The indole/AhR pathway is critical for gut barrier health, gut immune function, and resistance to gut infection. It also has implications for the health of many organ systems outside of the gut, including the liver, kidney, skin, brain, and cardiovascular system. Deficiency in this pathway is a feature of many chronic diseases.
To begin, I’ll cover the basics of the aryl hydrocarbon receptor (AhR). We’ll then dive into the benefits of AhR signaling, why most people are deficient in this pathway, potential strategies to increase AhR activity in the gut, and a few exceptions where AhR might be overstimulated.
AhR: The aryl hydrocarbon receptor
The aryl hydrocarbon receptor (AhR) is a transcription factor – a protein that regulates gene expression. The molecules that bind to and activate a receptor are called agonists.
There are three primary groups of molecules that are agonists (i.e. activators) of AhR:
Environmental pollutants. AhR was first identified for its role in the response to environmental toxins like dioxin and other aryl hydrocarbons. These pollutants are very strong activators of AhR. Their binding increases the expression of enzymes that help to facilitate their detoxification.
Gut bacterial tryptophan metabolites. Gut bacteria, including various Clostridium, Bacteroides, Eubacterium, Lactobacillus, and Bifidobacterium species, can directly convert tryptophan to compounds called indoles, many of which bind to and activate AhR.
Dietary compounds. In recent years, dietary compounds have also been shown to activate AhR. Indole-3-carbinol (I3C), a compound derived from the breakdown of cruciferous vegetables, can bind to and activate AhR.
While chronic activation of AhR by environmental pollutants may have negative health effects, the transient activation of AhR by gut metabolites and dietary compounds has many positive downstream effects. We’ll explore many of these in the next section.
The many benefits of intestinal AhR activation
Regular, transient AhR signaling plays a number of important roles in gut and overall health.
1) Maintains gut barrier function. AhR stimulates innate immune cells in the gut to produce the cytokine IL-22, a signaling molecule that promotes mucus production and antimicrobial peptide secretion.1 In pockets of the gut barrier called crypts, AhR also supports stem cell proliferation, which is essential for normal gut turnover and repair.2
2) Regulates the composition of the gut microbiota. Lack of AhR stimulation leads to an expansion of the pro-inflammatory family Enterobacteriaceae and a reduction of butyrate-producing Clostridiales, a common signature of gut dysbiosis.3
3) Maintains gut immune cell populations and reduces inflammation. AhR supports adequate populations of lymphocytes within the gut epithelium.4 It also plays a key role in directing regulatory T cells to the gut and supports their ability to quell inflammation.5
4) Regulates the enteric nervous system and gut motility. AhR has been shown to play a role in regulating peristalsis, the muscle contractions that move food along the GI tract.6 AhR may also have relevance in the regeneration of enteric nerves after injury.7
5) Protects against Candida and other gut infections. AhR activation plays a significant role in maintaining colonization resistance against the yeast Candida albicans and bacterial pathogens via supporting IL-22 signaling.1,8
6) Supports immune defenses in the lungs. Intestinal AhR also plays an important role in protection against infection at other mucosal surfaces, such as the lungs. A 2019 study found that boosting AhR activity in the gut following antibiotic treatment significantly decreased pathogenic bacterial counts in the lung.9
7) Promotes healthy skin barrier function. Gut AhR is essential for maintaining skin barrier integrity. A 2016 study found that removing AhR ligands from the diet impaired skin barrier function, while re-addition of the AhR activator indole-3-carbinol rescued barrier deficiency, even in aged mice.10
8) Activates detoxification pathways. AhR plays a role in the detoxification of many substances, including polycyclic aromatic hydrocarbons, mycotoxins, heavy metals, and estrogen,11,12 activating both phase I and phase II detoxification pathways throughout the body.13
9) Protects liver and kidney function. AhR signaling from gut tryptophan metabolism has also been shown to protect against non-alcoholic fatty liver disease, alcohol-induced liver injury, and renal fibrosis.14–17
10) Supports neurological health. Dietary tryptophan metabolite signaling through AhR in astrocytes has been shown to limit inflammation in the central nervous system.18 Intestinal AhR activity also promotes adult neurogenesis, the formation of new neurons.19
Decreased AhR signaling: a feature of many chronic diseases
Decreased intestinal AhR activity is observed across a wide range of chronic diseases, including inflammatory bowel disease, irritable bowel syndrome, colorectal cancer, obesity, metabolic syndrome, hypertension, atherosclerosis, depression, inflammatory skin conditions, celiac disease, and multiple sclerosis, to name a few.
So what causes reduced AhR signaling? There are many contributing factors, including:
Gut dysbiosis: An altered gut microbiota composition often has less capacity to produce compounds known to activate AhR, including tryptophan-derived indoles and the short-chain fatty acid butyrate (yes, butyrate activates AhR! 25,26)
Low protein or poor-quality diet. Reduced intake of tryptophan, the substrate for bacterial indole formation and/or low intake of AhR agonists from plant foods can both reduce the overall pool of AhR agonists.20 Consumption of artificial sweeteners has also been shown to reduce AhR signaling.16
Stress, inflammation, or infection. Stress, inflammation, and certain types of infection can shift tryptophan metabolism away from AhR towards other pathways (to be discussed in parts 3 and 4 of this series).
Addressing these underlying causes is always the first step towards restoring AhR activity.
Other strategies to increase AhR activity
The following is a summary of other interventions known to transiently increase AhR activity, which may be helpful until the underlying causes in the previous section can be addressed. It is important to note that AhR agonists have species-specific and tissue-specific effects.21 Their effects also depend on concentration, and in the presence of numerous compounds, they may even compete with one another – so while I’ve listed a lot of possibilities here, the “kitchen sink” approach is not necessarily ideal. I’m hopeful that in the next few years, we will see more human clinical trials to clarify which of these therapeutics might be most helpful in disease states characterized by AhR-deficiency.
This information should not be taken as medical advice. Always consult with your personal physician about whether a particular intervention is appropriate for you. I have no affiliations with any of the brands mentioned – recommended products are provided only to pre-empt requests for where to find these.
- Indole-3-carbinol (I3C): this compound, produced from the breakdown of glucobrassicin in cruciferous vegetables like brussels sprouts, cabbage, broccoli, cauliflower, and mustard greens, is a potent AhR activator. In animal models, I3C has been shown to induce the formation of regulatory T cells, suppress Th17, protect the mucus layer, increase butyrate production, upregulate PPAR-gamma, and protect against colitis.22 It has also been studied for its potential anticarcinogenic and antioxidant effects. While I3C or its derivative diindolylmethane (DIM) are available in supplement form, there may be risks at higher doses and human studies are limited, so it is best to consume I3C in its whole food form. To maximize dietary I3C bioavailability, consume cruciferous vegetables in a raw fermented form like sauerkraut,23 or add powdered mustard seed (containing the enzyme myrosinase) back after cooking.24
- Butyrate: a short-chain fatty acid and direct activator of AhR in human intestinal epithelial cells.25,26 In a healthy gut, butyrate is produced from the fermentation of dietary fiber and, to a lesser extent, protein. It is also available in supplement form. If you choose to supplement, I recommend ProButyrate or ButyCaps Tributyrin, which are more targeted to the colon.
- Urolithin A: this compound, produced from the breakdown of ellagitannins found in pomegranates, raspberries, and blackberries, has been shown to enhance gut barrier function via AhR.27 However, only an estimated 30-40 percent of people have the bacteria that can perform this conversion.28 Urolithin A can also be taken as a supplement and has received Generally Recognized as Safe status by the FDA as a food ingredient.
- Sun exposure: a 2019 study found that, in mice, just 15 minutes of UV-B exposure induced the expression of AhR target genes in the blood and in peripheral tissues, including the gut!29
- Bifidobacterium infantis This strain produces indole-3-lactic acid, an activator of AhR, after growth on human milk oligosaccharides.30,31 It has been well-studied in infants and is available as the infant probiotic Evivo. This strain has not been yet studied in adults. This formula does contain a significant amount of lactose and residual amounts of soy.
- Lactobacillus rhamnosus Certain Lactobacillus strains have been shown to naturally produce AhR agonists when tryptophan is abundant.32 The only strain that I have found that is known to increase AhR activity and is commercially available is Lactobacillus rhamnosus GG. Note that Lactobacillus-based probiotics are not recommended during or immediately after antibiotics, or for those with histamine intolerance/mast cell activation syndrome.
- Akkermansia muciniphila: In at least one animal study, this bacterium or a protein from its outer membrane increased circulating indole compounds and upregulated AhR target genes.33 I will discuss Akkermansia more in part 3 of this series.
- Mesalamine (5-ASA): this drug is the first-line treatment for inflammatory bowel disease (IBD). I have previously written about the ability of this drug to upregulate PPARgamma and promote gut hypoxia.34 Interestingly, mesalamine also seems to activate AhR.35
- Coffee: coffee extracts, especially less filtered coffees like Turkish coffee,36 have been shown to induce AhR expression in intestinal epithelial cells and protect against colitis in rodent models.37
- Sulforaphane: while the effects of this compound are often attributed to the Nrf2 pathway, AhR appears to mediate many of its protective effects.38,39 In mice fed a Western diet, sulforaphane increased gut production of indole-acetic-acid, upregulating AhR activity.40
- Polyphenols: Quercetin, resveratrol, and curcumin can all indirectly activate AhR by inhibiting the enzyme CYP1A1, which controls the breakdown of AhR agonists. Of these, quercetin was the most effective in potentiating AhR signaling.41
- Serotonin: this neurotransmitter and its byproducts (5-HIAA) can also indirectly activate AhR by partially inhibiting the clearance of AhR ligands. This effect is dependent on functioning serotonin transport.42 More on serotonin in part 4.
A note on the importance of feedback regulation and not chronically over-stimulating AhR
Lastly, we need to discuss AhR over-stimulation. While most chronic inflammatory diseases are characterized by AhR deficiency, there are a few cases where AhR can become overactivated, with negative consequences. This is most often due to significant environmental toxicity from pollutant or mold exposure,11,45 severe viral infection,43 or chronic kidney disease.44
These conditions are characterized by sustained AhR activation, which has very different effects on gene expression than transient AhR activation.46 The natural compounds that bind AhR, in contrast, are metabolized efficiently when they bind AhR, due to the upregulation of certain detoxification enzymes. This negative feedback loop ensures that AhR signaling is short-lived.
Having adequate vitamin B12 and folate status may protect against chronic AhR overstimulation.47 Nonetheless, there may be some cases of extreme toxicity or infection where transient AhR stimulation is contraindicated. I’ll continue to update this article as we learn more!
That’s all for this time. Stay tuned for part 3, where I’ll cover the kynurenine/IDO1 pathway!