Age-dependent involvement of gut mast cells and histamine in post-stroke inflammation.

BACKGROUND: Risk of stroke-related morbidity and mortality increases significantly with age. Aging is associated with chronic, low-grade inflammation, which is thought to contribute to the poorer outcomes after stroke seen in the elderly. Histamine (HA) is a major molecular mediator of inflammation, and mast cells residing in the gut are a primary source of histamine. METHODS: Stroke was induced in male C57BL/6 J mice at 3 months (young) and 20 months (aged) of age. Role of histamine after stroke was examined using young (Yg) and aged (Ag) mice; mice underwent MCAO surgery and were euthanized at 6 h, 24 h, and 7 days post-ischemia; sham mice received the same surgery but no MCAO. In this work, we evaluated whether worsened outcomes after experimental stroke in aged mice were associated with age-related changes in mast cells, histamine levels, and histamine receptor expression in the gut, brain, and plasma. RESULTS: We found increased numbers of mast cells in the gut and the brain with aging. Using the middle cerebral artery occlusion (MCAO) model of ischemic stroke, we demonstrate that stroke leads to increased numbers of gut mast cells and gut histamine receptor expression levels. These gut-centric changes are associated with elevated levels of HA and other pro-inflammatory cytokines including IL-6, G-CSF, TNF-α, and IFN-γ in the peripheral circulation. Our data also shows that post-stroke gut inflammation led to a significant reduction of mucin-producing goblet cells and a loss of gut barrier integrity. Lastly, gut inflammation after stroke is associated with changes in the composition of the gut microbiota as early as 24-h post-stroke. CONCLUSION: An important theme emerging from our results is that acute inflammatory events following ischemic insults in the brain persist longer in the aged mice when compared to younger animals. Taken together, our findings implicate mast cell activation and histamine signaling as a part of peripheral inflammatory response after ischemic stroke, which are profound in aged animals. Interfering with histamine signaling orally might provide translational value to improve stroke outcome.

Prebiotics, Probiotics, and Acetate Supplementation Prevent Hypertension in a Model of Obstructive Sleep Apnea.

Disruption of the gut microbiota, termed gut dysbiosis, has been described in animal models of hypertension and hypertensive patients. We have shown that gut dysbiosis plays a causal role in the development of hypertension in a rat model of obstructive sleep apnea (OSA). Functional analysis of the dysbiotic microbiota in OSA demonstrates a loss of short chain fatty acid-producing bacteria. However, measurements of short chain fatty acid concentrations and testing of their role in blood pressure regulation are lacking. We hypothesized that reduced short chain fatty acids in the gut are responsible for OSA-induced hypertension. OSA significantly increased systolic blood pressure at 7 and 14 days ( P<0.05), an effect that was abolished by the probiotic Clostridium butyricum or the prebiotic Hylon VII. The 16S rRNA analysis identified several short chain fatty acid-producing bacteria that were significantly increased by Cbutyricum and Hylon treatment. Acetate concentration in the cecum was decreased by 48% after OSA ( P<0.05), an effect that was prevented by Cbutyricum and Hylon. Cbutyricum and Hylon reduced OSA-induced dysbiosis, epithelial goblet cell loss, mucus barrier thinning, and activation of brain microglia ( P<0.05 for each). To examine the role of acetate in OSA-induced hypertension, we chronically infused acetate into the cecum during 2 weeks of sham or OSA. Restoring cecal acetate concentration prevented OSA-induced gut inflammation and hypertension ( P<0.05). These studies identify acetate as a key player in OSA-induced hypertension. We demonstrate that various methods to increase cecal acetate concentrations are protective from the adverse effects of OSA on the microbiota, gut, brain, and blood pressure.