Pain From Your Second Brain

Most people can agree they’ve experienced stomachaches that have made them cancel plans or put off work because the pain overrides motivation to interact with others or focus on simple tasks. The ability of our stomach to influence our thoughts and feelings has given rise to the idea of the gut being our second brain”. This second brain, or the enteric nervous system (ENS), is a collection of nerve and immune cells that surround the gut to control digestive processes. In the past decade however, the scientific community has expanded our understanding of the ENS and how it communicates with and influences our brain.  Importantly, there has been growing interest in uncovering how this communication goes awry in gastrointestinal (GI) dysfunction such as stomach pain and more serious GI disorders like irritable bowel syndrome.

Figure 1. Model of communication between enteric glia cells and macrophages that lead to our perception of pain in the gut.

Scientists agree that the immune system of our gut plays an important role in the development of what they call “visceral hypersensitivity”, or the internal pain we feel when we experience a stomachache or cramping. We know that nerve cells in the gut react to immune responses and alter messages sent to the brain. This communication ultimately transforms the immune response into a perception of pain. The authors of a recent paper published in Cell Reports, reasoned that because altered immune response contributes to GI dysfunction, the resident immune cells of the gut (named enteric glia cells and macrophages), must have a significant contribution to this perception of pain. Members of the Gulbranson lab had previously discovered connexin43, an important type of enteric glia protein, allows for enteric glia cells to communicate with each other and with other nerve cells in the gut. Using a mouse model that lacks connexin43, they were able to find it is also important in protecting our gut from harmful substances like toxins and bacteria, a process referred to as inflammation. This further motivated the authors to believe this protein could be involved in interfering with messages sent to the brain during inflammation.

The researchers modeled inflammation in the mouse gut with the chemical dextran sodium sulphate (DSS). DSS enables harmful bacteria and microbes to invade the gut and cause an immune response. They were then able to replicate the sensation of stomach pain in mice and measure this pain by recording abdominal contractions. They found following DSS treatment in mice without the connexin protein, the pain was significantly reduced when compared to mice that had normal levels of connexin43. To determine how enteric glia cells could be causing this effect, the authors looked at levels of signals that indicate the process of inflammation has begun to determine if any could be altered in mice lacking connexin43. They identified one signal called M-CSF that was decreased in connexin43 deficient mice. This was interesting as M-CSF signals to macrophages, another type of immune cell that is important for recognizing and “eating” or destroying harmful bacteria or other foreign invaders of the body.  These macrophages then become activated or take a new physical form that allows them to properly carry out their job in inflammation. Activation of macrophages by glial M-CSF results in signals from macrophages to nerve cells that ultimately affect the communication of pain to our brain.

The discovery that these two immune cells can interact and interfere with pain perception is an important step in our understanding of GI disorders. It will be essential to look further into these cell types as possible targets for the treatment of irritable bowel syndrome and irritable bowel disease. Interestingly, GI dysfunction is being reported in neurodegenerative diseases such as Parkinson’s and Alzheimer’s. Could this connexin also be involved in the progression of these debilitating diseases? While many questions remain, uncovering the communication between the two cells types is essential in discovering more ways our second brain can communicate with our first.

Edited by Manasi Iyer