Tumor Necrosis Factor Alpha and the Gastrointestinal Epithelium: Implications for the Gut-Brain Axis and Hypertension

Abstract

The colonic epithelium is the site of production and transport of many vasoactive metabolites and neurotransmitters that can modulate the immune system, affect cellular metabolism, and subsequently regulate blood pressure. As an important interface between the microbiome and its host, the colon can contribute to the development of hypertension. In this critical review, we highlight the role of colonic inflammation and microbial metabolites on the gut brain axis in the pathology of hypertension, with special emphasis on the interaction between tumor necrosis factor α (TNFα) and short chain fatty acid (SCFA) metabolites. Here, we review the current literature and identify novel pathways in the colonic epithelium related to hypertension. A network analysis on transcriptome data previously generated in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats reveals differences in several pathways associated with inflammation involving TNFα (NF-κB and STAT Expression Targets) as well as oxidative stress. We also identify down-regulation of networks associated with gastrointestinal function, cardiovascular function, enteric nervous system function, and cholinergic and adrenergic transmission. The analysis also uncovered transcriptome responses related to glycolysis, butyrate oxidation, and mitochondrial function, in addition to gut neuropeptides that serve as modulators of blood pressure and metabolic function. We present a model for the role of TNFα in regulating bacterial metabolite transport and neuropeptide signaling in the gastrointestinal system, highlighting the complexity of host-microbiota interactions in hypertension.

Keywords: Blood pressure; Butyrate; Gene networks; Hypertension; Inflammation; Microbiome.

Fig. 1

Literature connections established in Pathway Studio (Elsevier) between TNF-, SLC transporter transcriptional regulators, and downstream metabolites and hormones. The top graph (a) shows that TNF interacts at the level of the gene or protein with solute carriers on the plasma membrane. Cytokines also regulate these transporters which can affect production and synthesis of various short chain fatty acids (i.e. butyrate and propionate). There is direct evidence that TNF exerts regulatory control over SLC5A8 (bottom graph, b). This in turn can affect several small molecules, such as sex steroids and short chain fatty acids. Abbreviations are found is Supplemental Data 1

Fig. 2

Relative expression levels of downstream targets of TNFα and NF-κB signaling molecules in the colonic epithelium of WKY and SHR rodents. Red corresponds to genes that are upregulated in SHR, while blue corresponds to genes with higher expression in WKY. Shade denotes degree the transcript is differentially expressed, with darker shades corresponding to higher level of differential expression. Grey denotes genes whose transcription levels were not assessed in this dataset. Transcriptome data for gut epithelial cells were obtained from Yang et al. (2020). Abbreviations are found is Supplemental Data 1

Fig. 3

Conceptual model for the role of TNF-α in gastrointestinal dysbiosis and impacts on the gut-brain axis. Inflammation in the gut results in mitochondrial dysfunction and altered oxidative respiration, leading to oxidative stress and caspase-induced apoptosis. This in turn can impair butyrate uptake from the gastrointestinal tract, altering the expression of solute transporters. Gut dysbiosis can result in altered short chain fatty acids (e.g. butyrate, propionate) and neurotransmitter synthesis (serotonin, ghrelin, cholecystokinin and somatostatin) in gut epithelium. These mechanisms are proposed to contribute to a hypertensive state