New research indicates serotonin as a trigger for Crohn’s disease in the second brain

According to new studies, serotonin may have a key role in Crohn's disease. Getty Images/Callista Images
According to new studies, serotonin may have a key role in Crohn’s disease. Getty Images/Callista Images
  • According to recent research, increased serotonin levels may inhibit the stomach from cleaning away damaged or dead cells, a process known as autophagy.
  • As a result, the makeup of gut bacteria may alter, leading to inflammation and more severe illness in the gut.
  • Diabetes, Parkinson’s disease, and inflammatory bowel disorders (IBDs), such as Crohn’s disease, are all linked to autophagy malfunction.
  • The research is the first to show a link between serotonin, autophagy, and the gut microbiota in the context of intestinal inflammation, notably Crohn’s disease.

A recent study has revealed a relationship between serotonin, autophagy, and the gut microbiota, indicating that a high level of the neurotransmitter may be part of the cause of inflammation in chronic gastrointestinal disorders like Crohn’s disease.

Crohn’s disease is one of the two main types of IBD, in which the gastrointestinal tract becomes inflamed, resulting in sores, ulcers, or scarring. The reason of Crohn’s disease inflammation is yet unknown.

Autophagy is best described by health professionals as the cells’ normal “housework” of cleaning up damaged or dysfunctional subcellular components.

The findings add to the growing body of evidence associating IBDs with stress and gut microbiota health.

The research was published in the journal Science Advances by McMaster University in Hamilton, Canada.

The conclusions of the research

The researchers evaluated blood and tissue samples from 18 persons with Crohn’s disease as part of the study. They then compared them to a control group of healthy people with the same number of people.

A mouse model of IBD was also employed by the researchers.

They looked at how mucosal serotonin, autophagy, and the microbiome interact to control intestinal inflammation.

The following findings were reached by the scientists:

  • The autophagy process was suppressed by an increase in serotonin — 5-hydroxytryptamine (5-HT) — receptors in the colon.
  • The gut microbiota’s composition changed as a result of this.
  • As a result, the intensity of inflammation in the gut increased, resulting in disease flare-ups.

Lowered 5-HT in the gut, on the other hand, boosted colon autophagy and reduced the degree of intestinal inflammation.

As a result, serotonin was discovered to be a new regulator of the autophagy-microbiota axis in IBDs.

“Our findings imply that in IBD, such as Crohn’s disease, there is an increase in gut serotonin, which acts as a brake on the autophagy process of intestinal epithelial cells.” Prof. Waliul Khan, senior author of the study and professor of pathology and molecular medicine at McMaster University, said, “This impairment of autophagy in epithelial cells leads to a reduction in antimicrobial peptide production, which changes the normal gut microbiota composition towards the colitogenic type.”

According to him, the disruption of the microbiota encourages the release of proinflammatory mediators, which worsens the severity of colitis.

The gut-serotonin relationship

Tillions of microorganisms exist in the digestive system, making up the gut microbiota. It promotes digestion, strengthens the immune system, and protects the body from diseases.

Recent research suggests that the gut microbiota plays a key role in Crohn’s disease etiology. A disrupted microbiome also has associations with an increased risk of  IBD

Serotonin, on the other hand, is a neurotransmitter that affects mood, behavior, and anxiety levels through regulating several systems in the brain and nervous system.

Serotonin levels were discovered to be higher in Crohn’s disease patients in previous studies.

The connection between the two has risen to prominence in recent years, with experts dubbing the stomach the body’s “second brain.”

This is due to the fact that the stomach generates the majority of serotonin in the body.

“What is often overlooked is that the stomach, not the brain, contains the vast majority of serotonin in the body. According to Prof. Khan, the gut contains 95 percent of the body’s serotonin, which is produced mostly in hormone-producing cells in the gut known as enterochromaffin cells.

He went on to say that variations in the number of these cells and their serotonin levels can be seen in a variety of GI disorders, including Crohn’s.

“Due to the strategic location of enterochromaffin cells near the gut microbiota and the important emerging role of serotonin and microbiota in GI pathology and pathophysiology, I decided to explore the relationship between serotonin, microbiota, and Crohn’s disease,” he stated “.

Uncovering one of Crohn’s disease’s numerous clues

The study reveals how cell death and inflammation are related, according to Dr. Arun Swaminath, head of gastroenterology and director of the Inflammatory Bowel Diseases division at Lenox Hill Hospital in New York.

“What’s interesting is that serotonin in the gut appears to mediate how well autophagy works [directly]. Increased levels inhibit autophagy, and this results in changes to the surrounding microbiota, increasing susceptibility to inflammation. This seems to hold true for cells collected from Crohn’s patients.”
– Dr. Arun Swaminath

Dr. Swaminath also discussed the role of genes in Crohn’s disease.

“There have been many genes associated with the potential development of Crohn’s [or] IBD (over 200 to date), but each gene mutation accounts for only a part of the risk, and the puzzle of how each gene is involved in the pathogenesis is still being unraveled,” he said.

“One of those identified gene mutations is ATG16, which has to do with cell autophagy. In this study, the authors have started to unravel exactly how autophagy is involved in intestinal inflammation using a Crohn’s mouse model,” he told MNT.

Meanwhile, Dr. Ashkan Farhadi, a gastroenterologist at MemorialCare Orange Coast Medical Center in California, said the findings were expected because serotonin is one of the gut’s most significant neurotransmitters.

“We know that stress has a major role in the disease. Stress works in a different way by messing up gut functions, causing changes in intestinal permeability. And then, when the permeability changes, bacteria or germs can get access to this system. He noted that the bacteria might harm the mucosa of the intestines.

As a result, the immune system is activated, and inflammation in the body is increased.

Although studies and talks on serotonin fingerprints in the etiology or pathophysiology of ulcerative colitis have been going on for a while, he thought it was intriguing to see it linked to autophagy.

He went on to say that the study was a step forward in identifying a target or trigger for IBDs like Crohn’s, but that it didn’t explain everything.

“What you see here is another part of the puzzle that they are putting together, with a focus on serotonin and autophagy. The whole concept is not that new, [but] it creates a hypothesis for future studies,” Dr. Farhadi told MNT.

However, he pointed out that, like many recent microbiome research, they all fell short of demonstrating causality vs association, and that it was too early to discuss clinical implications.

Is it possible that a new therapy is on the way?

In 2018, an estimated 135,000 Canadians were diagnosed with Crohn’s disease, with many more suffering from different kinds of inflammatory bowel disease (IBD). According to a study conducted by Crohn’s and Colitis Canada, the prevalence of Crohn’s disease would rise by 50% by 2030.

With the number of cases increasing, scientists are concentrating their efforts on finding a cure or therapy.

Prof. Khan suggested that inhibiting serotonin transmission in the colon might relax the brake on autophagy and encourage appropriate functioning, decreasing the severity of colitis.

The next step will be to apply what has been learned in the lab to the clinic in order to develop novel therapies.

Prof. Khan and his colleagues intend to investigate this link in bigger groups, as well as in those with ulcerative colitis, another kind of IBD. Ulcerative colitis has symptoms that are similar to Crohn’s disease, however it exclusively affects the intestines.

Dr. Swaminath stated that while the findings of the study had the potential to have a big impact on the treatment of Crohn’s disease, researchers would need to reproduce the findings in a broader patient population.

“[The findings] could provide new pathways for drugs that inhibit serotonin production or accelerate serotonin destruction to play a role in the treatment of Crohn’s disease. Currently, drugs that increase serotonin are sometimes used for Crohn’s patients to mitigate pain and visceral hypersensitivity.”
– Dr. Arun Swaminath

However, he pointed out a caveat.

“We may be dissuaded from that treatment strategy if long-term exposure actually potentiates underlying inflammation,” he said.