Brain-gut axis in stroke

2019 Vanguard Grant

Years funded: 2020-2022

Stroke is one of the leading contributors to morbidity and mortality worldwide. Despite its recognised debilitating neurological deficits, stroke is associated with various non-neurological medical complications, including pneumonia and bowel dysfunction. These complications contribute to extended hospital stay, poor neurological outcome, development of further complications, and even death. In our recent publications in Science and Nature Medicine, we discovered that stroke weakens intestinal barrier integrity and antibacterial defence, allowing gut bacteria to trans-locate to other organs, such as the lung, to cause fatal infections.

Our novel discovery uncovers an intricate communication network between the brain and the gut, with disruption of this brain-gut axis contributing to altered intestinal homeostasis and worsening of stroke outcome. Thus, the major focus of this project is to investigate the mechanisms underlying stroke-induced impairment of gut homeostasis. Intestinal macrophages are a dominant immune cell type present in gut tissues that are crucial for homeostatic maintenance of this organ.

Key functions include bactericidal activity with limited inflammatory cytokine production, maintenance of intestinal epithelial cells, and supporting neuro-immune interactions. Indeed, inappropriate macrophage activity has been implicated in driving patho-physiological complications in the gut. As such, we propose the impairment of intestinal macrophage function after stroke is pivotal in mediating gut barrier breakdown, weakened antibacterial defence, and to the associated life-threatening sequelae of gastrointestinal and infectious complications.

Moreover, emerging data suggests that short chain fatty acids, mainly butyrate, have shown promise in improving gut barrier integrity. Therefore, a further aim of this project is to test if therapeutic administration of butyrate can modulate intestinal macrophage function and strengthen gut barrier integrity in such a way to reduce stroke-associated bacterial translocation and infection, and ultimately improve patient outcomes.