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MICROBIAL METABOLISM OF DIETARY INPUT IN CARDIOMETABOLIC DISEASE PATHOGENESIS

Osborn, Lucas Jerry
http://orcid.org/0000-0003-0077-9192
http://rave.ohiolink.edu/etdc/view?acc_num=case1624359488777241

Abstract Details

2021, Doctor of Philosophy, Case Western Reserve University, Molecular Medicine.
Objective – The dietary contribution to human health and disease has been long appreciated. However, the metabolism of dietary substrates by commensal gut microbiota and ultimately the impact of microbe-derived metabolites on host physiology, remain poorly understood. Approach and Results – Here, we interrogated the role of a single microbial metabolite stemming from a flavonoid-rich diet, 4-hydroxyphenylacetic acid (4- HPAA), in a mouse model of high fat diet-induced obesity. Subcutaneous administration of 4-HPAA led to a marked reversal of hepatic steatosis when compared to scaffold control treated mice resulting from hepatic activation of AMPKa and its downstream effectors. Furthermore, we revealed the rarity of the bacterial genes required to catabolize dietary flavonoids into 4-HPAA in human metagenomic datasets. Next, we used a multi-omics approach to identify microbe-derived metabolites stemming postprandially from a single meal equivalent of a human-relevant fast food diet. Here, we provided mice with control drinking water or antibiotic drinking water to ablate the gut microbial community prior to a single oral gavage of either chow control diet or fast food. Using untargeted mass spectrometry, we identified several putative metabolites that were postprandially enriched in the portal blood of fast food-fed mice in a microbe-dependent manner. Furthermore, we utilized an unbiased RNA sequencing approach to survey diet and microbe-associated hepatic transcriptional changes, highlighting the influence of both diet and the gut microbial metabolome on the liver transcriptome. Finally, we developed a novel surgical technique to continuously administer gut microbial metabolites intraportally, thus recapitulating the natural delivery of gut microbes from the mesentery to the liver via the portal vein. Here, we show the suitability of this method for metabolites with a high degree of hepatic first rate metabolism. Conclusion – These results underscore the microbial contribution to the metabolism of dietary intake and suggest that a single microbial metabolite such as 4-HPAA is sufficient to influence host physiology. Moreover, we used a human relevant fast food diet to identify putative gut microbe-derived metabolites that may influence host physiology in the postprandial state. Finally, we developed a novel surgical technique to better recapitulate the physiologic delivery of gut microbial metabolites for future studies.
Jan Claesen, Ph.D. (Advisor)
J. Mark Brown, Ph.D. (Advisor)
Christine McDonald, Ph.D. (Committee Chair)
Philip Ahern, D.Phil. (Committee Member)
Betul Hatipoglu, M.D. (Committee Member)
202 p.
Microbiology; Nutrition
Microbiology; Microbiome; Microbial Metabolites; Flavonoids; Cardiometabolic Disease; Obesity; Non-Alcoholic Fatty Liver Disease; NAFLD

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Citations

  • Osborn, L. J. (2021). MICROBIAL METABOLISM OF DIETARY INPUT IN CARDIOMETABOLIC DISEASE PATHOGENESIS [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1624359488777241

    APA Style (7th edition)

  • Osborn, Lucas. MICROBIAL METABOLISM OF DIETARY INPUT IN CARDIOMETABOLIC DISEASE PATHOGENESIS. 2021. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1624359488777241.

    MLA Style (8th edition)

  • Osborn, Lucas. "MICROBIAL METABOLISM OF DIETARY INPUT IN CARDIOMETABOLIC DISEASE PATHOGENESIS." Doctoral dissertation, Case Western Reserve University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case1624359488777241

    Chicago Manual of Style (17th edition)

case1624359488777241
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© 2021, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.