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Exploring the Gut-Brain Connection: How Pain Neurons Influence Gut Health

In the last decade or so, there has been a lot of discussion about the importance of your gut health. The gut has been found to be one of the most important factors in our overall well-being and health. In fact, many experts have even gone ahead and called it our ‘second brain’ due to the presence of an intricate nervous system known as the enteric nervous system in your gut. The gut has a system within it that communicates directly with your brain, a connection known as the gut-brain axis. And it has been found to have a connection with chronic pain. Read on to find out whether there is a connection between pain nerves and a healthy gut.

Exploring the Gut-Brain Connection: How Pain Neurons Influence Gut Health

Connection Between Your Pain Nerves and a Healthy Gut

A recent study carried out on mice has discovered that the pain neurons in the gut have a role to play in regulating the secretion of protective mucus in the body. These neurons responded to painful gut inflammation, and they began signaling other cells nearby to immediately increase the production of mucus. In a healthy gut, the friendly bacteria were found to interact with these neurons to control how much mucus was being produced, leading the study researchers to speculate that certain pain relief drugs can disrupt the ability of pain neurons to increase the production of mucus.

It is important to remember that pain, no matter how unpleasant it is, is also necessary for the body as it warns us about any potentially damaging stimuli in the body, causing us to take preventive action at the earliest. For example, when you feel pain in your gut after eating certain foods, it might be a sign that you need to avoid these particular foods.

In cases where the pain becomes intense and unavoidable, it definitely makes sense to take medicine to relieve the pain. However, what happens when the pain itself is promoting body healing and regulation? This is the main hypothesis of the study conducted by researchers at the Harvard Medical School in Boston, Massachusetts.

The study authors stimulated a painful and inflammatory condition known as colitis in mice. In this, the pain nerves present in the mice’s gut triggers an increased production of mucus, which is a gel-like, slippery substance composed of sugars and proteins. (1,2,3)

The researchers believe that this response of mucus production to painful stimuli can help clear out any harmful substances from the gut. The study researchers also discovered that even when painful stimuli are absent, gut bacteria keep interacting with the pain neurons to help control mucus secretion. (4)

This shows that pain might actually help protect us in a direct manner as compared to its conventional job of detecting potential harm being caused to the body and sending the signals of pain to the brain. It won’t be incorrect to say that the pain nerves present in your gut actually communicate with the nearby mucus-producing cells that are located in the intestinal lining. This shows that the nervous system of your gut has a huge role to play, and it goes much beyond just causing an unpleasant sensation of pain. It is also the main player in ensuring the proper maintenance of the gut barrier. It also lends protective abilities during inflammation. The results of the study were recently published in the Cell journal. (5,6,7)

What is the Importance of the Mucus Layer?

The mucus layer in the gut keeps the linings of your intestines safe. At the same time, it prevents the airways from abrasion and any type of damage. In both your lungs and the gut, there are cup-shaped goblet cells that produce mucus. (8,9,10)

When the mucus is present in the gut, it helps prevent the contents of the gut from leaking out into the surrounding and underlying tissue. At the same time, it also acts as a protective barrier against harmful pathogens.

Mucus also supports the growth of friendly gut bacteria, which are known to have a critical role to play in our well-being and overall health. (11,12)

The research team also found that the guts of mice that did not have pain neurons were producing less mucus. (13) Additionally, there was also an imbalance of the beneficial and harmful gut bacteria, known as dysbiosis. (14,15)

The study carried out at Harvard Medical School showed that the pain neurons communicated directly with the goblet cells that produced mucus through a signaling molecule known as CGRP. (16)

The nerve cells, in response to painful stimuli, ended up producing more CGRP. CGRP then binds to a receptor found on the surface of goblet cells in both mice and humans, known as RAMP1. The research team discovered that this molecular signaling is what triggers the goblet cells to start producing more mucus whenever there is any inflammation in the gut, as what happens in colitis. (17)

What is the Role Of Friendly Gut Bacteria?

What is the Role Of Friendly Gut Bacteria?

The study also found that when there were no painful stimuli present, the friendly bacteria could stimulate the pain neurons to start releasing small amounts of CGRP. This finding is important as it tells us that the pain nerves are not only triggered by acute inflammation but they can also be triggered at baseline. Even having regular friendly gut microbes in the area can trigger the nerves, causing the goblet cells to start releasing mucus.

This is beneficial for your health because these friendly gut microbes ensure that there is a steady supply of mucus present that helps them thrive.

Another trigger for mucus production can be certain substances present in food, such as the compound capsaicin, which lends chili peppers their intense heat and flavor. Researchers of the study even showed how capsaicin activated the pain neurons in the gut of mice, thus promoting the production and release of mucus. (18)

What is the Role of Pain Neurons, Gut Dysbiosis, and Inflammation?

According to the authors of this study, it is believed that there is a link between pain neurons, gut dysbiosis, and inflammatory bowel diseases like ulcerative colitis. (19)

The study found that mice that lacked either RAMP1 (which is the receptor for CGRP on the goblet cells) or pain neurons were more susceptible to colitis. They also suffered from more severe colitis. However, when the scientists administered CGRP to the mice who did not have any pain neurons in their gut, it was able to rapidly restore the production of mucus.

Pain is a common symptom of conditions that cause inflammation of the gut, such as colitis. However, the study showed that acute pain also has a direct and protective role to play in these diseases. The authors of the study further suggested that acute pain helped maintain the gut barrier in conditions like inflammatory bowel disease.

When the researchers stimulated colitis in mice, those animals without the pain receptors in their gut experienced a more severe form of the disease. It is commonly observed that in people who suffer from inflammation of the gut, the most common symptom is pain. This is why it is but natural to assume that the focus will be on treating and blocking this pain to give relief from the suffering. However, a part of this pain signal is believed to be directly connected to being a protective neural reflex of the body. This raises many questions about how best to manage pain in a way that does not cause more harm but also relieves the suffering of the person.

Can Pain Killer Cause Certain Unintended Consequences?

Keeping the study in mind, it won’t be incorrect to say that certain pain-relieving medications could have some unintended consequences. Opioid drugs are known to cause some major microbial dysbiosis in the gut. In some instances, doctors also use medicines that work by blocking CGRP in the treatment and prevention of chronic migraine. The authors of the study believe that over a period of time, this could disrupt the mucosal gut barrier and also disturb the balance of gut bacteria.

While there is no evidence currently to show that these drugs cause an increase in gut inflammation or dysbiosis, but it has been found that anti-CGRP migraine medicines can cause constipation in over 50 percent of patients who take them regularly. (20,21)

Conclusion

It is essential to further investigate if other gut issues arise due to taking pain relievers, including changes in the microbiome and inflammation of the gut. At the same time, this study has many limitations. For example, when the researchers carried out stimulation of colitis in mice, some of the mice experienced less severe inflammation as they drank less water. Furthermore, to recreate colitis, the researchers further added a toxic chemical known as DSS to the drinking water of the mice, which might even have inadvertently conditioned some of the mice to avoid having water.

Due to these limitations, further studies are needed, especially in humans, to better understand how pain neurons in the gut help regulate the production and secretion of mucus.

References:

  1. Yang, D., Jacobson, A., Meerschaert, K.A., Sifakis, J.J., Wu, M., Chen, X., Yang, T., Zhou, Y., Anekal, P.V., Rucker, R.A. and Sharma, D., 2022. Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection. Cell, 185(22), pp.4190-4205.
  2. Okayasu, I., Hatakeyama, S., Yamada, M., Ohkusa, T., Inagaki, Y. and Nakaya, R., 1990. A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology, 98(3), pp.694-702.
  3. Spencer, D.M., Veldman, G.M., Banerjee, S., Willis, J. and Levine, A.D., 2002. Distinct inflammatory mechanisms mediate early versus late colitis in mice. Gastroenterology, 122(1), pp.94-105.
  4. Joscelyn, J. and Kasper, L.H., 2014. Digesting the emerging role for the gut microbiome in central nervous system demyelination. Multiple Sclerosis Journal, 20(12), pp.1553-1559.
  5. Young, E., 2012. Gut instincts: The secrets of your second brain. New Scientist, 216(2895), pp.38-42.
  6. Raybould, H.E., 1998. Does your gut taste? Sensory transduction in the gastrointestinal tract. Physiology, 13(6), pp.275-280.
  7. Mayer, E.A. and Tillisch, K., 2011. The brain-gut axis in abdominal pain syndromes. Annual review of medicine, 62.
  8. Birchenough, G.M., Johansson, M.E., Gustafsson, J.K., Bergström, J.H. and Hansson, G., 2015. New developments in goblet cell mucus secretion and function. Mucosal immunology, 8(4), pp.712-719.
  9. Rogers, D.F., 2003. The airway goblet cell. The international journal of biochemistry & cell biology, 35(1), pp.1-6.
  10. Gustafsson, J.K. and Johansson, M.E., 2022. The role of goblet cells and mucus in intestinal homeostasis. Nature Reviews Gastroenterology & Hepatology, pp.1-19.
  11. Schroeder, B.O., 2019. Fight them or feed them: how the intestinal mucus layer manages the gut microbiota. Gastroenterology report, 7(1), pp.3-12.
  12. Shan, M., Gentile, M., Yeiser, J.R., Walland, A.C., Bornstein, V.U., Chen, K., He, B., Cassis, L., Bigas, A., Cols, M. and Comerma, L., 2013. Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals. Science, 342(6157), pp.447-453.
  13. Hansson, G.C., 2012. Role of mucus layers in gut infection and inflammation. Current opinion in microbiology, 15(1), pp.57-62.
  14. Walker, W.A., 2017. Dysbiosis. In The microbiota in gastrointestinal pathophysiology (pp. 227-232). Academic Press.
  15. Carding, S., Verbeke, K., Vipond, D.T., Corfe, B.M. and Owen, L.J., 2015. Dysbiosis of the gut microbiota in disease. Microbial ecology in health and disease, 26(1), p.26191.
  16. Yang, D., Jacobson, A., Meerschaert, K.A., Sifakis, J.J., Wu, M., Chen, X., Yang, T., Zhou, Y., Anekal, P.V., Rucker, R.A. and Sharma, D., 2022. Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection. Cell, 185(22), pp.4190-4205.
  17. Yang, D., Jacobson, A., Meerschaert, K.A., Sifakis, J.J., Wu, M., Chen, X., Yang, T., Zhou, Y., Anekal, P.V., Rucker, R.A. and Sharma, D., 2022. Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection. Cell, 185(22), pp.4190-4205.
  18. Rosca, A.E., Iesanu, M.I., Zahiu, C.D.M., Voiculescu, S.E., Paslaru, A.C. and Zagrean, A.M., 2020. Capsaicin and gut microbiota in health and disease. Molecules, 25(23), p.5681.
  19. Banfi, D., Moro, E., Bosi, A., Bistoletti, M., Cerantola, S., Crema, F., Maggi, F., Giron, M.C., Giaroni, C. and Baj, A., 2021. Impact of microbial metabolites on microbiota–gut–brain axis in inflammatory bowel disease. International journal of molecular sciences, 22(4), p.1623.
  20. Holzer, P. and Holzer-Petsche, U., 2021. Constipation Caused by Anti-calcitonin Gene-Related Peptide Migraine Therapeutics Explained by Antagonism of Calcitonin Gene-Related Peptide’s Motor-Stimulating and Prosecretory Function in the Intestine. Frontiers in Physiology, 12.
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Also Read:

Pramod Kerkar, M.D., FFARCSI, DA
Pramod Kerkar, M.D., FFARCSI, DA
Written, Edited or Reviewed By: Pramod Kerkar, M.D., FFARCSI, DA Pain Assist Inc. This article does not provide medical advice. See disclaimer
Last Modified On:January 12, 2024

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