MICROBIAL METABOLISM OF DIETARY INPUT IN CARDIOMETABOLICDISEASE PATHOGENESIS

MICROBIAL METABOLISM OF DIETARY INPUT IN CARDIOMETABOLICDISEASE PATHOGENESIS

Bibliographic Details
Main Author: Osborn, Lucas Jerry
Language:English
Published: Case Western Reserve University School of Graduate Studies / OhioLINK 2021
Subjects:
Microbiology
Nutrition
Microbiome
Microbial Metabolites
Flavonoids
Cardiometabolic Disease
Obesity
Non-Alcoholic Fatty Liver Disease
NAFLD
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=case1624359488777241
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-case16243594887772412021-09-02T05:10:44Z MICROBIAL METABOLISM OF DIETARY INPUT IN CARDIOMETABOLICDISEASE PATHOGENESIS Osborn, Lucas Jerry Microbiology Nutrition Microbiology Microbiome Microbial Metabolites Flavonoids Cardiometabolic Disease Obesity Non-Alcoholic Fatty Liver Disease NAFLD Objective – The dietary contribution to human health and disease has been longappreciated. However, the metabolism of dietary substrates by commensal gutmicrobiota and ultimately the impact of microbe-derived metabolites on hostphysiology, remain poorly understood.Approach and Results – Here, we interrogated the role of a single microbialmetabolite stemming from a flavonoid-rich diet, 4-hydroxyphenylacetic acid (4-HPAA), in a mouse model of high fat diet-induced obesity. Subcutaneousadministration of 4-HPAA led to a marked reversal of hepatic steatosis whencompared to scaffold control treated mice resulting from hepatic activation ofAMPKa and its downstream effectors. Furthermore, we revealed the rarity of thebacterial genes required to catabolize dietary flavonoids into 4-HPAA in humanmetagenomic datasets.Next, we used a multi-omics approach to identify microbe-derived metabolitesstemming postprandially from a single meal equivalent of a human-relevant fastfood diet. Here, we provided mice with control drinking water or antibiotic drinkingwater to ablate the gut microbial community prior to a single oral gavage of eitherchow control diet or fast food. Using untargeted mass spectrometry, we identifiedseveral putative metabolites that were postprandially enriched in the portal bloodof fast food-fed mice in a microbe-dependent manner. Furthermore, we utilized anunbiased RNA sequencing approach to survey diet and microbe-associatedhepatic transcriptional changes, highlighting the influence of both diet and the gutmicrobial metabolome on the liver transcriptome.Finally, we developed a novel surgical technique to continuously administer gutmicrobial metabolites intraportally, thus recapitulating the natural delivery of gutmicrobes from the mesentery to the liver via the portal vein. Here, we show thesuitability of this method for metabolites with a high degree of hepatic first ratemetabolism.Conclusion – These results underscore the microbial contribution to themetabolism of dietary intake and suggest that a single microbial metabolite suchas 4-HPAA is sufficient to influence host physiology. Moreover, we used a humanrelevant fast food diet to identify putative gut microbe-derived metabolites that mayinfluence host physiology in the postprandial state. Finally, we developed a novelsurgical technique to better recapitulate the physiologic delivery of gut microbialmetabolites for future studies. 2021-09-01 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1624359488777241 http://rave.ohiolink.edu/etdc/view?acc_num=case1624359488777241 restricted--full text unavailable until 2023-08-13 This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic Microbiology
Nutrition
Microbiology
Microbiome
Microbial Metabolites
Flavonoids
Cardiometabolic Disease
Obesity
Non-Alcoholic Fatty Liver Disease
NAFLD
spellingShingle Microbiology
Nutrition
Microbiology
Microbiome
Microbial Metabolites
Flavonoids
Cardiometabolic Disease
Obesity
Non-Alcoholic Fatty Liver Disease
NAFLD
Osborn, Lucas Jerry
MICROBIAL METABOLISM OF DIETARY INPUT IN CARDIOMETABOLICDISEASE PATHOGENESIS
author Osborn, Lucas Jerry
author_facet Osborn, Lucas Jerry
author_sort Osborn, Lucas Jerry
title MICROBIAL METABOLISM OF DIETARY INPUT IN CARDIOMETABOLICDISEASE PATHOGENESIS
title_short MICROBIAL METABOLISM OF DIETARY INPUT IN CARDIOMETABOLICDISEASE PATHOGENESIS
title_full MICROBIAL METABOLISM OF DIETARY INPUT IN CARDIOMETABOLICDISEASE PATHOGENESIS
title_fullStr MICROBIAL METABOLISM OF DIETARY INPUT IN CARDIOMETABOLICDISEASE PATHOGENESIS
title_full_unstemmed MICROBIAL METABOLISM OF DIETARY INPUT IN CARDIOMETABOLICDISEASE PATHOGENESIS
title_sort microbial metabolism of dietary input in cardiometabolicdisease pathogenesis
publisher Case Western Reserve University School of Graduate Studies / OhioLINK
publishDate 2021
url http://rave.ohiolink.edu/etdc/view?acc_num=case1624359488777241
work_keys_str_mv AT osbornlucasjerry microbialmetabolismofdietaryinputincardiometabolicdiseasepathogenesis
_version_ 1719474102732849152

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