The Potential Role of Intestinal Macrophages in the Gut-Brain Axis

Intestinal macrophages are crucial for maintaining gastrointestinal (GI) homeostasis and also contribute to various inflammatory disorders within the gut. As the most abundant immune cells in the GI tract, intestinal macrophages perform multifaceted functions. These include balancing immune responses to either innocuous antigens or harmful stimuli, supporting mucosal barrier integrity, and affecting gut secretion and motility through interactions with the enteric nervous system (ENS) and other nerves. A complex communication system, known as the “gut-brain axis” (GBA), exists between the intestine and the central nervous system (CNS). It integrates multilevel signals and modulates the functions of these two organs. A myriad of studies have revealed that alterations in the enteric microbiota are linked to various CNS disorders, such as Alzheimer’s disease, Parkinson’s disease, brain malignancies, multiple sclerosis, stroke, stress, anxiety, depression, autism, and schizophrenia. The mechanisms underlying the impact of gut dysbiosis on neuroinflammatory and neuropsychiatric diseases involve microbial metabolites and products, neurotransmitters and neuropeptides, immune regulation (including cytokines and chemokines), and neuroendocrine pathways. Notably, the functional status of intestinal macrophages is highly sensitive to the composition of the microbiota and thus can regulate the progression of CNS diseases via the GBA. Intestinal macrophages are found throughout the GI tract and may communicate with the brain through the nervous, circulatory, and immune systems. Thus far, there are relatively few studies that have explored the cellular and molecular mechanisms by which intestinal macrophages regulate CNS homeostasis and pathological conditions. The heterogeneity and niche-specific phenotypes of intestinal macrophages may have hindered a complete understanding of their specific roles in the context of homeostasis and disease. Here, we describe the progress made in understanding the distinct populations of intestinal macrophages and their roles in the GBA, providing an overview of their contributions to CNS homeostasis and dysfunction.