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In a recently published review article, researchers synthesized cutting-edge findings on brain–gut neuroimmune interactions in critical illness.

In a recent Current Opinion in Critical Care review, Jacob W. Larsson, MD, Karolinska University Hospital, and colleagues synthesized cutting-edge findings on brain–gut neuroimmune interactions in critical illness, underscoring the significance of gut innervation, neural regulation of intestinal inflammation, and the broader brain–gut axis (BGA) in orchestrating systemic immune responses.

“Critical illness involves complex organ dysfunction, not least in the gastrointestinal system,” the authors stated. “A multitude of neuroimmune interactions between the intestinal wall, immune cells, peripheral nerves, and the central nervous system regulate inflammation.”

Gut Innervation & Neurotransport Pathways

Beyond conventional synaptic signaling, gut innervation may facilitate the transport of macromolecules to the central nervous system, according to the authors. They highlighted a study of rodents and nonhuman primates that demonstrated that nanoparticles could traverse from the gut to the brain via peripheral nerve conduits. They noted that this proof-of-concept for a highly specific neurointestinal conduit raises compelling questions about the role of these nerve conduit-based transport pathways in both normal physiology and during inflammation, infection, and conditions with compromised intestinal barrier function.

 Vagal Modulation of Intestinal Inflammation

The review noted that although the vagus nerve is recognized for its anti-inflammatory reflex, the precise mechanisms by which vagus nerve signaling regulates gut inflammation remain unclear.

“While experimental evidence supports the role of neural reflexes in controlling immune responses, clinical validation is lacking in the context of critical care,” the team wrote. Given recent advances in understanding how neural pathways regulate inflammation, it has been suggested that alterations in neural signaling during critical illness may impair the physiological regulation of organ function, including within the GI [gastrointestinal] and immune systems, according to the authors.

Future Research Necessary

Gaining insight into the clinical relevance of the BGA in critical illness will require more extensive research of the clinical course and outcomes in the ICU, likely involving the development of novel methodologies to specifically isolate BGA-related effects in this setting, according to the authors.

“Understanding the clinical implications of the BGA and [enteric nervous system] in critical care could pave the way for innovative treatments aimed at improving patient outcomes by targeting neuroimmune crosstalk,” the researchers concluded. “Further research is needed to identify specific neural signals and mechanisms involved in GI neuroimmune crosstalk, to open potential therapeutic avenues of exploration in critical care.”