thereafter, except for the continued upregulation of a single polysaccharide utilization locus responsible for the degradation of raffinose-family oligosaccharides rich in the standard chow diet fed to our mice. Spontaneous mutations in wildtype Bt also evolve around this locus, highlighting the importance of efficient carbohydrate metabolism in long-term persistence within a monoassociated gut. To improve microbiome-based therapies, it will be important to appreciate and meet the distinct needs of the organism during each stage of colonization. ImportanceMicrobes regularly disperse across and adapt to new environments and ecological niches. A clinically significant microbial niche home to trillions of microbes is the mammalian gut. Temporal processes of microbial adaptation over the course of gut colonization are poorly understood on a genetic, transcriptional, and metabolite level. In this study, we leverage a three-pronged approach to characterize gut colonization as a dynamic process with shifting genetic determinants of microbial fitness. This study sheds light on host colonization by Bacteroides thetaiotaomicron, an organism that is prevalent and dominant across healthy human microbiomes, and not only identifies key pathways involved in colonization, but determines the timing of when these pathways are most vital to colonization success. By demonstrating that the key determinants of colonization success in the gut change over time, the results of this study highlight the importance of considering ecological dynamics in developing more effective microbiome-based therapies.

microbiology↗