Biology subjects

Leone, V. A.

Publications and source records attributed to Leone, V. A..

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

Time of Sample Collection Critical for Microbiome Replicability

Although many aspects of microbiome studies have been standardized to improve experimental replicability, none account for how the daily diurnal fluctuations in the gut lumen cause dynamic changes in 16S amplicon sequencing. Here we show that sample collection time affects the conclusions drawn from microbiome studies and are larger than the effect size of a daily experimental intervention or dietary changes. The timing of divergence of the microbiome composition between experimental and control groups are unique to each experiment. Sample collection times as short as only four hours apart lead to vastly different conclusions. Lack of consistency in the time of sample collection may explain poor cross-study replicability in microbiome research. Without looking at other data, the impact on other fields is unknown but potentially significant. One-Sentence SummaryIf we are not controlling for host circadian rhythm time in microbiome studies when performing experiments, it is like trying to measure sea level rise while not knowing that tides or waves exist.

systems biology↗

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↗