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Urolithin A Modulates The Aryl Hydrocarbon Receptor. Inhibition of AHR Resolves MS in Mice. MS Drug Copaxone Ender Eval by ME CFS Researcher Ron Davis

This article is not medical advice. Before embarking on any health related regimen, you should seek the advice of your Primary Care Physician, or an M.D.


Urolithin A has received much attention, especially since long haul covid, in part due to its benefits to lower mitochondrial oxidative stress. I have received many reports from clients that they have experienced benefits from it - however, as a single supplement, it is super expensive. There are always trade offs and cost vs benefit is one of them.


This article [1] covers another VERY important effect from Urolithin A - it attenuates the Aryl Hydrocarbon Receptor (AHR) which is a key gene that modulates many immune functions, NMDA receptors, tryptophan metabolism, STAT pathway, and of course our friend IL-10. IL-10 can inhibit heme synthesis. When the AHR is over active it can create alot of immune over activation - and certain drugs like Calpaxone , used to treat MS, have shown benefit, and they inhibit the AHR. If IL-10 is too high, Heme synthesis is inhibited, and this joins an over active immune system.


One of the mechanisms of action of the MS drug is Copaxone. Ron Davis at Stanford has been investigating this drug for use in ME CFS. Why ? Somebody alerted him to it, who was originally diagnosed with MS, then changed to ME CFS.


Blocking AHR In T Cells - Resolved Inflammation in MS Mice

"Researchers believe the ability to block receptors within cells offers a path to new treatments.

"Gaultier and his collaborators blocked the activity of the regulator, called "aryl hydrocarbon receptor," in immune cells called T cells and found that doing so had a dramatic effect on the production of bile acids and other metabolites in the microbiomes of lab mice. With this receptor out of commission, inflammation decreased and the mice recovered," the release said.

"Due to the complexity of the gut flora, probiotics are difficult to use clinically. This receptor can easily be targeted with medications, so we may have found a more reliable route to promote a healthy gut microbiome," Merchak said."[4]


"While researchers have shown that signals from AHR influence multiple sclerosis development, how it does so is unclear. To better understand what AHR is doing specifically in the guts of patients with MS, we genetically engineered mice that are missing AHR in some of their immune cells. By silencing AHR's activity, we could understand what role it may be playing in autoimmunity. We expected to learn more from this experiment about the molecular communication of immune cells. Instead we found something surprising: The gut environment in these mice had changed. Specifically, the chemical composition of their guts had been altered, indicating that the metabolism of gut bacteria had shifted. This meant that AHR is not only sensing what's going on in the gut, but the receptor is also actively shaping its environment. More importantly, we found that mice without AHR were able to recover from MS. In our mouse model of MS, we induced autoimmunity by immunizing mice against myelin, the protective layer surrounding neurons. This meant that the immune system of the mice was primed to attack myelin, leading to the poor muscle control and paralysis seen in MS. We wanted to test whether the gut microbiome played a role in why mice without AHR were able to recover. When we transplanted the gut bacteria from the digestive tracts of mice without AHR into mice with AHR, we found that the mice with AHR were also able to recover from paralysis. This meant that the gut microbiome was driving recovery from MS."[5]


"We also found that the guts of mice without AHR had high levels of bile acids—chemicals produced in the liver and secreted into the intestines that help with digestion. Bile acids are often broken down by the resident bacteria in the gut. One bile acid in particular, called taurocholic acid, was especially concentrated in mice without AHR. To test whether taurocholic acid offered protection against MS, we fed this chemical to mice with AHR as they started to develop autoimmunity to myelin. While control mice that were fed saline became paralyzed from the waist down, the mice that were fed taurocholic acid just got a little wobbly before they recovered. With further investigation, we discovered that these mice were able to recover their motor control because their immune cells were not as strong. Exposing their immune cells to bile acids shortened the life span of the cells, thus preventing them from causing as much damage to myelin and motor neurons. While we still do not understand why bile acids weaken immune cells, we believe it may be a key step to understanding how to interrupt autoimmunity in MS and other autoimmune disorders."[5]


AHR is interesting - in that when activated can induce anti inflammatory effects, but chronic over activation from dietary sources (think vegetables), can lead to chronic immune up regulation. On the flip side, if its under activated, the inflammation source never gets addressed. Serotonin producing bacteria like some lactobacillus strains show AHR induction, and these have been helpful for some. Its the regulated modulation of AHR that appears to be the key. AHR is connected to HSP90, ARNT, and AHRR - that help regulate it. We know that chronic CD8 T cell exhaustion is a hallmark of ME CFS and post viral illness [2].


"Urolithins (e.g., UroA and B) are gut microbiota-derived metabolites of the natural polyphenol ellagic acid. Urolithins are associated with various health benefits, including attenuation of inflammatory signaling, anti-cancer effects and repression of lipid accumulation. The molecular mechanisms underlying the beneficial effects of urolithins remain unclear. We hypothesize that some of the human health benefits of urolithins are mediated through the aryl hydrocarbon receptor (AHR). Utilizing a cell-based reporter system, we tested urolithins for the capacity to modulate AHR activity. Cytochrome P450 1A1 (CYP1A1) mRNA levels were assessed by real-time quantitative polymerase chain reaction. Competitive ligand binding assays were performed to determine whether UroA is a direct ligand for the AHR. Subcellular AHR protein levels were examined utilizing immunoblotting analysis. AHR expression was repressed in Caco-2 cells by siRNA transfection to investigate AHR-dependency. UroA and B were able to antagonize 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced AHR-mediated transcriptional activity. Furthermore, UroA and B attenuated TCDD-mediated stimulation of CYP1A1 mRNA levels. In addition, competitive ligand binding assays characterized UroA as a direct AHR ligand. Consistent with other AHR antagonists, UroA failed to induce AHR retention in the nucleus. AHR is necessary for UroA-mediated attenuation of cytokine-induced interleukin 6 (IL6) and prostaglandin-endoperoxide synthase 2 (PTGS2) expression in Caco-2 cells. Here we identified UroA as the first dietary-derived human selective AHR antagonist produced by the gut microbiota through multi-step metabolism. Furthermore, previously reported anti-inflammatory activity of UroA may at least in part be mediated through AHR."[1]


CD8 T Cell Exhaustion In ME CFS and Post Viral Illnesses

"Proper regulation of CD8+ T cell memory development is critical to long-term protection against morbid infection. Multiple transcription factors have been suggested to contribute to the regulation of this process; however, data describing their cell-intrinsic effects are lacking. A role for Ahr supporting TRM has been previously described.Ahr expression was shown to be higher in skin compared with spleen CD8+ T cells, and Ahr functions to facilitate TRM persistence in the epidermis. Our study provided mechanistic insights into how Ahr regulates the transcriptional programs of CD8+ T cells and elucidated a role for Ahr in early TRM differentiation, specifically in a gut-specific infection model.

Other studies, using an influenza infection model, demonstrated that early-life Ahr activation via TCDD impairs the priming of virus-specific CTLs; however, this phenotype is mediated by regulation of DNA methylation and found to be cell extrinsic. Of additional importance, the cellular toxicity and long half-life of TCDD could lead to non-physiological activation of Ahr, thus complicating data interpretation. Given that Ahr is expressed in various cell types and plays a complex role, we ablated Ahr expression specifically in CD8+ T cells. We noted that differences in TRM under the steady state between Ahr-deficient mice and their littermate controls were modest, presumably due to the lack of antigen-specific pathogen exposure and non-competitive environment. Although our data suggest that Ahr plays a cell-intrinsic role in CD8+ T cell differentiation and function, we opted to test this hypothesis in the context of gut infection as well. In the intestine, on day 9 post oral infection, we showed that Ahr-deficient CD8+ T cells exhibited a reduction of TRM precursors with a concomitant increase in TSLE and TCM-like cells compared with wild-type counterparts. This decrease in precursors led to a marked reduction in the IEL resident TRM cell compartment at the memory time point of day 34 post infection. Of note, for the gut infection model Ahr-deficient OTI CD8+ T cells responded to infection in the presence of an equal number of wild-type OTI CD8+ T cells. This allows for a well-controlled experiment because both are exposed to the same environment and stimuli; however, the magnitude of the observed phenotype could be due to competition. Furthermore, we showed that Ahr functions to promote in vitro TRM-like cell differentiation while suppressing the TCM phenotype. Collectively, these data prompted us to conclude that differentiation at least is one of the key mechanisms underlying the defective CD8+ T cell memory development that occurs in the absence of Ahr.

A previous report has shown Ahr is a critical regulator of monocyte differentiation acting to promote dendritic cell differentiation while suppressing macrophage differentiation. In the current study, we demonstrate that in CD8+ T cells, Ahr acts as a cell fate decision regulator to suppress the differentiation of TCM while promoting TRM. Blimp1 is a well-described positive regulator of TRM differentiation and function. We showed that Prdm1 (Blimp1) is one of the top Ahr-regulated direct target genes in CD8+ T cells, consistent with the role of Ahr in promoting Prdm1 expression in monocytes. We further showed that forced expression of Blimp1 was able to rescue in vitro TRM-like differentiation defect in the absence of Ahr, suggesting that Blimp1 acts downstream of Ahr to regulate CD8+ T cell memory development. It is important to note that Ahr/− CD8+ T cells were still able to differentiate into CD69+CD103+ cells in vitro and in vivo; therefore, Ahr is likely acting as a promoter rather than a main driver of TRM and in vitro TRM-like differentiation.

Recent publications describe that Ahr promotes CD8+ T cell exhaustion in tumor immunity. However, activated T cells as well as tissue-resident memory cells express many of the exhaustion-associated molecules (PD-1, Tim-3, CTLA-4, etc.). It is also important to keep in mind that interpretation of the role of Ahr in tumor immunity with ligand treatment has to consider both cell-autonomous and non-autonomous effects, given the cell-specific role of Ahr in different immune cell types that infiltrate the tumor microenvironment, and in the tumor cells as well. It has been reported that when TRM responses are diminished, polyfunctional CD8+ TILs are also reduced, consistent with our findings. These polyfunctional tumor-resident memory-like cells have been positively associated with productive anti-tumor immunity.

Activation of the Ahr pathway in CD8+ T cells may be of therapeutic interest in the context of infection or cancer immunotherapy when a long-lived tissue-resident memory response is of utmost importance."[3]


AHR Is A Target In MS Treatment

"Multiple sclerosis (MS) is a T cell-driven autoimmune disease that attacks the myelin of the central nervous system (CNS) and currently has no cure. MS etiology is linked to both the gut flora and external environmental factors but this connection is not well understood. One immune system regulator responsive to nonpathogenic external stimuli is the aryl hydrocarbon receptor (AHR). The AHR, which binds diverse molecules present in the environment in barrier tissues, is a therapeutic target for MS. However, AHR's precise function in T lymphocytes, the orchestrators of MS, has not been described. Here, we show that in a mouse model of MS, T cell-specific Ahr knockout leads to recovery driven by a decrease in T cell fitness. At the mechanistic level, we demonstrate that the absence of AHR changes the gut microenvironment composition to generate metabolites that impact T cell viability, such as bile salts and short chain fatty acids. Our study demonstrates a newly emerging role for AHR in mediating the interdependence between T lymphocytes and the microbiota, while simultaneously identifying new potential molecular targets for the treatment of MS and other autoimmune diseases."[6]


"Aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a classical exogenous synthetic ligand of AHR that has significant immunotoxic effects. Activation of AHR has beneficial effects on intestinal immune responses, but inactivation or overactivation of AHR can lead to intestinal immune dysregulation and even intestinal diseases. Sustained potent activation of AHR by TCDD results in impairment of the intestinal epithelial barrier. However, currently, AHR research has been more focused on elucidating physiologic AHR function than on dioxin toxicity. The appropriate level of AHR activation plays a role in maintaining gut health and protecting against intestinal inflammation. Therefore, AHR offers a crucial target to modulate intestinal immunity and inflammation. Herein, we summarize our current understanding of the relationship between AHR and intestinal immunity, the ways in which AHR affects intestinal immunity and inflammation, the effects of AHR activity on intestinal immunity and inflammation, and the effect of dietary habits on intestinal health through AHR. Finally, we discuss the therapeutic role of AHR in maintaining gut homeostasis and relieving inflammation."[7]


References:

  1. Urolithin A Is a Dietary Microbiota-Derived Human Aryl Hydrocarbon Receptor Antagonist Gulsum E Muku 1 2, Iain A Murray, et. al. Metabolites. . 2018 Nov 29;8(4):86. doi: 10.3390/metabo8040086. PMID: 30501068. PMCID: PMC6315438. DOI: 10.3390/metabo8040086.

  2. Surveying the Metabolic and Dysfunctional Profiles of T Cells and NK Cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. by Jessica Maya Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14850, USA Int. J. Mol. Sci. 2023, 24(15), 11937; https://doi.org/10.3390/ijms241511937 Submission received: 27 June 2023 / Revised: 20 July 2023 / Accepted: 24 July 2023 / Published: 26 July 2023

  3. The aryl hydrocarbon receptor cell intrinsically promotes resident memory CD8+ T cell differentiation and function. Joseph W. Dean,1 Eric Y. Helm. Cell Rep. Author manuscript; available in PMC 2023 Feb 20. Cell Rep. 2023 Jan 31; 42(1): 111963. Published online 2023 Jan 4. doi: 10.1016/j.celrep.2022.111963. PMCID: PMC9940759 NIHMSID: NIHMS1870514. PMID: 36640340

  4. Blocking cell receptors could treat multiple sclerosis, U. of Virginia researchers say By Patrick Hilsman. HEALTH NEWS. FEB. 15, 2023 / 3:42 PM

  5. Bile acids and gut microbes could potentially treat multiple sclerosis, according to new research in mice March 1 2023, by Andrea Merchak. Medical Press.

  6. The activity of the aryl hydrocarbon receptor in T cells tunes the gut microenvironment to sustain autoimmunity and neuroinflammation. By Andrea R Merchak 1 2 3, Hannah J Cahill 1, Lucille C Brown, et. al. PLoS Biol. . 2023 Feb 14;21(2):e3002000. doi: 10.1371/journal.pbio.3002000. eCollection 2023 Feb. PMID: 36787309 PMCID: PMC9928083. DOI: 10.1371/journal.pbio.3002000

  7. Modulating AHR function offers exciting therapeutic potential in gut immunity and inflammation. By Yue Chen, Yadong Wang, Cell & Bioscience volume 13, Article number: 85 (2023)



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