Researchers Uncover How Tryptophan, a Common Amino Acid in Food, Can Lead to Arthritis

It may be an essential amino acid, but tryptophan has a concerning connection to arthritis.

Now, researchers from the University of Colorado say they have identified the means in which bacteria in the digestive system can break down tryptophan into an inflammatory chemical that primes the immune system for arthritis.

The research was carried out on mouse subjects; its findings were published in the Journal of Clinical Investigation.

Tripping the immune system

Tryptophan is an amino acid found in a variety of foods, including oats, milk, eggs, fish and almonds. The body needs the chemical to build proteins and neurotransmitters like serotonin.

Previous research has evidenced that the body’s gut microbiome (all the microbiota in a person’s stomach and intestines) breaks down tryptophan into both anti-inflammatory and inflammatory indole products, the latter of which can contribute to the development of arthritis and spondyloarthritis (arthritis of the spine).

To detail this process further, the researchers from the University of Colorado induced arthritis in mice then treated some with different levels of antibiotics, to weaken their microbiomes. Some of the mice were then fed tryptophan. These mice experienced a reduction in arthritis severity, indicating that tryptophan metabolism is a key element of the disease.

“We put mice on antibiotics to wipe out their microbiome, and they didn’t get arthritis, and they didn’t have indole,” said Kristine Kuhn, head of Colorado University’s rheumatology department.

“So we said, ‘OK, what if they do have a microbiome and we put them on a diet with little tryptophan?’ The microbiome can’t break down tryptophan into indole, and the mice didn't get arthritis. So, [in] two different ways, we showed that it’s tryptophan that’s broken down by the microbiome into indole.”

How could tryptophan’s indole by-products lead to arthritic pain? After recording a rise in T-cell levels in the mice, Kuhn and her colleagues believe the indole leads to an increase in damaging, auto-immunity.

“We found that when indole is present, the mice start to develop autoreactive T-cells that are more inflammatory,” she said. “They have less of those regulatory T-cells that help maintain balance in the immune system, and they start to develop antibodies that are more pathogenic. We found that the antibodies had flags for being more inflammatory when indole was present.”

Kuhn and her colleagues concluded their paper by positing that a “blockade of indole generation may present a unique therapeutic pathway” for rheumatoid arthritis and spondyloarthritis.

“If tryptophan hits our body’s cells, it tends to go get broken down into anti-inflammatory products versus when it hits the bacterial cells and goes more inflammatory,” she explained. “The ways we think about how this could lead to therapies are: How do you keep that balance tipped so that tryptophan goes towards that anti-inflammatory pathway? How can you manipulate intestinal bacteria to tip that balance? That's where we’re interested in going in the future.”

This article is a rework of a press release issued by the University of Colorado. Material has been edited for length and content.

Reference: Seymour BJ, Trent B, Allen BE, et al. Microbiota-dependent indole production stimulates the development of collagen-induced arthritis in mice. J Clinic Investig. 2023.doi: 10.1172/JCI167671