Microglial Cells Impact Gut Microbiota and Gut Pathology in Angiotensin II-Induced Hypertension

Abstract

Rationale: Increased microglial activation and neuroinflammation within autonomic brain regions have been implicated in sustained hypertension (HTN) and their inhibition by minocycline, an anti-inflammatory antibiotic, produces beneficial effects. These observations led us to propose a dysfunctional brain-gut communication hypothesis for HTN. However, it has been difficult to reconcile whether an anti-inflammatory or antimicrobial action is the primary beneficial effect of minocycline in HTN. Accordingly, we utilized chemically modified tetracycline-3 (CMT-3), a derivative of tetracycline that has potent anti-inflammatory activity, to address this question. Objective: Test the hypothesis that central administration of CMT-3 would inhibit microglial activation, attenuate neuroinflammation, alter selective gut microbial communities, protect the gut wall from developing HTN-associated pathology, and attenuate HTN. Methods and Results: Rats were implanted with radio-telemetry devices for recording mean arterial pressure (MAP). Angiotensin II (AngII) was infused subcutaneously using osmotic minipumps to induce HTN. Another osmotic mini-pump was surgically implanted to infuse CMT-3 intracerebroventricularly (ICV). ICV CMT-3 infusion was also investigated in spontaneously hypertensive rats (SHR). Physiological, pathological, immuno-histological parameters, and fecal microbiota were analyzed. ICV CMT-3 significantly inhibited AngII-induced increases in number of microglia, their activation and proinflammatory cytokines in the paraventricular nucleus of hypothalamus. Further, ICV CMT-3 attenuated increased MAP, normalized sympathetic activity and left ventricular hypertrophy in AngII-rats as well as in the SHR. Finally, CMT-3 beneficially restored certain gut microbial communities altered by AngII and attenuated pathological alterations in gut wall. Conclusions: These observations demonstrate that inhibition of microglial activation alone was sufficient to induce significant antihypertensive effects. This was associated with unique changes

Probiotic Bifidobacterium breve prevents DOCA‐salt hypertension

“…However, what is novel here is the evidence of unique changes in gut microbial populations in low renin model of hypertension. The features of the gut microbiota from DOCA-salt rats are different that than found in SHR, 8,[11][12][13] angiotensin II-infused mice, 1,19,39,44,45 or hypertensive patients. 1,4 The main characteristics of dysbiotic microbiota in DOCA-salt were: (a) microbial richness, evenness, and diversity were similar to control rats; (b) no significant change in F/B ratio were observed, and (c) an increased proportion in acetate-, butyrate-, and lactate-producing bacteria were observed.…”

Changes to the gut microbiota induced by losartan contributes to its antihypertensive effects

“…Recently, the hypothesis posing the presence of a brain–gut communication driven by a sympathetic system has been reinforced. Central administration of a modified tetracycline inhibited microglial activation, normalised sympathetic activity, attenuated pathological alterations in gut wall, restored certain gut microbial communities altered by angiotensin II, and reduced BP (Sharma et al, ). Our data also support the proposal that gut sympathetic drive is a key regulator of gut integrity and microbiota composition.…”

Impaired Autonomic Nervous System-Microbiome Circuit in Hypertension

“…Our group has recently linked hypothalamic neuroinflammation and increased sympathetic drive with changes in gut physiology and microbiota associated with angiotensin II-induced hypertension. This suggests a role for a dysfunctional autonomic nervous system in gut dysbiosis, although we were not able to discount a direct effect of hypertension and/or angiotensin II on the gut 40 . This, along with our evidence of decreased proteins that mediate cell-cell connections in gut epithelium of prehypertensive spontaneously hypertensive rats, as well as of gut dysbiosis in prehypertensive and hypertensive populations 13,24,28,35,38,[41][42][43][44][45], led us to propose a dysfunctional autonomic nervous system-gut hypothesis that contributes to development and maintenance of hypertension ( Figure 2).…”