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

Abstract

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/6J 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 6h, 24h 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 was 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 mast cells and histamine receptors in the gut. 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 hours 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.

Crosstalk between the Gut and Brain in Ischemic Stroke: Mechanistic Insights and Therapeutic Options

“…However, a recent study in aged mice following experimental stroke showed that stroke resulted in increased intestinal mast cell numbers and intestinal histamine receptor expression levels. In the peripheral circulation, these gut-centered changes were linked to increased histamine levels and other proinflammatory cytokines (such as IL-6, TNF-α, and IFN-γ) [71]. It is obvious that histamine mediates host-microbe crosstalk as a neuroimmune system; however, it is still unclear how host histamine may affect microbial activity.…”

“…Recent research using experimental animal models has revealed that older mice tend to be more susceptible to infection after IS, which is at least partially caused by decreased intestinal barrier integrity and intestinal inflammation, as well as reduced expression of mucin and tight-junction proteins, which facilitates bacterial translocation [71]. Aged mice had a worse prognosis after IS than young mice.…”

Dietary butyrate treatment enhances healthy metabolites by longitudinal untargeted metabolomic analysis in amyotrophic lateral sclerosis mice

“…In the CNS, the neuroactive metabolites histamine and tryptophan play a crucial role in neuroprotection against neuroinflammation in SOD1 G93A mice 31,32 and mediates inflammation in the PNS via production of mast cells in the gut 33 and producing commensal gut microorganisms via microbial decarboxylation of amino acids 34 . Thus, we observed changes in histamine, tryptophan and glutamate related amino acids.…”

Mast Cells and their Role in Health and Disease

“…CRH also increased intestinal permeability in humans [211] via stimulation of mast cells by CRH. In fact, gut mast cells are now invoked in the pathogenesis of brain injury [212,213] and as a therapeutic target for neurodegenerative diseases [208,214].…”