The brain-gut-lung circuit

This 2023 rodent study investigated mechanisms of improving stress-worsened respiratory viral infection:

“Our study demonstrates that chronic psychological stress significantly increases host vulnerability to influenza A virus (IAV) infection characterized by a distorted gut microbiome and deregulated alveolar macrophages (AMs) response. We show that microbiome-derived γ-aminobutyric acid (GABA) functions as a tonic signal to support survival, self-renewing, and immunoregulation of AMs, and hence optimized pulmonary defensive response.

Chronic psychological stress causes gut microbiome dysbiosis and defective GABA generation, leading to loss of AMs homeostasis and aggravated viral pneumonia. The data indicate that:

Microbial GABA is released in the circulation,

Sensed by AMs via the GABA_A receptor,

Promoting cellular mitochondrial metabolism,

For increased production of α-ketoglutarate (αKG),

Which triggers Tet2-mediated DNA hydroxymethylation,

To enable PPARγ-centered gene program,

Supporting AMs homeostasis and function.

Re-localization of GABA-generating probiotics,

Supplementation of αKG, or

Adoptive transfer of GABA-conditioned macrophages,

Substantially rectifies stress-induced disruption inter-organ communication, and

Alleviates symptoms of viral pneumonia.

Our current study unveils an unappreciated regulatory circuitry that connects the brain, gut, and lung to mediate neurological modulation of host defensive response.”

https://www.sciencedirect.com/science/article/pii/S2090123223001716 “Gut microbial GABAergic signaling improves stress-associated innate immunity to respiratory viral infection”