Sensory Innervation of the Colon: Implications for GI Disease Management

The gut-brain axis, the link between the enteric nervous system and the central nervous system, has been elusive to neurobiology researchers in recent years. Although mounting evidence has established that the GI system has an intricate neurological connection to the brain, the understanding of this connection has remained incomplete. 

Interestingly, recent studies show that the neurological relationship between the gut and the brain is bidirectional. In other words, gut health is related to cognitive and mental health, and brain activity can affect gastrointestinal function. For example, mental health conditions such as depression and anxiety have been induced by gut bacteria profiles in mice. On the other hand, excessive stress can have an impact on GI motility in diseases such as IBS. However, the details of this mechanism, including the specific neurons involved, were always poorly understood. 

The August 2023 Breakthrough: From Skin to Colon Sensation

In their August 2023 study, Harvard Medical School researchers made a significant breakthrough that has revolutionized our understanding of the innervation of the colon and its relationship to the brain. They discovered 5 different types of neurons that mediate mechanosensation in the large intestine in mouse models. The significance of this is that we can now understand the neurological mechanism behind the motility and pain sensation processes that occur in the colon due to various GI diseases. These include but are not limited to diarrhea, and constipation, and inflammatory conditions such as IBD. 

In the past, specific subtypes of sensory neurons in the skin have been extensively studied. Genetic information has been utilized to determine the structure, function, and organizational pattern of various skin neurons. However, the properties of the sensory neurons in the enteric nervous system were not explored as extensively. This is the gap in knowledge Wolfson et al. aimed to address in their new study. 

In genetically modified mice, the HMS researchers studied neurological responses to various types of mechanical stimulation including gentle stretching, intense stretching, and induced inflammation. Different neurons in the colon responded to these various stimuli, suggesting the presence of various subtypes of neurons in the ENS. Interestingly, the subtypes of neurons in the colon matched the functions of the subtypes of neurons previously studied in the skin. Not only does this reveal previously unknown categories of neurons in the colon, but it also suggests a possible conservation of function between neurons in different organ systems. 

Types of Neurons in the Colon

In this study, 5 different subtypes of neurons were delineated within the colon based on form and function. Two of these subtypes of neurons sensed more gentle stretching, which may be analogous to the sensation of food moving through the digestive tract. On the other hand, two other subtypes were more sensitive to higher amounts of stretching force. These neurons may be implicated in sensation of pain during more extreme colonic distension, as they induced pain-sensing behaviors in the mice being studied.  

Image from here

The different subtypes of neurons were found to have varying thresholds for sensing force. Interestingly, when the highest force-threshold neuron was removed, pain-sensing behavior in response to extreme colonic distension was diminished. This suggests that certain neuron types have a greater role in inducing pain sensation than others.

Perhaps the most significant discovery of this study is a specific subtype of colonic neuron called a Bmpr1b+ high-threshold mechanoreceptor (HTMR). This neuron was found to be responsible for the colonic pain hypersensitivity in inflammatory bowel disease. Both gain-of-function and loss-of-function experiments confirmed this neuron’s role in pain sensation under conditions of induced inflammation similar to IBD in mice. If found to be translatable to humans, this finding could be groundbreaking in enhancing understanding of IBD pathophysiology and treatment. 

What this Means for GI Disease Treatment

The colon is involved in a wide variety of gastrointestinal conditions, many of which cause patients pain and discomfort. According to lead author Rachel Wolfson, a gastroenterology fellow at Massachusetts General Hospital, a key patient complaint is pain sensation in the GI system. Until now, the mechanisms of such pain have been poorly understood, leading to a lack of feasible treatments. 

However, this study provides several potential therapeutic targets for GI disease. For example, the two neuron subtypes that sense gentle stretching could be targeted in diseases that impact gut motility, such as constipation and diarrhea. On the other hand, the subtypes that sense higher levels of stretching force could be exploited for pain relief purposes, which Wolfson calls a “great therapeutic need.” 

Of specific interest is the Bmpr1b+ HTMR subtype that is implicated in inflammation-induced pain hypersensitivity in an IBD model. These neurons become more sensitive when inflammation is induced in mouse models, revealing a concrete mechanism for the pain and discomfort commonly reported by IBD patients. More importantly, the discovery of this neuronal subtype provides a potential therapeutic target for pain management in IBD, which could drastically improve the quality of life for patients living with this condition. 

Summary

An August 2023 study published in Cell has revolutionized our understanding of the gut-brain axis with particular emphasis on mechanosensation within the colon. The authors discovered 5 different subtypes of sensory neurons in the large intestine. Two of these subtypes respond to more gentle stretching and could be involved in motility-related GI diseases. Another two subtypes are implicated in pain sensation in response to higher intensity stretching, and these could be potential targets in treating common abdominal pain. Of most interest is the Bmpr1b+ HTMR subtype, which is involved in pain hypersensitivity in inflammatory conditions. This neuron could be a target for pain relief therapy in IBD patients living in constant discomfort, greatly improving their quality of life.