This common food ingredient could lead to arthritis, study finds
Researchers have unveiled a significant discovery concerning the breakdown of tryptophan in the digestive system. (CREDIT: Creative Commons)
Researchers at the University of Colorado Department of Medicine have unveiled a significant discovery concerning the breakdown of tryptophan in the digestive system. This breakdown process, facilitated by gut bacteria, produces an inflammatory chemical that can trigger immune responses leading to arthritis.
The study, led by Kristine Kuhn, MD, PhD, who serves as the Scoville Endowed Chair and heads the CU Division of Rheumatology, involved collaboration with several colleagues from the division.
Their findings, published in the Journal of Clinical Investigation, shed light on the conversion of tryptophan, an essential amino acid found in various protein-rich foods, into inflammatory byproducts by gut bacteria.
Graphical abstract representation of the study and it's findings. (CREDIT: Journal of Clinical Investigation)
Tryptophan serves multiple vital functions in the body, including aiding in protein production, muscle development, enzyme activity, and neurotransmitter regulation within the nervous system. Despite its importance, the body does not produce tryptophan internally; instead, it must be acquired through dietary sources.
While commonly associated with causing drowsiness, particularly after consuming turkey, which is rich in tryptophan, researchers clarify that the amount of tryptophan present in turkey is unlikely to be the primary cause of post-meal tiredness. However, the role of tryptophan in regulating sleep cycles is acknowledged.
Kuhn and her team embarked on this research endeavor to understand how a substance beneficial to the body could be transformed into a catalyst for inflammatory diseases like rheumatoid arthritis, affecting approximately 1% of the population.
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Rheumatoid arthritis is characterized by painful swelling in the hands and feet, along with potential joint deformities if left untreated.
"It’s been known that the microbiome – the bacteria in our gut – can break down tryptophan into byproducts. Some of those byproducts are anti-inflammatory, but we’ve also associated some inflammatory causes of those products,” explains Kuhn. “We’re the first to highlight which products are contributing to inflammation, and how they are doing that.”
The research builds upon previous observations made in patients with spondyloarthritis, a condition closely related to rheumatoid arthritis, where changes in the microbiome were linked to increased production of indoles, byproducts derived from tryptophan. Similar findings were replicated in arthritis studies conducted on mice.
CIA was induced in male 6-week-old DBA/1 mice, and cecal contents were harvested at day 35 from mice with CIA, mice with CIA that were depleted of microbiota by antibiotic administration after day 21, or untreated DBA/1 mice (Untx DBA). (CREDIT: Journal of Clinical Investigation)
“We put mice on antibiotics to wipe out their microbiome, and they didn’t get arthritis, and they didn’t have indole,” Kuhn elaborates. “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 two different ways, we showed that it’s tryptophan that’s broken down by the microbiome into indole.”
Further investigation revealed that the presence of indole in the system prompts the development of autoreactive T-cells, which are more inflammatory. Additionally, there is a reduction in regulatory T-cells responsible for maintaining immune system balance, alongside an increase in the production of pathogenic antibodies, which exhibit heightened inflammatory properties in the presence of indole.
CIA was induced in 6-week-old male DBA/1 mice. On days 21–35, mice were treated with antibiotics with or without 0.1 mg/mL indole in the drinking water, and arthritis scores were assessed every other day. n = 10 (Abx+Indole); n = 7 (CIA+Abx). (CREDIT: Journal of Clinical Investigation)
The researchers propose that blocking the generation of indole could offer a unique therapeutic approach for rheumatoid arthritis and spondyloarthritis. This strategy revolves around redirecting the breakdown pathway of tryptophan in the body towards anti-inflammatory processes.
Kuhn emphasizes the importance of maintaining a balanced state where tryptophan is directed towards its anti-inflammatory pathway. This balance can be influenced by dietary choices, with plant-based fiber-rich diets and lean meats, characteristic of the Mediterranean diet, promoting a healthier gut microbiome and favoring the anti-inflammatory properties of tryptophan.
LPMCs isolated from healthy human colon tissue were stimulated with 1 mM indole or vehicle for 4 hours. CD19+ B cells and CD3+ T cells were flow sorted, and RNA was isolated for RNA-Seq. Differentially expressed pathways (indole versus vehicle) were identified with Ingenuity Pathway Analysis for CD19+ B cells. (CREDIT: Journal of Clinical Investigation)
In terms of intervention strategies, Kuhn mentions ongoing research within her Division of Rheumatology aimed at identifying individuals at risk of progressing to rheumatoid arthritis based on specific blood markers. While there is promising data suggesting the potential for disease prevention during this at-risk stage, the optimal intervention methods remain uncertain.
By understanding and manipulating this pathway, there is hope for developing novel therapeutic approaches to mitigate the impact of these debilitating conditions.
Symptoms of Rheumatoid Arthritis
According to the Mayo Clinic, signs and symptoms of rheumatoid arthritis may include:
Tender, warm, swollen joints
Joint stiffness that is usually worse in the mornings and after inactivity
Fatigue, fever and loss of appetite
Early rheumatoid arthritis tends to affect your smaller joints first — particularly the joints that attach your fingers to your hands and your toes to your feet.
As the disease progresses, symptoms often spread to the wrists, knees, ankles, elbows, hips and shoulders. In most cases, symptoms occur in the same joints on both sides of your body.
About 40% of people who have rheumatoid arthritis also experience signs and symptoms that don't involve the joints. Areas that may be affected include:
Skin
Eyes
Lungs
Heart
Kidneys
Salivary glands
Nerve tissue
Bone marrow
Blood vessels
Rheumatoid arthritis signs and symptoms may vary in severity and may even come and go. Periods of increased disease activity, called flares, alternate with periods of relative remission — when the swelling and pain fade or disappear. Over time, rheumatoid arthritis can cause joints to deform and shift out of place.
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