HomeENGLISH MAGAZINEDealing with microbiota, autoimmunity and cancer: are polyphenols the right AhRresting molecules?

Dealing with microbiota, autoimmunity and cancer: are polyphenols the right AhRresting molecules?

A common finding in autoimmune patients is the alterations in the composition of gut microbiota that are suspected to be involved in disease etiopathogenesis. In normal conditions, the dominant gut microbial phyla are Actinobacteria, Proteobacteria, Fusobacteria, Verrucomicrobia, Firmicutes, and Bacteroidetes, with these last two representing 90% of gut microbiota. The Firmicutes are composed of more than 200 different genera such as Lactobacillus, Bacillus, Enterococcus, Ruminicoccus, and Clostridium, this last accounting for 95% of the phylum. Patients with autoimmune diseases in general exhibit an increment of the taxa Bacteroidetes at the expense of the Firmicutes, when compared to healthy subjects. For example, in patients with lupus, strains of Rhodococcus, Eggerthella, Klebsiella, Prevotella, Eubacterium and Flavonifractor are significantly enriched, whereas Dialister and Pseudobutyrivibrio decreased.

In rheumatoid arthritis, the gut microbiome was characterized by an increase of Prevotella and lower numbers of Bifidobacteria, Bacteroides and Clostridium. Patients affected by multiple sclerosis display a decrease in Bacteroides, Faecalibacterium whereas Methanobrevibacter, Enterobacteriaceae, and Akkermansia showed an increment. The disturbance in the balance of the microbiota and its reduction in complexity is also called dysbiosis and together with the diminution in the levels of Tregs lymphocytes that seem closely connected with the loss of tolerance to autoantigens. Remarkably, the Firmicutes of the class Clostridia are reduced in autoimmune patients and these types of microorganisms demonstrate an important role in the induction of Tregs lymphocytes. Tregs are a unique subpopulation of CD4+ T cells with properties in the maintenance of immune tolerance, thus preventing responses against food and self-antigens.

The reduction in their levels is associated with higher disease activity and poor prognosis in autoimmune patients. Therefore, the deficiency of these cells has been linked to the etiopathogenesis of autoimmunity. Recent discoveries have underscored that gut microbiota not only modulate the immune system through their antigens or fiber fermentation but also by the biotransformation of indoles. The most studied example is tryptophan and their products of metabolism that act as AhR ligands. Tryptophan is converted to tryptamine by the Firmicutes, Clostridium and Ruminococcus. Its derivatization to indole pyruvic acid is catalyzed by tryptophanase and then, indole pyruvic acid is converted into indole acetic acid or to 3-methyl indole by Lactobacillus, Clostridium and Bacteroides. Indole pyruvic acid can also be converted to indole lactate, indole acrylic acid, and indole propionic acid by commensal microorganisms.

Studies show that it is possible to modify the intestinal microbiota with drugs, natural products, diet, probiotics, and prebiotics. In autoimmune patients, this is of utmost importance since dysbiosis plays a key role, and therapies used to control the symptoms such as antibiotics and methotrexate could negatively influence the microbiome composition. The AhR pathway is a key for the homeostasis in the intestine and promotes epithelial renewal and barrier integrity along with immunomodulatory properties. In addition, the induction of AhR signaling enhances de secretion of the antiinflammatory cytokines such as IL-22 and IL-10 while reducing the production of the proinflammatory cytokines such as tumor necrosis factor-alpha, IL-1, IL-6, and IL-12 that are also the desirable effects against autoimmunity. Overall, the dietary administration of AhR ligands is a promising strategy for the management of autoimmune diseases.

A controlled diet may positively influences the cytokine microenvironment and the phenotype of dendritic, T helper and B cells. Polyphenols are very common phytochemicals in plants, vegetables and fruit. Polyphenols like quercetin and resveratrol are the prototypical AhR ligands that can modulate and promote their nuclear translocation. In the case of flavonoids, they are considered natural AhR ligands. The potential of food to restore gut bacteria balance or to provide AhR ligands for the therapeutic management of autoimmune diseases has been previously debated. Furthermore, it is well-described that flavonoids at levels achieved through feeding can activate the AhR, and that many health-promoting effects derived from dietary polyphenols are mediated by this pathway. In second place, the antioxidant and antinflammatory properties of polyphenols and flavonoids may also contribute.

Diets mainly made of legumes, vegetables, fruits and grains reduce symptoms, biomarkers of disease severity and demonstrate overall benefits for autoimmune patients. These are also the foods that are recommended by the scientific community for effective prevention of cancers of the digestive system in general and also of the prostate, breast, stomach and pancreas. Their richness in polyphenols is the main reason for their chemopreventive effects on cancer. But, once again, aside from the anti-inflammatory and antioxidant effect, the modulation that polyphenols and flavonoids exert on the AhR receptor is an important reason for their effects. AhR is expressed in multiple tumor types and exhibits tumor-specific antitumor activities or similar to tumor-promoting molecules. AhR expression plays an important role in the development of colon cancer in various lab models. Not to mention that its activation in immune cells is a central factor for the tumor to evade the immune defenses.

Loss of the AhR also significantly enhanced tumorigenesis in an inflammation-induced mouse model in which animals are treated with dextrane sulphate to induce mucosal inflammation and the carcinogen azoxymethane. In animals where AhR expression is deleted in gut mucosa, the risk of malignant transformation is higher. demonstrating the critical role of intestinal epithelial AhR as an inhibitor of intestinal tumor formation. Thus, the AhR is protective with respect to development of colon cancer and colitis, and this is consistent with the role of colitis as a risk factor for colon cancer. And many polyphenols can activate it in such respect, such as kampferol, baicalein, galangin and quercitin. Soy isoflavones such as genistein and formonetin are also ligands of the AhR receptor and also citrus flavanols, such as naringenin and hesperitin. It has been proven that these compounds exhibit tissue- and responsive-specific AhR agonist or antagonist activities.

In immune cells they are antagonists, causing indeed antinflammatory, cytokine-suppressing and anti-autoreactive responses. Most of these substances are represented in food of the Mediterranean diet, which incidentally has been also demonstrated to be effective in opposing against colitis, intestinal inflammation and the development of colon cancers. Evidence showing the preventive effects of the Mediterranean diet on autoimmune conditions is also piling up. Together with the fact that polyphenols can also have a modulating effect on the composition of the microbiota itself, their direct use or through the diet for the management of autoimmune diseases is a biomedical path to exploit, considering that much has already been discovered in this regard and that it would be a natural way of fighting against autoimmune conditions by acting on their roots.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Goya-Jorge E, Jorge RME et al. Molecules. 2021; 26:2315.

Horta-Baas G et al. Curr Rheumatol Rep. 2021; 23:1–14.

Yue T, Sun F, Yang C et al. Front immunol. 2020; 11:1510.

Mohammadi S et al. Autoimmunity 2018; 51:199–209.

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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