Microbes, microglia, and pain

Abstract

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.

Keywords: Chronic pain; Gut microbiome; Gut permeability; Gut-brain axis; Microglia; Vagus nerve.

Fig. 1

The intersection between the gut microbiome, microglia, and pain. There is significant evidence in support of the connections between microglia-pain, microglia-microbiome, and pain-microbiome; however, we currently lack conclusive studies that link the communication between gut bacteria and microglia to the development and maintenance of chronic pain.

Fig. 2

Mechanisms by which the gut microbiome might influence microglial activation to drive chronic pain. There are numerous mechanisms through which gut bacteria might influence microglial reactivity to drive the initiation and maintenance of chronic pain. Bidirectional signaling between gut bacteria and the brain via the vagus nerve plays a role in modulating microglial proliferation and activation. Impaired gut barrier function permits leakage of bacterial products into the systemic circulation, causing a peripheral immune response and subsequent microglial activation. Cytokines and immune cells can activate microglia either by directly crossing the intact BBB or through regions of enhanced permeability. Through these routes, microglia are activated and contribute to the production of chronic pain. LPS: lipopolysaccharide; BBB: blood brain barrier.