A Brain–Gut Pathway for Stress-Induced Microbiome Changes

Chang H, Perkins MH, Novaes LS, et al. Stress-sensitive neural circuits change the gut microbiome via duodenal glands. Cell 2024;187:1–20.

A growing body of evidence shows that psychological stress is associated with an altered gut microbiome, specifically a reduction in species of Lactobacillus bacteria, which has implications for gut function and immunity. Reduced mucus secretion in the gut is also associated with stress and affects the microbiome composition. The brain-gut signaling pathways underlying stress, mucus secretion, and their effects on the microbiome are not yet well understood.

This study defines the neuronal connections between the brain and Brunner’s glands (BGs), specialized structures in the duodenum primarily consisting of mucus-secreting cells (Cell 2024;187:1–20).

The investigators show how a polysynaptic pathway from the central nucleus of the amygdala to the duodenum via the vagus nerve is implicated in stress-initiated immune and gut microbiome dysregulation.

The investigators first used in vivo calcium imaging in mice to demonstrate that the vagus nerve directly signals to the cells comprising the BGs, leading to mucus secretion, which then stimulates the proliferation of Lactobacillus species throughout the intestinal tract. Using viral tracing, BGs are shown to be synaptically connected with vagal efferent fibers originating in the dorsal motor nucleus of the vagus (DMV) of the brainstem. Mucus-secreting cells of the BGs were found to express the muscarinic acetylcholine receptor M3, priming them to receive input from these parasympathetic cholinergic fibers. Using chemogenetics to stimulate the DMV neurons and cell-specific ablation to silence them, the investigators showed that vagal efferent fibers originating in the DMV have a crucial role in stimulating mucus production in the BGs thus leading to Lactobacillus proliferation.

Using ablation techniques, the investigators demonstrated that BGs are critical for maintaining homeostatic sympathetic tone and immunity. BG ablation resulted in increased intestinal permeability, microbial dysbiosis, and increased vulnerability to pathogenic bacterial infections that was accompanied by a decreased B cell population and increase in inflammatory cytokines. These adverse effects could be reversed by introducing beneficial probiotic strains including Lactobacillus and by replacing the mucus lost after BG ablation.

Like BG ablation, psychological stress has also been shown to be associated with microbial dysbiosis and decreased immune function. To determine whether psychological stress might influence BG function, the investigators traced the polysynaptic circuit from the BGs to the brain. They found that acute and chronic stress resulted in decreased neuronal activity in the circuit leading from the BGs to the central nucleus of the amygdala via the vagus nerve and DMV, leading to decreased Lactobacillus counts. Conversely, stimulation of this circuit in stressed animals reversed this deficiency, normalized mucus secretion, and abolished the stress-induced detrimental effects on immunity.

This study is compelling in that it demonstrates a novel neuroglandular pathway that may explain, in part, how stress is connected to gut and immune dysfunction. Further elucidation of the mediators involved in this pathway may thus lead to novel interventions for the peripheral effects of psychological stress. Further investigation into how Lactobacillus itself regulates host immunity would further expand the potential pathways by which these bacteria more directly effect change.