Kidney-gut-brain cross talk in longterm IRI
Introduction: Although epidemiological studies suggest that long-term survivors of AKI have an increased risk of dementia, underlying mechanisms remain uncertain. Based on well-known brain-gut crosstalk and also on recently introduced kidney-gut crosstalk, we hypothesized that gut dysbiosis and altered gut microenvironments might contribute to the long-term development of dementia in AKI.  Methods: We performed a 1-year study in mice model of kidney ischemia/reperfusion injury (IRI) and determined the long-term brain, gut, and kidney outcomes. Cognitive dysfunction and structural brain damage, as well as long-term changes in gut microenvironments including microbiota were determined. For causal relationship, we also tested the effect of gut microbiota transfer either by fecal microbiota transplantation (FMT) or cohousing on brain as well as on kidneys.  Results: One year after kidney IRI, mice showed cognitive dysfunction compared to age matched sham control. Transcriptosome of hippocampus demonstrated more than 120 differentially regulated genes including those involved in angiogenesis/immune and inflammatory response. We also found structural brain injury including neuroinflammation, oxidative stress as well as accumulation of hyperphosphorylated tau proteins, suggesting the development of Alzheimer like dementia long after AKI. Gut microbiota structure 1-year after kidney IRI was also clearly distinguished from that of age matched sham control and the gut dysbiosis was associated with decreased level of short chain fatty acids and Th17 polarization. Both cohousing and FMT partially restored the gut microenvironments and this also led to not only decreased kidney fibrosis but also improved cognitive function as well as neuroinflammation and tauopathy.  Conclusion: This is the first animal study showed that AKI can lead to Alzheimer like neurodegeneration. Persistent gut dysbiosis and aberrant mucosal immune response are thought to contribute to the development of dementia long after AKI. Our data provide new insights into “kidney-gut-brain” axis in the field of AKI and suggest that gut might be a new therapeutic target for the prevention of long-term adverse outcomes in AKI patients.