Gut instincts in neuroimmunity from the eighteenth to twenty-first centuries

In the past two decades, work on the microbiota-gut-brain axis has led to a renewed appreciation for the interconnectedness between body systems in both clinical and scientific circles. In the USA alone, millions of adults are burdened with non-communicable chronic diseases whose putative etiologies were previously thought to be restricted to either the gut or brain, such as inflammatory bowel disease, irritable bowel syndrome, Parkinson's and Alzheimer's disease, and autism spectrum disorder. However, the recent explosion of research into the impacts of the gut microbiome on diverse aspects of human health has revealed the potentially critical importance of reciprocal interactions between the gut microbiota, the immune system, and the brain in diverse diseases and disorders. In this review, we revisit the history of gut-brain interactions in science and medicine, which dates back to at least the eighteenth century, and outline how concepts in this field have shifted and evolved across eras. Next, we highlight the modern resurgence of gut-brain axis research, focusing on neuro-immune-microbiota interactions and recent progress towards a mechanistic understanding of the diverse impacts of the microbiome on human health. Finally, we offer a forward-looking perspective on the future of microbiota-gut-brain research, which may eventually reveal new paths towards the treatment of diverse diseases influenced by the complex connections between the microbiota and the brain.