Microbes, microglia, and pain

•Explore the connection between the gut microbiome and microglia in chronic pain.•Discuss mechanisms by which gut bacteria might influence microglia to contribute to chronic pain.•Highlight gaps in knowledge and discuss future directions for the field. Globally, it is estimated that one in five people suffer from chronic pain, with prevalence increasing with age. The pathophysiology of chronic pain encompasses complex sensory, immune, and inflammatory interactions within both the central and peripheral nervous systems. Microglia, the resident macrophages of the central nervous system (CNS), are critically involved in the initiation and persistence of chronic pain. Microglia respond to local signals from the CNS but are also modulated by signals from the gastrointestinal tract. Emerging data from preclinical and clinical studies suggest that communication between the gut microbiome, the community of bacteria residing within the gut, and microglia is involved in producing chronic pain. Targeted strategies that manipulate or restore the gut microbiome have been shown to reduce microglial activation and alleviate symptoms associated with inflammation. These data indicate that manipulations of the gut microbiome in chronic pain patients might be a viable strategy in improving pain outcomes. Herein, we discuss the evidence for a connection between microglia and the gut microbiome and explore the mechanisms by which commensal bacteria might influence microglial reactivity to drive chronic pain.