Abstract P112: Elevated Blood Pressure In Conventionalized Germ-free Rats Is Coupled With Upregulation Of Kynurenic Pathway Metabolites And Central Immune Responses

Abstract

Background: Recent evidence supports that metabolic dysfunction underlies hypertension. Injection of kynurenate, a metabolite of tryptophan pathway, into the paraventricular nucleus of the hypothalamus (PVN) lowers blood pressure (BP). Intestinal absorption and metabolism of tryptophan are impacted by gut microbiota. Since gut-brain axis contributes to gut dysbiosis-inducd hypertension, we hypothesized that gut microbiota modulates the levels of kynurenic pathway metabolites that have central impact on BP regulation. Methods: We, for the first time, used 7 weeks old male Germ-free (GF) Spague Dawley (SD) rats (n=5) and GF rats co-housed with conventional SD rats for 10 days (GFC) (n=6). BP was measured by tail-cuff. Serum metabolites were quantified by 6495 triple quandrople mass spectrometryand data was normalized using isotoplic labelled compounds. The nucleus of the solitary tract (NTS), the principal sensory nucleus for peripheral changes, and the PVN, a relay center projecting sympathetic output based on the integrated afferent inputs from brain regions including NTS, were analyzed by microarray hybridization for mRNA expression. Results: Compared to the GF rats, GFC rats had significantly higher systolic (139 mmHg vs 115 mmHg, p <0.05), diastolic BP (96 mmHg vs 79 mmHg, p <0.05), and serum levels of kynurenic acid (-9.76 vs -10.21, p <0.05) and 3-hydroxy kynurenine (-6.49 vs -7.34, p <0.01). Coupled with these increases in kynurenic pathway metabolites, microarray analyses demonstrated increased immune responses (e.g. Cd74, Il1b, Cxcl1, Mmp14 ) in the PVN (gene ontology analysis, p <0.001) and increased cell differentiation and synaptic plasticity (e.g. Sox11, Tp53, Cdk6, Hoxb4, Foxo4, Cyr61 ) in the NTS (gene ontology analysis, p <0.01). Conclusion: Colonization of gut microbiota in GF rats induced increased cell differentiation and synaptic plasticity in the NTS and immune responses in the PVN, indicating the restructured sensory neurons of the NTS and enhanced sympathetic output from the PVN. These are in line with increased levels of kynurenic acid and 3-hydroxy kynurenine, and BP, respectively, suggesting that BP regulation by the gut-brain axis may be mediated by kynurenic pathway.