Tryptophan Metabolism and Aryl‐Hydrocarbon Receptor Agonists in the Gut Microbiome of People With [ME/CFS], 2026, Esteban et al

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forestglip

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Tryptophan Metabolism and Aryl‐Hydrocarbon Receptor Agonists in the Gut Microbiome of People With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Esteban, David J.; Conrad, Brynn; Cullinan, Autumn; Luong, Sharon; Albaum, Jason; Wilk, Victoria

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease with unknown biological basis and no cure. Microbiome dysbiosis has been reported in people with ME/CFS but its relevance to pathophysiology is unknown. Gut microbes are an important source of tryptophan metabolites that activate the aryl hydrocarbon receptor (AHR), a regulator of homeostatic and inflammatory genes. Dysregulated activation of AHR contributes to pathophysiology of several neuroimmune and chronic diseases but its role in ME/CFS has not been investigated.

The purpose of this study was to investigate the production of tryptophan metabolites and AHR agonists by gut microbes of people with ME/CFS.

We found lower diversity and altered microbiome community structure in people with ME/CFS and changes in the subcommunity of microbes that correlated with tryptophan metabolites. Using targeted metabolomics we identified nine metabolites elevated in the stool of people with ME/CFS, including three AHR agonists.

Stool ex vivo cultures were tested for their capacity to activate AHR in a reporter cell line and by qPCR. AHR activation did not differ between people with ME/CFS and controls, however, we detected elevated agonist activity in people with neurocognitive symptoms, regardless of underlying disease.

These findings are consistent with previous work revealing changes in the gut microbiome of people with ME/CFS and adds further support to alterations in tryptophan metabolism associated with the disease. Altered AHR activity by gut microbial metabolites may be a common mechanism contributing to neurocognitive symptoms in diseases including ME/CFS.

Web | DOI | PDF | MicrobiologyOpen | Open Access
 
forestglip said:
Using targeted metabolomics we identified nine metabolites elevated in the stool of people with ME/CFS, including three AHR agonists.
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I can't get to the study, would you mind listing the three AHR agonists?

Also, if you don't mind, does the study list the microbes that correlated with tryptophan metabolites?

Thank you
 
Violeta said:
I can't get to the study, would you mind listing the three AHR agonists?
Click to expand...
Yes, these:
Notably, indole, indole acetate, and tryptophan are all AHR agonists.
Click to expand...

Violeta said:
Also, if you don't mind, does the study list the microbes that correlated with tryptophan metabolites?
Click to expand...
I can't read the paper in detail right now, but this looks like the relevant part:
We identified 373 ASVs [amplicon sequence variants] with a significant correlation to at least one tryptophan metabolite (Figure 4A). The majority were Clostridia, a Class known to be important producers of metabolites that affect host physiology. Although some bacteria correlated both positively or negatively with different tryptophan metabolites, most species consistently showed only negative or only positive correlations with the metabolites.
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@mariovitali posted the link to this study on X. See what you think.


While canonical immune sensors have been primarily characterized based on their response to pathogenic material, the AHR is a homeostatic regulator that is activated by a variety of nonpathogenic exogenous ligands present in barrier tissues. These ligands include indoles [14], kynurenines [15], and other small molecules [16]. Downstream immune effects are dependent on the cell type and ligand. The AHR has also been directly tied to MS. AHR activation is the suspected mechanism by which the novel MS therapeutic, laquinimod, acts [17,18]. It is thought that AHR activation by laquinimod in antigen presenting cells reduces the ratio between inflammatory T cells and regulatory T cells (Treg).

Am I understanding correctly, AHR activation can have positive or negative ramifications?

Either that or I am not understanding the action of laquinimod.

journals.plos.org

The activity of the aryl hydrocarbon receptor in T cells tunes the gut microenvironment to sustain autoimmunity and neuroinflammation

Multiple sclerosis is a T cell-driven autoimmune disease that is linked to both gut flora and external environmental factors. This study shows that deleting the aryl hydrocarbon receptor (a sensor for the gut microbiota) in T lymphocytes triggers a change in intestinal bile acids and short chain...
journals.plos.org journals.plos.org
 
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Jonathan Edwards said:
I don't think we have any evidence for MS being T cell driven, or for T cell driven mouse diseases being relevant. You can modulate mouse experimental encephalitis with just about anything so I am not sure where this sort of study takes us.
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Although there are multiple studies identifying T cells involved in MS, I am seeing other links in this study that may be of interest in this thread.

The Role of CD4 T Cells in the Pathogenesis of Multiple Sclerosis - PMC

T lymphocytes play a central role in the pathogenesis of multiple sclerosis (MS) (Zhang et al., 1992). Both CD4+ and CD8+ T cells have been demonstrated in MS lesions, with CD4+ T cells predominating in acute lesions and CD8+ T cells being observed ...
pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov



www.frontiersin.org

Frontiers | Cytotoxic CD4+ T Cells Drive Multiple Sclerosis Progression

The disease course of multiple sclerosis (MS) varies greatly between individuals, making prognosis almost impossible. We previously discovered that cytotoxic...
www.frontiersin.org www.frontiersin.org
 
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Violeta said:
Although there are multiple studies identifying T cells involved in MS, I am seeing other links in this study that may be of interest in this thread.
Click to expand...

Yes, I am aware that since the 1980s the vast majority of immunologists have assumed that T cells 'drive' MS. They assumed that for RA too, based initially on a misinterpretation of my own data and sloppy thinking. It turned out to be wrong. Ablating T cells did nothing. T cells are involved in both conditions inasmuch as T cells are involved in all inflammation and all adaptive responses. Immunologists are almost all sheep - they will follow an idea for years despite there being no basis for it.

The problem is that if this paper studies a dud T cell driven animal system then whatever it finds is probably of no great interest.
 
Wow, aryl-hydrocarbon, amazing!

Just read the whole paper!




"Interestingly, a multitude of naturally occurring compounds from dietary sources have been found to directly influence the AhR signaling pathway. Accumulating evidence supports that extracts from vegetables or vegetable-derived materials can stimulate CYP1A1 activity (154, 155). Cruciferous vegetables, including broccoli, cabbage, turnips, cauliflower, kale, and Brussels sprouts, contain the compound glucobrassicin, which is converted into I3C and indole-3-acetonitrile (I3AC) during digestion, which acts as activating AhR ligands (154, 156, 157). Dietary compounds from plant sources including carotenoids, curcumin, and tryptophan, have been found to bind to AhR and trigger target gene expression (123, 153, 158). Flavonoids, present in tea and various fruits, are naturally occurring dietary AhR ligands, with most functioning as AhR antagonists. However, certain flavonoids, such as quercetin, diosmin, tangeritin, tamarixetin, taxifolin, and robinetin are the flavonoids capable of activating AhR (159–161). Importantly, as though these plant-derived AhR ligands are found in micromolar plasma concentrations, they still act as potent AhR signaling modulators (162, 163). Tryptophan metabolism within the gastrointestinal tract involves the following three major pathways (164). In the first pathway, the gut microbiota directly transforms tryptophan to yield various AhR-activating ligands, such as indole, tryptamine, indole acrylic acid, indole-3-acetamide, indole-3-aldehyde, indole-3-acetic acid, indole-3-propionic acid, indole-3-lactic acid (ILA), and indole-3-pyruvate. Indole further metabolizes into biologically-active compounds like dioxindole, indoxyl-3-sulfate, and indole-3-propionic acid (165). Thus, the intestinal commensal microflora is a continual source of potential AhR-activating ligands, underscoring the role of AhR as a sensor of the gut microbiota communities and as a regulator of host-microbe homeostasis (134). In the second pathway called the KYN pathway (KP), commonly operative in immune and epithelial cells, IDO1 activity generates KYN (109, 166), which is a precursor for potent AhR ligands including kynurenic acid, xanthurenic acid, and cinnabarinic acid, with effects on neurotransmission, inflammation, and immune responses (166). In the third pathway, called the serotonin 5-hydroxytryptamine (5-HT) production pathway, tryptophan hydroxylase 1 generates the AhR activating ligands (167). Butyrate supplements improved arthritis in mice by altering microbiota and favoring the production of 5-hydroxyindole-3-acetic acid (5-HIAA), a serotonin-derived metabolite that reduces the severity of arthritis (168). In addition to biliverdin, unconjugated bilirubin (UCB) also acted as an AhR agonist and induced target gene expression (169, 170), while bilirubin activated AhR in Th17 cells and stimulated the production of CD39 and exerted an immunosuppressive effect to alleviate inflammation in an experimental model of colitis in mice (43)."

If metabolism of tryptophan goes down the quinolinic acid pathway, how does that affect aryl-hydrocarbon?
Let's see if the answer is in this paper.

link.springer.com

Gut–Brain Axis and Neuroinflammation: The Role of Gut Permeability and the Kynurenine Pathway in Neurological Disorders - Cellular and Molecular Neurobiology

The increasing prevalence of neurological disorders such as Alzheimer’s, Parkinson’s, and multiple sclerosis presents a significant global health challenge. Despite extensive research, the precise mechanisms underlying these conditions remain elusive, with current treatments primarily addressing...
link.springer.com link.springer.com

"Dysregulation of the kynurenine pathway in the context of inflammation leads to the production of neurotoxic metabolites, such as quinolinic acid, which contribute to neuronal damage and the progression of neurological disorders."
 

Targeting aryl hydrocarbon receptor functionally restores tolerogenic dendritic cells derived from patients with multiple sclerosis​


pubmed.ncbi.nlm.nih.gov

Targeting aryl hydrocarbon receptor functionally restores tolerogenic dendritic cells derived from patients with multiple sclerosis - PubMed

Multiple sclerosis (MS) is a chronic disease characterized by dysregulated self-reactive immune responses that damage the neurons' myelin sheath, leading to progressive disability. The primary therapeutic option, immunosuppressants, inhibits pathogenic anti-myelin responses but depresses the...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov

"Here, we characterized CD14+ monocytes, mature dendritic cells, and vitamin D3-tolDCs (VitD3-tolDCs) from active, treatment-naive MS patients and healthy donors (HDs). Using multiomics, we identified a switch in these cell types toward proinflammatory features characterized by alterations in the aryl hydrocarbon receptor (AhR) and NF-κB pathways. MS patient-derived VitD3-tolDCs showed reduced tolerogenic properties compared with those from HDs, which were fully restored through direct AhR agonism and by use of in vivo or in vitro dimethyl fumarate (DMF) supplementation. "
 
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