Dr. David Esteban is a professor of biology at Vassar College. He specializes in understanding how diseases like ME/CFS affect microbes that live in the human gut. These microbes make a wide range of critical metabolites that affect other parts of the body, like the nervous and immune systems.
In 2021, Dr. Esteban won a Solve Ramsay Grant to study a family of gut microbe–derived metabolites that activate the aryl hydrocarbon receptor (in other words, functioning as receptor agonists). Several types of immune cells and neuronal cells express aryl hydrocarbon receptors. After being produced by microbes in the gut from the amino acid tryptophan, these agonists can circulate throughout the body and influence immune responses and neuronal activity. Aryl hydrocarbon receptor signaling is dysregulated in several chronic conditions affecting the immune and nervous systems, like Alzheimer’s disease, irritable bowel syndrome, and Long COVID. In these conditions, gut microbial dysbiosis and aryl hydrocarbon dysregulation significantly correlate with neurocognitive symptoms.
To understand how ME/CFS affects aryl hydrocarbon receptor signaling, Dr. Esteban and colleagues compared gut microbial communities and microbe-derived metabolites in stool samples from 35 people with ME/CFS and 32 healthy people. They found that the microbial communities in people with ME/CFS were less diverse than those in healthy people, including reduced diversity of Clostridia, a class of bacteria that makes aryl hydrocarbon receptor agonists. Levels of several key tryptophan-derived metabolites were higher than normal, too. In cultured-cell experiments, gut metabolites from people reporting neurocognitive symptoms activated the aryl hydrocarbon receptor significantly more strongly than did metabolites from people without such symptoms. This was true regardless of whether people had ME/CFS.
Overall, these results show that ME/CFS is associated with reduced gut microbial diversity and changed levels of microbial metabolites regulating immune and neurological functions. The study also confirms observations from other neuroinflammatory diseases that aryl hydrocarbon receptor agonist activity in samples correlates with neurocognitive symptoms. Thus, interventions that regulate aryl hydrocarbon receptor signaling (like specific diets, strategies to regulate tryptophan levels, and certain FDA-approved drugs) may help reduce neurocognitive symptoms of ME/CFS and other diseases.
The researchers noted some limitations to their study, which would be important for future studies to consider. Follow-up studies should account for variability in diet and medications, which can strongly influence the composition of gut microbes. And instead of relying on participants’ self-reported neurocognitive symptoms, which can vary by individual perceptions and experiences, future studies should measure these symptoms by using validated tests or clinical evaluations.
This study appeared in MicrobiologyOpen, and the authors thanked Solve staff for helping with recruiting participants and collecting data.
Why This Study Matters:
- Extends a mechanism of neurocognitive dysfunction to ME/CFS: Shows how microbial dysbiosis and aryl hydrocarbon receptor dysregulation correlates with neurocognitive symptoms across diseases like Alzheimer’s disease, irritable bowel syndrome, Long COVID, and now, ME/CFS.
- Lays the Groundwork for Preventative Treatments: Suggests that treatments designed to regulate aryl hydrocarbon receptor signaling, like specific diets, strategies to regulate tryptophan levels, and some FDA-approved drugs, may reduce neurocognitive symptoms of ME/CFS and other important diseases.
- Advances Diagnostic Tools: Validates microbial and metabolic analyses of stool samples for studying ME/CFS-associated changes in gut, immune, and brain functions.
Read other study summaries in our Solve Science Spotlight archive here.