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Immune Modulation 101: IL-10 and AHR (Aryl Hydrocarbon Receptor) and Why Carnivore Diet May Be Helpful For Some

This article is not intended to be healthcare or medical advice. Before starting any health or medical related regimen seek advice from your Primary Care Physician or an M.D.


IL-10 has a hand in many important things, many of which appear to be related to different chronic illnesses. Similarly, the ARH (Aryl Hydrocarbon Receptor), modulates many immune related functions, pathways, and genes. A summary is noted directly below, with details forthcoming later on. For now, this is a work in progress.


IL-10 Summary:

  • Master regulator of the innate immune system

  • Inhibits the pro inflammatory cytokine TNF-alpha and IL-6

  • Regulates the gene CPOX, in the heme biosynthesis pathway. Heme and the gene HMOX1 regulate mast cells.

  • IL-10 is inhibited by the mycotoxins Citrinin and Gliotoxin[1]

  • IL-10 increased by the mycotoxin Zearalanone

  • Certain IL-10 mutations are linked to IBD, Chrone's Disease, and gut wall barrier disruption when exposed to emulsifiers in food and supplements [2, 3]. IL-10 gets elevated with exposure to emulsifiers in the diet, and then can block heme synthesis.

  • Most authors believe that IL-10 levels are higher in patients with CFS than in healthy controls . A longitudinal study reported increased IL-10 levels accompanied by decreased IFN-γ/IL-10 ratio in patients with CFS during a 1-year observation period. In a longitudinal research, IL-10 was assessed in PBMCs of patients with CFS and in healthy controls; IL-10 levels exhibited a significant increase at baseline, followed by a significant drop at 6 months and finally no significant variation at 12 months. Thus, the role of IL-10 in CFS requires further investigation.[20]

  • Concentration levels of IL-10 in CFS/ME patients in comparison to controls. IL-10 was the only cytokine significantly decreased in the CSF samples of the CFS/ME patients. The black bars represent data from the CFS/ME patients and the white bars represent data from the control patients. Data is represented as mean ± standard error of the mean (SEM)[21]

  • The Aryl Hydrocarbon Receptor is a cofactor for IL-10.

  • Binding of IL-10 to its receptor activates a major JAK1-TYK2-STAT3 signaling cascade, which culminates with the induction of the STAT3-mediated anti-inflammatory response. [25]

  • AhR regulates IL-10-production in T R 1 cells induced by TGF-β and IL-27 Naïve CD4 + T-cells from IL-10 reporter mice (Vert-X mice) were cultured with IL-27 and TGF-β in the absence (Control: Ctrl) or presence of the AhR agonists FICZ (100nM) or TCDD (100nM) a) IL-10.

  • When considering the data obtained for the two anti-inflammatory cytokines (IL-10 and IFN-β) detected, it is interesting to note the increases registered in the presence of CMC, with this augmented production being statistically significant (p < 0.05) for IFN-β. This behavior is even more relevant if one considers that IL-10 is associated with the dampening of intestinal inflammation, IBD and ulcerative colitis risk reduction, as this interferon limits the secretion of pro-inflammatory cytokines, deactivates macrophages and inhibits the secretion of Th1-related cytokines.

Aryl Hydrocarbon Receptor

  • Modulates IL-10; and thus heme - which implies indirect regulation of tryptophan metabolism (think The Metabolic Trap)

  • Modulates IDO1 directly, and thus directly regulates tryptophan metabolism

  • Modulates a number of downstream pathways including the JAK-STAT pathway

  • Two other genes (AHRR) and ARNT (also known as HIF1a - Hypoxia Inducible Factor 1) regulate ARH (Aryl Hydrocarbon Receptor)

  • Co regulates hypoxia states

  • Regulates the NMDA Receptors

  • Regulates IL-6, and NQO1 (ubiquination)

  • Regulates NADPH Oxidase, and KIT genes and thus mast cells


The aryl hydrocarbon receptor can be activated (and over activated) by specific fruits, vegetables, and herbs. ARH under expressed is problematic, and over expressed is problematic. For some a plant based diet can help express a compromised AHR gene to appropriate levels, while for others, too much stimulation from certain vegetables and fruits causes immune over activation. This could be one plausible explanation why some people benefit immune wise (fatigue) from a carnivore diet, and why some very much benefit from more vegetables and fruits. This article will be a series related to immune modulation, and will be expanded over time.


Similarly, IL-10 is strongly effected by mycotoxins, and intestinal inflammatory conditions. Here we see why both mold and diet can play such a strong role in recover from chronic illness. IL-10 is dysregulated with intestinal inflammatory conditions that vary from emulsifiers, and infections like clostridia difficile. Many studies exist, where modulation of IL-10 and AHR, can help resolve these conditions, mostly in mice studies (see references).


References

1.       The mycotoxins citrinin and gliotoxin differentially affect production of the pro-inflammatory cytokines tumour necrosis factor-alpha and interleukin-6, and the anti-inflammatory cytokine interleukin-10. L N Johannessen , A M NilsenM Løvik. Clin Exp Allergy. 2005 Jun;35(6):782-9. doi: 10.1111/j.1365-2222.2005.02249.x. PMID: 15969670. DOI: 10.1111/j.1365-2222.2005.02249.x

2.       Direct impact of commonly used dietary emulsifiers on human gut microbiota. Sabrine Naimi, Emilie Viennois, Andrew T. Gewirtz , Benoit Chassaing. Microbiome volume 9, Article number: 66 (2021). March 22, 2021.


3.       Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Benoit Chassaing,1 Omry Koren. Nature. 2015 Mar 5; 519(7541): 92–96. Published online 2015 Feb 25. doi: 10.1038/nature14232. PMCID: PMC4910713. NIHMSID: NIHMS656221. PMID: 25731162

4.       Dietary Emulsifier-Induced Low-Grade Inflammation Promotes Colon Carcinogenesis. Emilie Viennois 1Didier Merlin. Cancer Research. . 2017 Jan 1;77(1):27-40. doi: 10.1158/0008-5472.CAN-16-1359. Epub 2016 Nov 7. PMID: 27821485. PMCID: PMC5214513. DOI: 10.1158/0008-5472.CAN-16-1359

5.       Acute Exposure to Commonly Ingested Emulsifiers Alters Intestinal Mucus Structure and Transport Properties. Jaclyn Y. Lock,1 Taylor L. Carlson. Sci Rep. 2018; 8: 10008. Published online 2018 Jul 3. doi: 10.1038/s41598-018-27957-2. PMCID: PMC6030187. PMID: 29968743

6.       Dietary Emulsifiers Alter Composition and Activity of the Human Gut Microbiota in vitro, Irrespective of Chemical or Natural Emulsifier Origin. Lisa Miclotte 1Kim De Paepe Front Microbiology. 2020 Nov 5:11:577474. doi: 10.3389/fmicb.2020.577474. eCollection 2020. PMID: 33250870. PMCID: PMC7676226. DOI: 10.3389/fmicb.2020.577474

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10.   PHYSIOLOGICAL ACTION OP SODIUM CARBOXYMETHYL-CELLULOSE ON LABORATORY ANIMALS AND HUMANS. HERMAN A. SHELANSKI, ARNOLD M. CLARK. First published: January 1948. https://doi.org/10.1111/j.1365-2621.1948.tb16591.x.

11.   Subchronic oral toxicity study with regular and enzymatically depolymerized sodium carboxymethylcellulose in rats.  A Bär 1H P TilM Timonen. Food Chem Toxicology. . 1995 Nov;33(11):909-17.  doi: 10.1016/0278-6915(95)00069-e. PMID: 7590537. DOI: 10.1016/0278-6915(95)00069-e

12.   Biochemical effects of gum arabic, gum tragacanth, methylcellulose and carboxymethylcellulose-Na in rat heart and liver. E Bachmann, E WeberM PostG Zbinden. Pharmacology. 1978;17(1):39-49. doi: 10.1159/000136833. PMID: 684072. DOI: 10.1159/000136833

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21.   INFLAMMATION, CYTOKINES, NEUROIMMUNE INTERACTIONS

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23.   LPS-induced IL-10 production in whole blood cultures from chronic fatigue syndrome patients is increased but supersensitive to inhibition by dexamethasone. Jeroen Visser , Willy Graffelman c, https://doi.org/10.1016/S0165-5728(01)00400-3

24.   The multifaceted nature of IL-10: regulation, role in immunological homeostasis and its relevance to cancer, COVID-19 and post-COVID conditions. Valentina Carlini1 Douglas M. Noonan1,Front. Immunol., 08 June 2023. Sec. Cancer Immunity and Immunotherapy. Volume 14 - 2023 | https://doi.org/10.3389/fimmu.2023.1161067.

25.   A Potential Role of Interleukin 10 in COVID-19 Pathogenesis.  Ligong Lu,1,⁎ Hui Zhang,2 Danielle J. Dauphars,3 and You-Wen He. Trends Immunol. 2021 Jan; 42(1): 3–5. doi: 10.1016/j.it.2020.10.012. PMCID: PMC7605819. PMID: 33214057

26.   Hematological alterations associated with long COVID-19.  Guilherme C. Lechuga, 1 , 2 , 3 Carlos M. Morel, 1 and Salvatore Giovanni De-Simone. Front Physiol. 2023; 14: 1203472. Published online 2023 Jul 24. doi: 10.3389/fphys.2023.1203472. PMCID: PMC10411895. PMID: 37565145

27.   Aryl hydrocarbon receptor activity downstream of IL-10 signaling is required to promote regulatory functions in human dendritic cells.  Daniele Avancini 1Alessandro Testori . Cell Rep. . 2023 Mar 28;42(3):112193.  doi: 10.1016/j.celrep.2023.112193. Epub 2023 Mar 3. PMID: 36870061. PMCID: PMC10066577.  DOI: 10.1016/j.celrep.2023.112193

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29.   The Aryl Hydrocarbon Receptor Promotes IL-10 Production by NK Cells. Sagie Wagage; Beena John; J Immunol (2014) 192 (4): 1661–1670.  https://doi.org/10.4049/jimmunol.1300497. nature communications.

30.   The survival and function of IL-10-producing regulatory B cells are negatively controlled by SLAMF5. Lihi Radomir, Matthias P. Kramer, Nature Communications volume 12, Article number: 1893 (2021)

31.   25.Cytokines Focus Biology and therapeutic potential of interleukin-10 Margarida Saraiva1,2, Paulo Vieira3,4,5, and Anne O’Garra. Journal of Experimental Medicine 2019. Rockefeller University Press. https://doi.org/10.1084/jem.20190418

32.   Tryptophan metabolite activation of the aryl hydrocarbon receptor regulates IL-10 receptor expression on intestinal epithelia. J.M. Lanis, E.E. Alexeev. https://doi.org/10.1038/mi.2016.133. Mucosal Immunology.  Volume 10, Issue 5, September 2017, Pages 1133-1144. 

33.   The Aryl hydrocarbon Receptor (AhR) interacts with c-Maf to promote the differentiation of IL-27-induced regulatory type 1 (TR1) cells. Sep 2010. Lionel Apetoh, Francisco J Quintana.

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35.   Carboxymethyl Cellulose as a Food Emulsifier: Are Its Days Numbered? by Eduardo M. Costa, Sara Silva, et. al. Polymers 2023, 15(10), 2408; https://doi.org/10.3390/polym15102408.  Submission received: 27 April 2023 / Revised: 17 May 2023 / Accepted: 19 May 2023 / Published: 22 May 2023

36.   Hypothesis: Increased consumption of emulsifiers as an explanation for the rising incidence of Crohn's disease.  Carol L Roberts 1Sarah L Rushworth. J Crohns Colitis.. 2013 May;7(4):338-41.  doi: 10.1016/j.crohns.2013.01.004. Epub 2013 Jan 27. PMID: 23360575 . DOI: 10.1016/j.crohns.2013.01.004

37.   Clostridium difficile infection aggravates colitis in interleukin 10-deficient mice. World J Gastroenterol 2014; 20(45): 17084-17091 [PMID: 25493020 DOI: 10.3748/wjg.v20.i45.17084]. Kim MN, Koh SJ, Kim JM, Im JP, Jung HC, Kim JS.  2014 Baishideng Publishing Group Inc. All rights reserved. World J Gastroenterol. Dec 7, 2014; 20(45): 17084-17091 Published online Dec 7, 2014. doi: 10.3748/wjg.v20.i45.17084 .  Seoul National University Healthcare System Gangnam Center, Seoul National University Hospital, Seoul 135-984, South Korea. 

38.   The adaptive immune response to Clostridioides difficile: A tricky balance between immunoprotection and immunopathogenesis. Rodrigo Emanuel Hernández Del Pino, Angela María BarberoLaureano Ángel EspañolLorenzo Sebastián MorroVirginia Pasquinelli.. Journal of Leukocyte Biology.  First published: 23 August 2020.  https://doi.org/10.1002/JLB.4VMR0720-201R

39.   Indoles from the commensal microbiota act via the AHR and IL-10 to tune the cellular composition of the colonic epithelium during aging.  Domonica  N. Powell https://orcid.org/0000-0001-7756-2405Alyson Swimm https://orcid.org/0000-0001-9975-0247Robert Sonowal+3, and Daniel Kalman dkalman@emory.edu  Edited by Frederick M. Ausubel, Massachusetts General Hospital, Boston, MA, and approved July 13, 2020 (received for review February 18, 2020).  August 17, 2020.  117 (35) 21519-21526.  https://doi.org/10.1073/pnas.2003004117BIOLOGICAL SCIENCES.

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43.   Modulating AHR function offers exciting therapeutic potential in gut immunity and inflammation. Yue Chen, Yadong Wang, Yawei Fu, Yulong Yin & Kang Xu. Cell & Bioscience volume 13, Article number: 85 (2023)

44.   Involvement of Ahr Pathway in Toxicity of Aflatoxins and Other Mycotoxins.  Francisco Arenas-Huertero 1, Montserrat Zaragoza-Ojeda 1, Juana Sánchez-Alarcón 2, Mirta Mili? 3, Maja Šegvi? Klari? 4, José M Montiel-González 2, Rafael Valencia-Quintana 2. PMID: 31681212.  Front Microbiol.  2019 Oct 10:10:2347.   doi: 10.3389/fmicb.2019.02347. eCollection 2019.  PMCID: PMC6798329.  DOI: 10.3389/fmicb.2019.02347

45.   Amelioration of Clostridium difficile disease in mice by dietary supplementation with indole-3-carbinol.  Walker Julliard, MD,* Travis De Wolfe, BS,† John H. Fechner, MS,* Nasia Safdar, MD,‡ Rashmi Agni, MD,§ and Joshua D. Mezrich, MD*.  Ann Surg. Author manuscript; available in PMC 2018 Jun 1.  Published in final edited form as: Ann Surg. 2017 Jun; 265(6): 1183–1191.  doi: 10.1097/SLA.0000000000001830.  PMCID: PMC5743052. NIHMSID: NIHMS823331.  PMID: 27280500. Front. Cell. Infect. Microbiol., 09 November 2022

46.   The impact of dietary fibers on Clostridioides difficile infection in a mouse model.  (The Role of Probiotics, Postbiotics, and Microbial Metabolites in Preventing and Treating Chronic Diseases).  Wu, Xu, et. al.  Sec. Intestinal Microbiome. Volume 12 - 2022 | https://doi.org/10.3389/fcimb.2022.1028267. Volume 56, Issue 4, 11 April 2023, Pages 797-812.e4

47.   Repression of the aryl-hydrocarbon receptor prevents oxidative stress and ferroptosis of intestinal intraepithelial lymphocytes.  Santosh K. Panda, Vincent Peng, et. al. Journal home page for Immunity.  https://doi.org/10.1016/j.immuni.2023.01.023

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Benjamin L. Duell, Chee K. Tan, Alison J. Carey, Fan Wu, Allan W. Cripps, Glen C. Ulett 

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