The Digestive Tract Microbiome and Cardiometabolic Disease: Exploring Nitric Oxide and Lipopolysaccharide Synthesis as Mechanistic Intermediates

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The Digestive Tract Microbiome and Cardiometabolic Disease: Exploring Nitric Oxide and Lipopolysaccharide Synthesis as Mechanistic Intermediates

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Bohn, Bruno

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2023

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Abstract

Introduction: The role of the digestive tract microbiomes on cardiometabolic health is becoming ever clearer. However, mechanistic remain largely unexplored and methods exploring metabolic outputs are lacking. This dissertation explores a novel approach to quantify the microbiome's lipopolysaccharides (LPS) and nitric oxide (NO) producing potential, two molecules with known health effects. We investigated the association between functional metrics and cardiometabolic health among healthy individuals and heart failure (HF) patients.Methods: Cross-sectional data from adults free of cardiometabolic disease (ORIGINS) and with HF (HFM) were used. Blood pressure was measured and biomarkers or inflammation and/or endotoxemia quantified from blood serum. Oral (saliva) and/or gut microbiomes were characterized with 16S rRNA (HFM/ORIGINS) and/or metagenomic sequencing (ORIGINS). Pathway- and gene-level functional profiles were operationalized as metrics of LPS- and NO-producing potentials. Metrics were compared across sequencing approaches (ORIGINS). For each cohort, multivariable linear regression was used to explore associations between: i) blood pressure and NO-producing potential; ii) inflammation and NO-producing potential; iii) inflammation and LPS-producing potential; and iv) endotoxemia and LPS-producing potential (HFM). Results: In ORIGINS, 253 and 170 participants had 16S and metagenomic data, respectively. A modest positive association was observed between functional metrics, with more features detected through 16S methods. Metagenomic and 16S-derived NO-reducing potential metrics were linked to lower inflammation and blood pressure, respectively. No meaningful associations were observed for LPS-producing potential. In HFM, saliva and gut 16S sequencing data was available for 146 and 128 participants, respectively. No correlations were observed between gut and oral microbiomes. No meaningful associations were observed between NO-producing potential and blood pressure. Gut LPS-producing potential, but not oral, was associated with endotoxemia. Inflammation was not meaningfully linked to either functional feature. Conclusions: A novel approach to utilized microbiome functional profile metrics was explored. Findings were mixed, but highlighted the potential use of these approaches in population-based studied of the human microbiome and cardiometabolic health.

Keywords

Cardiovascular Disease

Heart Failure

Lipopolysaccharide

Microbiome

Nitrate

Nitric Oxide

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University of Minnesota Ph.D. dissertation. 2023. Major: Epidemiology. Advisor: Ryan Demmer. 1 computer file (PDF); vii, 276 pages.

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Bohn, Bruno. (2023). The Digestive Tract Microbiome and Cardiometabolic Disease: Exploring Nitric Oxide and Lipopolysaccharide Synthesis as Mechanistic Intermediates. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/258694.

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