Investigating the Gut-Brain Axis: Immunological Consequences of Stroke

Abstract

Stroke is a leading cause of disability and mortality worldwide. Cerebral ischaemic and haemorrhagic events result in pathology and inflammation both in the brain and periphery. In addition to neurological deficit and post-stroke infection, many patients will also experience gastrointestinal complications, including loss of intestinal motility, reduced epithelial barrier integrity and incontinence. Increasing evidence suggests stroke results in dysbiosis of gut-resident commensal bacteria, and the concept of a 'gut-brain axis' has been proposed, whereby the presence and activity of specific microbes influences brain function. The intestinal tract is also enriched in immune cells that reinforce the epithelium and maintain commensal homeostasis, and which are regulated by both neuronal and hormonal signals. However, whether immune regulation of intestinal barrier function and homeostatic host-commensal crosstalk is perturbed in stroke is poorly understood. Using murine models of experimental cerebral ischaemia and haemorrhage, we found that stroke results in rapid changes in intestinal function with implications for barrier integrity and microbial diversity. Analysis of the intestinal tissues revealed concurrent changes in homeostatic immune function, with aspects of intestinal humoral immunity affected after stroke. Specifically, intestinal Immunoglobulin (Ig)A responses, a key modifier of gut microbiome homeostasis, are altered in the acute phase post-stroke, while increased IgA-producing cells are found within the CNS after stroke. Investigations into the microbiota revealed the impact of IgA in driving post-stroke dysbiosis, with possible implications for stroke pathophysiology. In addition to adaptive immune responses, we also found that functional properties of key gut-immune regulators, group 3 innate lymphoid cells (ILC3), were profoundly affected in the acute phase post-stroke, and exhibited a markedly reduced capacity to produce the cytokine interleukin (IL)-22. We endeavoured to determine the mechanisms through which stroke triggers dysregulated intestinal immune function, by investigating glucocorticoid and neuropeptide control of ILC3, leading us to identify feeding circuits as a potentially relevant modifier of stroke-induced alterations to intestinal immunity. Taken together, our work highlights an unappreciated crosstalk between the brain, intestinal immune system and microbiota in stroke. Further study into the underlying mechanisms governing this axis could reveal future therapeutic avenues.

Date of Award	1 Aug 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Catherine Lawrence (Supervisor), Matthew Hepworth (Supervisor) & David Brough (Supervisor)