Gut neurons drive immune responses through adrenomedullin 2

Neurons in the gut produce a molecule that plays a pivotal role in shaping the gut's immune response during and after inflammation, according to a new study by Weill Cornell Medicine investigators. The findings suggest that targeting these neurons and the molecules they produce could open the door to new treatments for inflammatory bowel disease and other disorders driven by gut inflammation.

Hundreds of millions of neurons make up the enteric nervous system, the "second brain" of the body, where they orchestrate essential functions of the gut such as moving food through the intestines, nutrient absorption and blood flow. While this system is known for regulating these fundamental processes, its role in controlling intestinal inflammatory responses has remained far less clear.

In their study, reported August 15 in Nature Immunology, the investigators focused on group 2 innate lymphoid cells (ILC2s), immune cells that reside within the linings of the gut. Their previous work revealed that ILC2s are a major source of a tissue-healing growth factor called amphiregulin and have the capacity to receive neuronal signals that modulate their function and can impact disease progression and recovery. In the new study, they demonstrated that the tissue-protective function of ILC2s depends on production of a molecule called adrenomedullin 2 (ADM2) from the enteric nervous system; administering the molecule expanded this group of ILC2s and provided therapeutic benefit in a preclinical model of inflammatory bowel disease, whereas loss of ADM2 signaling exacerbated disease due to the lack of these protective cells.

The enteric nervous system has long been neglected when thinking of how we can resolve detrimental intestinal inflammation. Our work suggests there may be a previously unknown neuro-immune mechanism driving intestinal healing responses."

Dr. Jazib Uddin, lead author, an NIH Ruth L. Kirschstein postdoctoral fellow at Weill Cornell Medicine

Additionally, the investigators performed translational patient-based studies by analyzing human tissue and blood samples from Weill Cornell Medicine's Jill Roberts Institute for Research in Inflammatory Bowel Disease Live Cell Bank. This analysis revealed that patients with inflammatory bowel disease had elevated expression of ADM2 compared with control individuals and found that human ILC2s stimulated with ADM2 directly promoted production of tissue-protective amphiregulin. These findings indicate that the immune-nervous system communication identified in mice is also present in humans, highlighting the enteric nervous system as a promising therapeutic target for inflammatory bowel disease.

"The findings of this current study allow new insights into how the immune and nervous systems 'speak' to each other and coordinate complex processes, including tissue inflammation and repair, and offer the potential for new therapies targeting these neuro-immune interactions," said senior author Dr. David Artis, director of the Jill Roberts Institute for Research in Inflammatory Bowel Disease and the Michael Kors Professor in Immunology at Weill Cornell Medicine and co-director of the Allen Discovery Center for Neuro-immune Interaction.