Stress Alters the Gut Microbiome Via Vagus Nerve Stimulation
Chronic stress suppresses the activity of Brunner glands compromising beneficial gut bacteria populations and immunity.
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Negative psychological states impact immunity by changing the gut microbiome. However, it remains unclear how brain states control such changes.
Now, researchers at the Icahn School of Medicine have shown that stress inhibits vagus nerve stimulation of the glands of Brunner, which compromises gut Lactobacilli populations and host immunity.
The results of the study are published in the journal Cell.
Stress reduces beneficial bacteria in the gut
Gut microbes – the various bacteria, viruses, fungi and other microbes that inhabit the human gut – help the body perform key functions such as digestion and provide protection from foodborne pathogens.
Stressful events, such as maternal separation induce significant decreases in the levels of the beneficial bacteria Lactobacillus, which has been linked to an increased vulnerability to infections in non-human primates. Researchers have hypothesized that such influences of brain states on the gut microbiome may be due to changes in mucosal–bacterial interactions.
In the present study, the researchers set out to test this hypothesis and identify the neuronal pathways that enable the brain to impact the mucosa–microbiome system. They focused their attention on the glands of Brunner, which consist primarily of mucus-producing cells. Neural stimulation is necessary for mucus secretion by the glands with a significant proportion of the nerve terminals of vagal origin.
Using a combination of cell-specific approaches including single-cell sequencing, intravital imaging and behavioral studies, the researchers identified a stress-sensitive neuroglandular circuit linking brain states to changes in the gut microbiome.
They proposed that the following sequence of events occur in response to chronic stress: emotion-related brain circuits control the glands of Brunner via the vagus nerve, and stimulation of these nerves is inhibited during chronic stress. Inhibited nerve signaling reduces mucus release by the glands of Brunner. Mucosal secretions from these glands support the proliferation of microbes, particularly Lactobacilli. When stress inhibits mucus release, Lactobacilli growth is similarly suppressed. The effects of suppressed Lactobacilli growth result in a heightened vulnerability to infection.
“Our findings are therefore directly consistent with the notion that efferent vagal fibers promote immune function and anti-inflammatory signaling,” the researchers concluded.
The researchers mapped modulation of the glands of Brunner to the central amygdala, an area of the brain within the temporal lobes that plays a major role in conditioned fear and anxiety. “We found that stressor exposure robustly inhibited neuronal activity in the central amygdala and that central amygdala inhibition recapitulates the effects of stress on the gut microbiome and immunity,” said the researchers.
Excitation of the vagus nerve reduces the effects of stress on the microbiome
The researchers found that administering probiotics in mice lacking cells specific to the glands of Brunner mitigated the negative effects caused by suppressed mucus release: “While Lactobacillus and Bifidobacteria administration restored the integrity of the gut barrier and lessened sympathetic nerve activity, antibiotic-treated animals displayed enhanced gut permeability,” they explained.
Beyond probiotic solutions, excitation of either the central amygdala or parasympathetic vagal neurons activated the glands of Brunner and was effective in reversing the effects of stress on the gut microbiome and immunity. This result is consistent with preclinical studies where vagal stimulation has reversed stress-induced changes in intestinal permeability.
This study has revealed a tractable brain–body mechanism linking psychological states to the gut microbiome, but the researchers concluded that further research is needed to advance our understanding of the mechanisms linking Brunner’s glands, Lactobacillus and host immunity.
The approaches used to lesion the glands in the study involved invasive procedures that could compromise the germ-free status of the subjects. The researchers explained that while this limitation does not directly impact the study conclusions, future intersectional genetic approaches may enable the targeting of Brunner’s glands without the need for invasive interventions.
Reference: Chang H, Perkins MH, Novaes LS, et al. Stress-sensitive neural circuits change the gut microbiome via duodenal glands. Cell. 2024. doi: 10.1016/j.cell.2024.07.019
