Zinc and several physiologically relevant ligands of the aryl hydrocarbon receptor (AHR) are nutrients that promote intestinal barrier function. We have identified that AHR activation upregulates the expression of zinc importers in the intestinal epithelium to increase intracellular zinc concentrations, which leads to improved epithelial barrier function. Here, we investigated if an amino acid chelate of zinc, in cooperation with AHR activation, can improve the barrier function of a differentiated Caco-2 cell epithelium. Functional assays of the Caco-2 cell epithelium demonstrate that both ZnSO4 and a lysine and glutamic acid chelate of Zn, in combination with the physiological AHR agonist 6-formylindolo[3,2-b]carbazole (FICZ), increase expression of tight junction proteins at the mRNA and protein levels. FICZ increases uptake of zinc into the epithelium in the presence of ZnSO4 or the amino acid Zn chelate in the medium to equal extents. We conclude that the lysine and glutamic acid chelate of Zn is as efficacious as ZnSO4 in reducing permeability of the Caco-2 cell epithelium in the presence of FICZ. The results suggest that dietary supplementation with bioavailable forms of zinc together with nutritional AHR agonists may be beneficial in improving gut barrier function and help prevent inflammatory bowel disease (IBD).

This review and commentary outline the strong rationale for normalizing the abnormal microbiota of patients with ulcerative colitis, Crohn's disease, and pouchitis and focus on strategies to improve current variable outcomes of fecal microbial transplant (FMT) in ulcerative colitis. Applying lessons from successful FMT therapy of recurrent Clostridioides difficile and insights from basic scientific understanding of host/microbial interactions provide strategies to enhance clinical outcomes in IBD. We outline promising approaches to develop novel-defined consortia of live biotherapeutic products and combination treatments to improve current results and to optimize and personalize treatment approaches in individual patients and disease subsets.

The potential crosstalk between the host and gut microbiota (GM) under heavy metal compound pollution remains unexplored. Herein, using comprehensive analysis of metagenomics, metabolomics, behavioral analysis, and cell morphology to investigate the causal relationship between GM and host responses to cadmium (Cd) and lead (Pb) toxicities. Results indicate that Pb and Cd pollution, alone or together, hinder spider predatory behavior and change the composition and function of GM. Combined exposure reduces protein and exogenous compound metabolism, while single exposure affects energy and lipid metabolism. Gut microbiota helps spider antioxidant activity by increasing glutathione, lipoic acid, and L-cysteine. Oxidative damage, increased Enterobacteriaceae (Salmonella), and lipopolysaccharide (LPS) may harm the midgut barrier. Upregulation of choline and acetylcholine, and downregulation of spermidine, may initiate neurotoxicity. Inhibiting actinomycetes might boost sodium gallate for detoxifying single contaminants. Combined pollution detoxification may involve downregulation of indole synthesis metabolic bacteria, tryptophan, indole metabolites, cytochrome P450 (CYP450), and an increase in Desulfobulbia could remove heavy metals and reduce oxidative stress. Combined pollution has a synergistic effect, making the toxicity of multiple pollutants greater than their individual effects, impacting metal resistance genes (MRGs), and antibiotic resistance ontology (AROs) which used for classifying and describing antibiotic resistance, midgut barrier integrity, oxidative stress, and detoxification. The results help to elucidate the interplay of GM and host's reactions, and aid in monitoring and bioremediation of heavy metal pollution.

Tryptophan (Trp), an essential amino acid obtained through dietary sources, plays a crucial role in various physiological processes. The metabolism of Trp branches into three principal pathways: the serotonin pathway, the kynurenine pathway, and the indole pathway. The kynurenine and serotonin pathways are host pathways while the indole pathway is solely the result of bacterial metabolism. Trp metabolites extend their influence beyond protein biosynthesis to affect a spectrum of pathophysiological mechanisms including, but not limited to, neuronal function, immune modulation, inflammatory responses, oxidative stress regulation, and maintenance of intestinal health. This review focuses on indole derivatives and their impact on vascular health. Trp-containing dipeptides are highlighted as a targeted nutraceutical approach to modulate Trp metabolism, enhance beneficial metabolite production, and mitigate risk factors for vascular diseases. The importance of optimizing Trp intake and dietary strategies to harness the benefits of Trp-derived metabolites for vascular health is underscored, bringing to light the need for further research to refine these therapeutic approaches.

The aryl hydrocarbon receptor (AHR) plays important roles in intestinal homeostasis, limiting tumour growth and promoting differentiation in the intestinal epithelium. Spineless, the Drosophila homolog of AHR, has only been studied in the context of development but not in the adult intestine.

The role of Spineless in the Drosophila midgut was studied by overexpression or inactivation of Spineless in infection and tumour models and RNA sequencing of sorted midgut progenitor cells.

We show that spineless is upregulated in the adult intestinal epithelium after infection with Pseudomonas entomophila ( P. e.). Spineless inactivation increased stem cell proliferation following infection-induced injury. Spineless overexpression limited intestinal stem cell proliferation and reduced survival after infection. In two tumour models, using either Notch RNAi or constitutively active Yorkie, Spineless suppressed tumour growth and doubled the lifespan of tumour-bearing flies. At the transcriptional level it reversed the gene expression changes induced in Yorkie tumours, counteracting cell proliferation and altered metabolism.

These findings demonstrate a new role for Spineless in the adult Drosophila midgut and highlight the evolutionarily conserved functions of AHR/Spineless in the control of proliferation and differentiation of the intestinal epithelium.

This study investigates the role of the ligand-activated transcription factor AHR in repopulating the intestinal lining. Using organoid-derived cells and decellularized mouse intestinal scaffolds to investigate the importance of AHR in regulating intestinal regeneration, we found that silencing AHR expression hinders the capacity of colonic cells to repopulate decellularized colons. We therefore propose that AHR may play an important role in regulating intestinal regeneration. The ligand-dependent nature of AHR activity may provide an opportunity to interfere with disorders such as cancer and inflammatory bowel diseases which are caused by dysregulation in intestinal tissue renewal.

Intrinsic enteric neurons (iENs) form a crucial neuronal network within the myenteric and submucosal plexus of the gastrointestinal tract, primarily responsible for regulating gut peristalsis. The mechanisms by which iENs sense and integrate dietary and microbial signals to regulate intestinal homeostasis and inflammation remain unclear. Here, we showed that environmental sensor aryl hydrocarbon receptor (AHR) was expressed in different iEN subsets in the ileum and colon and that AHR ligands differentially modulated iEN activity in these regions. Genetic perturbation of Ahr in neurons increased iEN activation in the ileum but, conversely, decreased it in the colon in response to different intestinal pathogens. Furthermore, neuronal AHR deficiency enhanced the clearance of bacterial pathogens, which was associated with increased proliferation and abundance of group 3 innate lymphoid cells in the ileum. Together, our findings demonstrate the region-specific functions of AHR in neurons in response to infections.

Adult stem cells are a rare population of undifferentiated cells present in almost all body tissues. Depending on their location, stem cells can differentiate into various tissue types, primarily contributing to maintenance, repair, and immune system regulation. Stem cell therapies have significant potential in regenerative medicine and treatment of inflammatory diseases. However, many factors must be considered for successful clinical commercialization, including enhancing therapeutic potential, ensuring product differentiation, and optimizing the manufacturing process for large-scale production. The development of sophisticated regulatory mechanisms may enhance therapeutic applications. The aryl hydrocarbon receptor (AhR) is expressed in all adult stem cells, and its activation and function are tightly regulated. Understanding the role and regulation of AhR is crucial for developing effective stem cell therapies. This review examines the role of the AhR in regulating the fundamental characteristics of adult stem cells, which may contribute to advancing adult stem cell therapies.

Intestinal barrier dysfunction is a prevalent and varied manifestation of acute pancreatitis (AP). Molecular mechanisms underlying the early intestinal barrier in AP remain poorly understood.

To explore the biological processes and mechanisms of intestinal injury associated with AP, and to find potential targets for early prevention or treatment of intestinal barrier injury.

This study utilized single-cell RNA sequencing of the small intestine, alongside in vitro and in vivo experiments, to examine intestinal barrier function homeostasis during the early stages of AP and explore involved biological processes and potential mechanisms.

Seventeen major cell types and 33232 cells were identified across all samples, including normal, AP1 (4x caerulein injections, animals sacrificed 2 h after the last injection), and AP2 (8x caerulein injections, animals sacrificed 4 h after the last injection). An average of 980 genes per cell was found in the normal intestine, compared to 927 in the AP1 intestine and 1382 in the AP2 intestine. B cells, dendritic cells, mast cells (MCs), and monocytes in AP1 and AP2 showed reduced numbers compared to the normal intestine. Enterocytes, brush cells, enteroendocrine cells, and goblet cells maintained numbers similar to the normal intestine, while cytotoxic T cells and natural killer (NK) cells increased. Enterocytes in early AP exhibited elevated programmed cell death and intestinal barrier dysfunction but retained absorption capabilities. Cytotoxic T cells and NK cells showed enhanced pathogen-fighting abilities. Activated MCs, secreted chemokine (C-C motif) ligand 5 (CCL5), promoted neutrophil and macrophage infiltration and contributed to barrier dysfunction.

These findings enrich our understanding of biological processes and mechanisms in AP-associated intestinal injury, suggesting that CCL5 from MCs is a potential target for addressing dysfunction.

Excess dietary salt and salt-sensitivity contribute to cardiovascular disease. Distinct T cell phenotypic responses to high salt and hypertension, as well as influences from environmental cues, are not well understood. The aryl hydrocarbon receptor (AhR) is activated by dietary ligands, promoting T cell and systemic homeostasis. We hypothesized that activating AhR supports CD4+ homeostatic functions, such as cytokine production and mobilization, in response to high salt intake while mitigating salt-sensitive hypertension. In the intestinal mucosa, we demonstrate that a high-salt diet (HSD) is a key driving factor, independent of hypertension, in diminishing interleukin 17A (IL-17A) production by CD4+ T (Th17) cells without disrupting circulating cytokines associated with Th17 function. Previous studies suggest that hypertensive patients and individuals on a HSD are deficient in AhR ligands or agonistic metabolites. We found that activating AhR augments Th17 cells during experimental salt-sensitive hypertension. Further, we demonstrate that activating AhR in vitro contributes to sustaining Th17 cells in the setting of excess salt. Using photoconvertible Kikume Green-Red mice, we also revealed that HSD drives CD4+ T cell mobilization. Next, we found that excess salt augments T cell mobilization markers, validating HSD-driven T cell migration. Also, we found that activating AhR mitigates HSD-induced T cell migration markers. Using telemetry in a model of experimental salt-sensitivity, we found that activating AhR prevents the development of salt-sensitive hypertension. Collectively, stimulating AhR through dietary ligands facilitates immunologic and systemic functions amid excess salt intake and restrains the development of salt-sensitive hypertension.

Colorectal cancer (CRC) is a malignant tumor that originates from the epithelial cells of the colon and rectum. Global epidemiological data shows that in 2020, the incidence and mortality rate of CRC ranked third and second, respectively, posing a serious threat to people's health and lives. The factors influencing CRC are numerous and can be broadly categorized as modifiable and non-modifiable based on whether they can be managed or intervened upon. Non-modifiable factors include age, gender, family history, among others. Among the modifiable factors, dietary habits and behavioral practices are the main intervention measures that people can take to prevent CRC. Numerous studies indicate that a high intake of red and processed meats, fats, as well as habits such as smoking, alcohol consumption, and prolonged sitting, increase the risk of developing CRC. Conversely, consuming ample vegetables, fruits, high dietary fiber, and engaging in moderate regular exercise may reduce the risk of CRC. This article primarily discusses the impact of dietary habits and behavioral practices on the occurrence and development of CRC, along with possible mechanisms, laying the foundation and providing direction for the prevention and control of CRC occurrence and development.

Tryptophan (Trp), an essential amino acid, is solely acquired through dietary intake. It is vital for protein biosynthesis and acts as a precursor for numerous key bioactive compounds. The Kynurenine Pathway and the Indole Pathway are the main metabolic routes and are extensively involved in the occurrence and progression of diseases in the digestive, nervous, and urinary systems. In the Kynurenine Pathway, enzymes crucial to tryptophan metabolism, indoleamine-2,3-dioxygenase 1 (IDO1), IDO2, and Trp-2,3-dioxygenase (TDO), trigger tumor immune resistance within the tumor microenvironment and nearby lymph nodes by depleting Trp or by activating the Aromatic Hydrocarbon Receptor (AhR) through its metabolites. Furthermore, IDO1 can influence immune responses via non-enzymatic pathways. The Kynurenine Pathway exerts its effects on tumor growth through various mechanisms, including NAD+ regulation, angiogenesis promotion, tumor metastasis enhancement, and the inhibition of tumor ferroptosis. In the Indole Pathway, indole and its related metabolites are involved in gastrointestinal homeostasis, tumor immunity, and drug resistance. The gut microbiota related to indole metabolism plays a critical role in determining the effectiveness of tumor treatment strategies and can influence the efficacy of immunochemotherapy. It is worth noting that there are conflicting effects of the Kynurenine Pathway and the Indole Pathway on the same tumor phenotype. For example, different tryptophan metabolites affect the cell cycle differently, and indole metabolism has inconsistent protective effects on tumors in different regions. These differences may hold potential for enhancing therapeutic efficacy.

Background/Objective: The aryl hydrocarbon receptor (AHR) is an important mediator of intestinal homeostasis. The AHR senses certain classes of phytochemicals, including many flavonoids and tryptophan metabolites generated in the intestinal tract. Several in vitro studies demonstrate the presence of AHR ligands in numerous plants commonly consumed by humans. However, it has not been established that these foods can activate the AHR in vivo. The aim of this study was to evaluate how phytochemicals in foods can lead to AHR activation in vivo through modulating CYP1A1 activity. Methods: Freeze-dried spinach, corn, red potatoes, kidney beans, parsley, onion, carrots, bell peppers, and broccoli were fed to C57BL6/J female mice at 15% w/w in a semi-purified diet to evaluate the AHR activation potential. In vitro CYP1A1 microsomal assays were utilized to establish specific phytochemicals as CYP1A1 substrates. Results: Broccoli, onion, and carrots increased expression of the AHR target gene Cyp1a1 in the duodenum. Broccoli consumption led to the formation of the potent AHR ligand indolo[3,2-b]carbazole (ICZ), which is also a CYP1A1 substrate. Relative to the other vegetables, parsley contained a high concentration of apiin, a diglycoside of the flavone apigenin. Mice were fed a diet with either 10% parsley, 10% broccoli, or both vegetables. Parsley consumption increased broccoli-mediated Cyp1a1 induction in the duodenum, liver, and lung. Apigenin is a CYP1A1 substrate that can attenuate ICZ metabolism in vitro and increase broccoli-mediated Cyp1a1 expression in the lung. Conclusions: These results suggest that phytochemical competition for intestinal AHR binding and CYP1A1 metabolism modulates systemic AHR activity.

Myricetin is a bioactive compound in many edible plants. We have previously demonstrated that myricetin could significantly protect mice against colitis by regulating Treg/Th17 balance, while underlying mechanism remains unclear. The current study aimed to unravel the potential regulating mechanism of myricetin.

The concentrations of 22 amino acids in colon were determined using HPLC-MS/MS and principal component analysis (PCA) was performed on the data. MetaboAnalyst was used to detect potential biological pathway influenced by myricetin. The results were further verified using qPCR, molecular docking method, and AhR inhibitor.

Studies had found that the biosynthesis of phenylalanine, tyrosine, and tryptophan; phenylalanine metabolism; and histidine metabolism were the most important pathways related to myricetin. Therefore, the aryl hydrocarbon receptor (AhR), which is closely related to the metabolism of tryptophan, phenylalanine, and tyrosine, was postulated to be the underlying signaling pathways. Furthermore, administration of myricet in significantly increased the relative expressions of CYP1A1 and CYP1B1, whereas AhR inhibitor abolished the amelioration of myricetin on DSS-induced colitis. Moreover, AhR inhibitor weakened the regulatory effect of myricetin on Treg/Th17 balance. Furthermore, the results obtained by the molecular docking method speculated that myricetin could bind to AhR as a ligand and activate AhR.

The results suggested that myricetin could exert its protection against dextran sulfate sodium (DSS)-induced colitis by activating AhR signaling pathway.

New formyl indole derivatives based on thiobarbituric acid were designed for targeting parasitological applications. The new compounds (5-((1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (3a), and 5-((1-benzyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (3b) were synthesized as thioxodihydropyrimidine derivatives via aldol condensation reaction. The structures of the synthesized compounds were confirmed based on their spectral data via FT-IR, 1H and 13C NMR spectral characterization. In addition, the structure of 3a is confirmed using X-ray crystallography. The synthesized compounds were prepared in nm scale via chitosan as a matrix, and their size was measured via scanning electronic microscope. Interestingly, the newly synthesized nano formulations show higher positive zeta potential (mV) values + 29.6 and + 26.1 for compounds NP-3a, and NP-3b; respectively. These compounds were tested for their parasitological activity. The results revealed that 3b had a great activity against cryptosporidium infection. Moreover, the nano formulation of compound 3b showed a significant reduction percent of oocyst count of cryptosporidium infected mice representing 66%. Furthermore, these compounds were screened by in-vitro hemolytic activity assay (IC50) values (cytotoxicity on RBCs) to assess their cytotoxic potentials and safety profiles.

Pouchitis is the most common complication after IPAA for ulcerative colitis. The protective effect of tryptophan metabolites on the mucosal barrier may be effective for treating pouchitis. The role of tryptophan metabolites on pouchitis remained unclear.

We aimed to establish a murine model of dextran sulfate sodium-induced pouchitis to examine the roles of tryptophan metabolites in its pathogenesis.

This is a study that combines clinical patient data and animal research. A total of 22 patients were enrolled: 5 patients with familial adenomatous polyposis after IPAA, 8 patients with ulcerative colitis after IPAA with pouchitis, and 9 patients with ulcerative colitis after IPAA with normal pouch. The demographic data and fecal samples of patients were collected. Male C57BL/6 mice were purchased from a licensed breeder and underwent IPAA to establish a murine model of the pouch. The blood, feces, and tissues of mice were collected.

This study was performed in an academic medical center in China.

The demographic data of patients were observationally collected. The mice that underwent IPAA were divided into a control group that received a chow diet and 5 study groups: 1) dextran sulfate sodium, 2) 6-formylindolo[3,2-b] carbazole + dextran sulfate sodium, 3) high tryptophan diet + dextran sulfate sodium, 4) CH-223191 + dextran sulfate sodium, and 5) indole-3-carboxaldehyde + dextran sulfate sodium. Animals were euthanized after receiving dextran sulfate sodium for 7 days.

Fecal tryptophan metabolite level and microbiome composition, the severity of pouchitis, intestinal mucosal barrier function, and activation of the aryl hydrocarbon receptor-interleukin 22 pathway were assessed.

Patients with pouchitis had lower fecal microbial diversity and indole-3-acetic acid levels. In the murine pouchitis model, high tryptophan diet increased fecal levels of 3-indoleglyoxylic acid, indole-3-aldehyde, and indole. A high tryptophan diet and intraperitoneal aryl hydrocarbon receptor ligand 6-formylindolo[3,2-b] carbazole injection alleviated pouchitis. Tryptophan metabolites improved pouch mucosal barriers. Aryl hydrocarbon receptor inhibitors exacerbated experimental pouchitis and disrupted the mucosal barrier; however, the aryl hydrocarbon receptor ligand indole-3-carboxaldehyde reversed this effect.

This study was limited by a small human sample size and lacked an aryl hydrocarbon receptor knockout mouse model.

A high tryptophan diet and aryl hydrocarbon receptor ligand alleviated dextran sulfate sodium-induced pouchitis in a murine IPAA model, which might be achieved through regulating epithelial tight junctions and promoting goblet cell differentiation, as well as maintaining the integrity and function of the mucosal barrier. This study provides a rationale for the clinical application of aryl hydrocarbon receptor ligands in the treatment of pouchitis. See Video Abstract .

ANTECEDENTES:La reservoritis es la complicación más frecuente después de la anastomosis del reservorio ileal con el ano en la colitis ulcerosa. El efecto protector de los metabolitos del triptófano sobre la barrera mucosa puede ser un método eficaz para tratar la reservoritis. El papel de los metabolitos del triptófano en la reservoritis sigue sin estar claro.OBJETIVO:Nuestro objetivo era establecer un modelo murino de reservoritis inducida por sulfato de dextrano sódico para examinar el papel de los metabolitos del triptófano en su patogenia.DISEÑO:Este es un estudio que combina datos clínicos de pacientes e investigación animal. Se inscribieron un total de 22 pacientes: 5 con poliposis adenomatosa familiar después de un reservorio ileal, ocho pacientes con colitis ulcerosa después de un reservorio ileal que desarrollaron reservoritis y 9 pacientes con colitis ulcerosa después de un reservorio ileal que no presentaron reservoritis. Se recogieron los datos demográficos y las muestras fecales de los pacientes. Se adquirieron ratones macho C57BL/6 de un criador autorizado y se les realizó un reservorio ileal para establecer un modelo murino del reservorio. Se recogieron sangre, heces y tejidos de los ratones.CONFIGURACIÓN:Este estudio se realizó en un centro médico académico en China.INTERVENCIONES:Los datos demográficos de los pacientes se recogieron de forma observacional. Los ratones sometidos a un reservorio ileal se dividieron en seis grupos: grupo de control con dieta normal, sulfato de dextrano sódico, 6-formilindolo[3,2-b] carbazol + sulfato de dextrano sódico, dieta rica en triptófano + sulfato de dextrano sódico, CH-223191 + sulfato de dextrano sódico, indol-3-carboxaldehído + sulfato de dextrano sódico. Los animales fueron sacrificados después de la administración de sulfato de dextrano sódico durante 7 días.PRINCIPALES MEDIDAS DE RESULTADOS:Se evaluaron los niveles de metabolitos de triptófano y la composición del microbioma fecal, la gravedad de la reservoritis, la función de barrera de la mucosa intestinal y la activación de la vía del receptor de hidrocarburos de arilo-interleucina 22.RESULTADOS:Los pacientes con reservoritis tenían una menor diversidad microbiana fecal y niveles de ácido indol-3-acético. En el modelo de reservoritis murino, la dieta rica en triptófano aumentó los niveles fecales de ácido 3-indolglioxílico, indol-3-aldehído e indol. Una dieta rica en triptófano y una inyección intraperitoneal del ligando del receptor de hidrocarburos de arilo 6-formilindolo[3,2-b] carbazol aliviaron la reservoritis. Los metabolitos de triptófano mejoraron las barreras de la mucosa de la reservoritis. Los inhibidores del receptor de hidrocarburos de arilo exacerbaron la reservoritis experimental y alteraron la barrera mucosa; sin embargo, el ligando del receptor de hidrocarburos de arilo indol-3-carboxaldehído revirtió este efecto.LIMITACIONES:Este estudio estuvo limitado por el pequeño tamaño de la muestra humana y la falta de un modelo de ratón con deficiencia del receptor de hidrocarburos arílicos.CONCLUSIONES:Una dieta rica en triptófano y un ligando del receptor de hidrocarburos arílicos aliviaron la reservoritis inducida por sulfato de dextrano sódico en un modelo murino de anastomosis de reservorio ileo-anal, lo que podría deberse a la regulación de las uniones estrechas epiteliales y la promoción de la diferenciación de las células caliciformes, así como al mantenimiento de la integridad y la función de la barrera mucosa. Este estudio proporciona una justificación para la aplicación clínica de los ligandos del receptor de hidrocarburos arílicos en el tratamiento de la reservoritis. (Traducción-Dr. Felipe Bellolio ).

A solid scientific foundation is required to build the concept of personalized nutrition developed to promote health and a vision of disease prevention. Growing evidence indicates that nutrition can modulate the immune system through metabolites, which are either generated via microbiota metabolism or host digestion. The aryl hydrocarbon receptor (AhR) plays a crucial role in regulating immune responses, particularly in the gut, and has emerged as a key modulator of gut-mediated inflammation and related diseases. AhR is a ligand-activated transcription factor that responds to environmental, dietary, and microbial-derived signals, influencing immune balance and maintaining intestinal homeostasis. Nutritional AhR ligands play a significant role in modulating intestinal immunity and the function of mucosal immune cells, thereby exerting clinical effects on colitis and innate immunity. Additionally, they have the capacity to orchestrate autophagy, phagocytic cell function, and intestinal epithelial tight junctions. Therapeutic strategies aimed at enhancing AhR activity, restoring gut integrity, and optimizing immune responses hold promise as avenues for future research and potential treatments for critically ill patients.

Chronic obstructive pulmonary disease (COPD) is frequently associated with intestinal comorbidities. Damage to the intestinal barrier plays a crucial role in these disorders, leading to increased intestinal and systemic inflammation, and thereby promoting the progression of COPD. This study aims to investigate the mechanism of intestinal epithelial barrier damage, focusing on the roles of the Aryl hydrocarbon Receptor (AhR) and NF-κB in COPD-related intestinal damage. A COPD rat model was induced by cigarette smoke and bacterial infection, while Caco-2/HT29 intestinal epithelial cells were treated with TNF-α or IL-1β to assess intestinal disorder and the underlying mechanisms of barrier damage. COPD rats exhibited significant lung function decline, pathological damage, and inflammatory response in lung tissues. Additionally, significant intestinal injury was observed, accompanied by pronounced colonic pathological damage, an enhanced inflammatory response, and intestinal barrier disruption. This was evidenced by decreased expression of apical junction proteins and elevated serum diamine oxidase levels. Pro-inflammatory cytokines TNF-α or IL-1β significantly downregulated the expression of apical junction proteins in Caco-2/HT29 cells, reduced transepithelial electrical resistance of Caco-2 cells, and increased FD-4 permeability. Moreover, TNF-α or IL-1β induction activated NF-κB in Caco-2/HT29 cells, with a similar activation observed in the colonic tissues of COPD rats. The NF-κB inhibitor PDTC suppressed this activation and protected against intestinal epithelial barrier damage. Furthermore, AhR inhibition was observed both in vitro and in vivo. The AhR activator FICZ inhibited NF-κB activation and mitigated intestinal epithelial barrier damage, whereas the AhR inhibitor CH223191 inhibited AhR and exacerbated intestinal epithelial barrier damage by facilitating NF-κB activation. However, the NF-κB inhibitor PDTC did not significantly affect AhR. Additionally, TNF-α/IL-1β inhibited the binding of AhR and p-NF-κB. Consequently, AhR inhibition can downregulate the expression of apical junction proteins, probably through activation of NF-κB signaling leading to intestinal epithelial barrier damage. This study confirmed the presence of lesions in the lungs and intestines of COPD rats, as well as the associated damage to the intestinal epithelial barrier. The inhibition of AhR followed by the activation of NF-κB has been identified as a critical mechanism underlying the injury to the intestinal epithelial barrier.

Olive oil polyphenol hydroxytyrosol (HT) significantly repairs intestinal barrier function, but its absorption in the stomach and small intestine is limited. The metabolites of unabsorbed HT that reach the colon are crucial, yet their effects on colonic microbiota and intestinal barrier repair remain unclear. This study utilized in vitro simulated digestion and colonic fecal fermentation to investigate HT's digestion and fermentation. Results indicated that 79.25% of HT potentially reached the colon intact. Further 16S rDNA, targeted, and untargeted metabolomics analyses showed that HT can be decomposed by colonic microbiota, producing aromatic hydrocarbon metabolites and regulating gut microbiota structure. It promotes the growth of gut microbiota, such as Bacteroides, Faecalibacterium, Klebsiella, and Lachnospira, which degrade HT. Additionally, HT's intervention conversely affected the production of tryptophan-derived metabolites and short-chain fatty acids (SCFAs). Subsequently, computer-simulated molecular docking technology was used to simulate the binding affinity between HT metabolites and derived metabolites and the intestinal barrier repair-related receptor aryl hydrocarbon receptor (AhR). Indole-3-acetic acid, indole-3-acetaldehyde, skatole, kynurenine, and homovanillic acid could tightly bind to the amino acid residues of the AhR receptor, with binding energies all ˂-6.0 kcal/mol, suggesting that these metabolites may enhance the intestinal barrier function through the AhR signaling pathway.

The complex symbiotic relationship between inflammation, the gut microbiota, and the central nervous system (CNS) has become a pivotal focus of contemporary biomedical research. Inflammation, as a physiological defense mechanism, plays a dual role as both a protective and pathological factor, and is intricately associated with gut microbiota homeostasis, often termed the "second brain." The gutbrain axis (GBA) exemplifies this multifaceted interaction, where gut health exerts significantly regulatory effects on CNS functions. Antibacterial therapies represent both promising and challenging strategies for modulating inflammation and gut microbiota composition to confer CNS benefits. However, while such therapies may exert positive modulatory effects on the gut microbiota, they also carry the potential to disrupt microbial equilibrium, potentially exacerbating neurological dysfunction. Recent advances have provided critical insights into the therapeutic implications of antibacterial interventions; nevertheless, the application of these therapies in the context of CNS health warrants a judicious and evidence-based approach. As research progresses, deeper investigation into the microbial-neural interface is essential to fully realize the potential of therapies targeting inflammation and the gut microbiota for CNS health. Future efforts should focus on refining antibacterial interventions to modulate the gut microbiota while minimizing disruption to microbial balance, thereby reducing risks and enhancing efficacy in CNS-related conditions. In conclusion, despite challenges, a more comprehensive understanding of the GBA, along with precise modulation through targeted antibacterial therapies, offers significant promise for advancing CNS disorder treatment. Continued research in this area will lead to innovative interventions and improved patient outcomes.

In the intestinal tract, where numerous intestinal bacteria reside, intestinal epithelial cells produce and release various antimicrobial molecules that form a complex barrier on the mucosal surface. These barrier molecules can be classified into two groups based on their functions: those that exhibit bactericidal activity through chemical reactions, such as antimicrobial peptides, and those that physically hinder bacterial invasion, like mucins, which lack bactericidal properties. In the small intestine, where Paneth cells specialize in producing antimicrobial peptides, the chemical barrier molecules primarily inhibit bacterial growth. In contrast, in the large intestine, where Paneth cells are absent, allowing bacterial growth, the primary defense mechanism is the physical barrier, mainly composed of mucus, which controls bacterial movement and prevents their invasion of intestinal tissues. The expression of these barrier molecules is regulated by metabolites produced by bacteria in the intestinal lumen and cytokines produced by immune cells in the lamina propria. This regulation establishes a defense mechanism that adapts to changes in the intestinal environment, such as alterations in gut microbial composition and the presence of pathogenic bacterial infections. Consequently, when the integrity of the gut mucosal barrier is compromised, commensal bacteria and pathogenic microorganisms from outside the body can invade intestinal tissues, leading to conditions such as intestinal inflammation, as observed in cases of inflammatory bowel disease.

The aryl hydrocarbon receptor (AhR) is a cytosolic ligand-activated transcription factor integral to various physiological and pathological processes. Among its diverse ligands, indole-based compounds have garnered attention due to their significant biological activity and potential therapeutic applications. This study explores the activation of AhR by structurally diverse halogenated indoles. We evaluated the transcriptional activity of AhR and cell viability in the human LS174T-AhR-luc reporter cell line. Among the tested compounds, 4-FI, 7-FI, 6-BrI, 7-BrI, 6-Cl-2-ox, 5-Br-2-ox, and 6-Br-2-ox activated AhR in a concentration-dependent manner, displaying high efficacy and potency. Molecular docking analysis revealed moderate binding affinities of these compounds to the PAS-B domain of AhR, corroborated by competitive radioligand binding assays. Functional assays showed that halogenated indoles induce the formation of AhR-ARNT heterodimer and enhance the binding of the AhR to the CYP1A1 promoter. Additionally, 4-FI and 7-FI exhibited anti-inflammatory properties in Caco-2 cell models, highlighting their potential for therapeutic applications. This study underscores the significance of the type and position of halogen moiety in indole scaffold, suggesting their potential as candidates for developing therapeutics drugs to treat conditions such as inflammatory bowel disease via AhR activation.

Metabolism serves not only as the organism's energy source but also yields metabolites crucial for maintaining tissue homeostasis and overall health. Intestinal stem cells (ISCs) maintain intestinal homeostasis through continuous self-renewal and differentiation divisions. The intricate relationship between metabolic pathways and intestinal homeostasis underscores their crucial interplay. Metabolic pathways have been shown to directly regulate ISC self-renewal and influence ISC fate decisions under homeostatic conditions, but the cellular and molecular mechanisms remain incompletely understood. Understanding the intricate involvement of various pathways in maintaining intestinal homeostasis holds promise for devising innovative strategies to address intestinal diseases. Here, we provide a comprehensive review of recent advances in the regulation of intestinal homeostasis. We describe the regulation of intestinal homeostasis from multiple perspectives, including the regulation of intestinal epithelial cells, the regulation of the tissue microenvironment, and the key role of nutrient metabolism. We highlight the regulation of intestinal homeostasis and ISC by nutrient metabolism. This review provides a multifaceted perspective on how intestinal homeostasis is regulated and provides ideas for intestinal diseases and repair of intestinal damage.

The aryl hydrocarbon receptor is a ligand dependent transcription factor which functions as an environmental sensor. Originally discovered as the sensor for man made pollutants such as 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) it has recently gained prominence as an important mediator for environmental triggers via the diet or microbiota which influences many physiological functions in different cell types and tissues across the body. Notably AHR activity contributes to prevent excessive inflammation following tissue damage in barrier organs such as skin, lung or gut which has received wide attention in the past decade. In this review we will focus on emerging common AHR functions across cell types and tissues and discuss ongoing issues that confound the understanding of AHR physiology. Furthermore, we will discuss the need for deeper molecular understanding of the functional activity of AHR in different contexts with respect to development of potential therapeutic applications.

Sphingolipids play vital roles in metabolism and regulation. Previously, the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, was reported to directly regulate ceramide synthesis genes by binding to their promoters. Herein, sphingosine kinase 2 (SPHK2), responsible for producing sphingosine-1-phosphate (S1P), was found to interact with AHR through LXXLL motifs, influencing AHR nuclear localization. Through mutagenesis and co-transfection studies, AHR activation and subsequent nuclear translocation was hindered by SPHK2 LXXLL mutants or SPHK2 lacking a nuclear localization signal (NLS). Similarly, an NLS-deficient AHR mutant impaired SPHK2 nuclear translocation. Silencing SPHK2 reduced AHR expression and its target gene CYP1A1, while SPHK2 overexpression enhanced AHR activity. SPHK2 was found enriched on the CYP1A1 promoter, underscoring its role in AHR target gene activation. Additionally, S1P rapidly increased AHR expression at both the mRNA and protein levels and promoted AHR recruitment to the CYP1A1 promoter. Using mouse models, AHR deficiency compromised SPHK2 nuclear translocation, illustrating a critical interaction where SPHK2 facilitates AHR nuclear localization and supports a positive feedback loop between AHR and sphingolipid enzyme activity in the nucleus. These findings highlight a novel function of SPHK2 in regulating AHR activity and gene expression.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death worldwide. In recent years, the impact of the gut microbiota on the development of CRC has become clear. The gut microbiota is the community of microorganisms living in the gut symbiotic relationship with the host. These microorganisms contribute to the development of CRC through various mechanisms that are not yet fully understood. Increasing scientific evidence suggests that metabolites produced by the gut microbiota may influence CRC development by exerting protective and deleterious effects. This article reviews the metabolites produced by the gut microbiota, which are derived from the intake of complex carbohydrates, proteins, dairy products, and phytochemicals from plant foods and are associated with a reduced risk of CRC. These metabolites include short-chain fatty acids (SCFAs), indole and its derivatives, conjugated linoleic acid (CLA) and polyphenols. Each metabolite, its association with CRC risk, the possible mechanisms by which they exert anti-tumour functions and their relationship with the gut microbiota are described. In addition, other gut microbiota-derived metabolites that are gaining importance for their role as CRC suppressors are included.

Although a reasonable diet is essential for promoting human health, precise nutritional regulation presents a challenge for different physiological conditions. Irritable Bowel Syndrome (IBS) is characterized by recurrent abdominal pain and abnormal bowel habits, and diarrheal IBS (IBS-D) is the most common, seriously affecting patients' quality of life. Therefore, the implementation of precise nutritional interventions for IBS-D has become an urgent challenge in the fields of nutrition and food science. IBS-D intestinal homeostatic imbalance involves intestinal flora disorganization and impaired intestinal epithelial barrier function. A familiar interaction is evident between intestinal flora and intestinal epithelial cells (IECs), which together maintain intestinal homeostasis and health. Dietary patterns, such as the Mediterranean diet, have been shown to regulate gut flora, which in turn improves the body's health by influencing the immune system, the hormonal system, and other metabolic pathways.

This review summarized the relationship between intestinal flora, IECs, and IBS-D. It analyzed the mechanism behind IBS-D intestinal homeostatic imbalance by examining the interactions between intestinal flora and IECs, and proposed a precise dietary nutrient intervention strategy.

This increases the understanding of the IBS-D-targeted regulation pathways and provides guidance for designing related nutritional intervention strategies.

Tertiary lymphoid tissues (TLTs) are adaptive immune structures that develop during chronic inflammation and may worsen or lessen disease outcomes in a context-specific manner. Immune cell activity governing TLT formation in the intestines is dependent on immune cell aryl hydrocarbon receptor (AhR) activation. Homeostatic immune cell activity in the intestines is further dependent on ligand activation of AhR in intestinal epithelial cells (IECs), yet whether AhR activation and signaling in IECs influences the formation of TLTs in the presence of dietary AhR ligands is not known. To this end, we used IEC-specific AhR deletion coupled with a mouse model of dextran sodium sulfate (DSS)-induced colitis to understand how dietary AhR ligand 3, 3'-diindolylmethane (DIM) influenced TLT formation. DIM consumption increased the size of TLTs and decreased T-cell aggregation to TLT sites in an IEC-specific manner. In DSS-exposed female mice, DIM consumption increased the expression of genes implicated in TLT formation (Interleukin-22, Il-22; CXC motif chemokine ligand 13, CXCL13) in an IEC AhR-specific manner. Conversely, in female mice without DSS exposure, DIM significantly reduced the expression of Il-22 or CXCL13 in iAhRKO mice, but this effect was not observed in WT animals. Our findings suggest that DIM affects the immunological landscape of TLT formation during DSS-induced colitis in a manner contingent on AhR expression in IECs and biological sex. Further investigations into specific immune cell activity, IEC-specific AhR signaling pathways, and dietary AhR ligand-mediated effects on TLT formation are warranted.

Rehmanniae Radix Praeparata (RRP), a staple in traditional Chinese medicine, is derived from Rehmannia glutinosa Libosch and is renowned for its wound-healing properties. Despite its clinical prevalence, the molecular mechanisms underlying RRP's wound-healing effects have not been fully elucidated.

This research endeavored to delineate the molecular and cellular mechanisms underlying the beneficial effects of RRP on wound healing, utilizing a zebrafish model.

Zebrafish larvae at 3 days post-fertilization were amputated at the fin and subsequently treated with RRP. The pro-wound healing and regenerative effects of RRP were evaluated through morphological analysis, assessment of cell proliferation and apoptosis, Additionally, mechanistic insights were gained through a comprehensive approach encompassing network pharmacology analysis, cell tracing, RNA-sequencing, CRISPR/Cas9 gene editing, and pharmacological inhibition.

Our findings demonstrate that RRP significantly accelerates caudal fin regeneration in zebrafish following injury by suppressing cell apoptosis, promoting cell proliferation, and upregulating the expression of regenerative-related genes. Furthermore, RRP triggers autophagy signals during the regenerative process, which is attenuated by the autophagy inhibitor chloroquine (CQ). Notably, the administration of RRP enhances the expression of ahr1 and ahr2 in the regenerating fin. Genetic knockout of ahr1a, ahr1b, or ahr2 using CRISPR/Cas9, or pharmacological blockade of AHR signals with the antagonist CH-223191, diminishes the regenerative potential of RRP. Remarkably, zebrafish lacking ahr2 completely lose their fin regeneration ability. Additionally, inhibition of AHR signaling suppresses autophagy signaling during fin regeneration.

This study uncovers that RRP stimulates fin regeneration in zebrafish by inducing AHR signals and, at least partially, activating the autophagy process. These findings provide novel insights into the molecular mechanisms underlying the wound-healing effects of RRP and may pave the way for the development of novel therapeutic strategies.

Indole-3-carboxaldehyde (IAld) is a tryptophan (Trp) metabolite derived from gut microbiota, which has a potential protective effect on intestinal inflammatory diseases. Abnormal activation of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is an important cause of intestinal inflammation. However, the effect and mechanism of IAld on NLRP3 inflammasome activation remain unclear. Here, we found that IAld inhibited the activation of the NLRP3 inflammasome in intestinal epithelial cells, and effectively prevented intestinal epithelial barrier injury caused by lipopolysaccharide (LPS) stimulation. Mechanistically, we demonstrated that IAld activated the aryl hydrocarbon receptor (AhR), subsequently prevented reactive oxygen species (ROS) production, maintained mitochondrial membrane potential, and blocked the NF-κB/NLRP3 inflammatory pathway in intestinal epithelial cells. Also, the AhR-specific inhibitor CH-223191 effectively blocked the IAld-induced NLRP3 inhibition and intestinal epithelial barrier repairment. In addition, in vivo results showed that IAld prevented pro-inflammatory mediator production and intestinal inflammatory damage in LPS-induced mice, which is related to AhR activation and NLRP3 inflammasome inhibition. Collectively, our study unveiled that IAld is an effective endogenous antioxidant and suggested the AhR as a potential treatment target for NLRP3-induced intestinal inflammatory diseases.

The gastrointestinal tract is where the majority of gut microbiota settles; therefore, the composition of the gut microbiota and the changes in metabolites, as well as their modulatory effects on the immune system, have a very important impact on the development of gastrointestinal diseases. The purpose of this article was to review the role of the gut microbiota in the host environment and immunometabolic system and to summarize the beneficial effects of botanical active ingredients on gastrointestinal cancer, so as to provide prospective insights for the prevention and treatment of gastrointestinal diseases. A literature search was performed on the PubMed database with the keywords "gastrointestinal cancer", "gut microbiota", "immunometabolism", "SCFAs", "bile acids", "polyamines", "tryptophan", "bacteriocins", "immune cells", "energy metabolism", "polyphenols", "polysaccharides", "alkaloids", and "triterpenes". The changes in the composition of the gut microbiota influenced gastrointestinal disorders, whereas their metabolites, such as SCFAs, bacteriocins, and botanical metabolites, could impede gastrointestinal cancers and polyamine-, tryptophan-, and bile acid-induced carcinogenic mechanisms. GPRCs, HDACs, FXRs, and AHRs were important receptor signals for the gut microbial metabolites in influencing the development of gastrointestinal cancer. Botanical active ingredients exerted positive effects on gastrointestinal cancer by influencing the composition of gut microbes and modulating immune metabolism. Gastrointestinal cancer could be ameliorated by altering the gut microbial environment, administering botanical active ingredients for treatment, and stimulating or blocking the immune metabolism signaling molecules. Despite extensive and growing research on the microbiota, it appeared to represent more of an indicator of the gut health status associated with adequate fiber intake than an autonomous causative factor in the prevention of gastrointestinal diseases. This study detailed the pathogenesis of gastrointestinal cancers and the botanical active ingredients used for their treatment in the hope of providing inspiration for research into simpler, safer, and more effective treatment pathways or therapeutic agents in the field.

Depression is a highly prevalent disorder and a leading cause of disability worldwide. It has a major impact on the affected individual and on society as a whole. Regrettably, current available treatments for this condition are insufficient in many patients. In recent years, the gut microbiome has emerged as a promising alternative target for treating and preventing depressive disorders. However, the microbes that form this ecosystem do not act alone but are part of a complicated network connecting the gut and the brain that influences our mood. Host cells that are in intimate contact with gut microbes, such as the epithelial cells forming the gut barrier and the immune cells in their vicinity, play a key role in the process. These cells continuously shape immune responses to maintain healthy communication between gut microbes and the host. In this article, we review how the interplay among epithelial cells, the immune system, and gut microbes mediates gut-brain communication to influence mood. We also discuss how advances in our knowledge of the mechanisms underlying the gut-brain axis could contribute to addressing depression. SIGNIFICANCE STATEMENT: This review does not aim to systematically describe intestinal microbes that might be beneficial or detrimental for depression. We have adopted a novel point of view by focusing on potential mechanisms underlying the crosstalk between gut microbes and their intestinal environment to control mood. These pathways could be targeted by well defined and individually tailored dietary interventions, microbes, or microbial metabolites to ameliorate depression and decrease its important social and economic impact.

Mitochondrial dysfunction is associated with inflammatory bowel diseases (IBDs). To understand how microbial-metabolic circuits contribute to intestinal injury, we disrupt mitochondrial function in the epithelium by deleting the mitochondrial chaperone, heat shock protein 60 (Hsp60Δ/ΔIEC). This metabolic perturbation causes self-resolving tissue injury. Regeneration is disrupted in the absence of the aryl hydrocarbon receptor (Hsp60Δ/ΔIEC;AhR-/-) involved in intestinal homeostasis or inflammatory regulator interleukin (IL)-10 (Hsp60Δ/ΔIEC;Il10-/-), causing IBD-like pathology. Injury is absent in the distal colon of germ-free (GF) Hsp60Δ/ΔIEC mice, highlighting bacterial control of metabolic injury. Colonizing GF Hsp60Δ/ΔIEC mice with the synthetic community OMM12 reveals expansion of metabolically flexible Bacteroides, and B. caecimuris mono-colonization recapitulates the injury. Transcriptional profiling of the metabolically impaired epithelium reveals gene signatures involved in oxidative stress (Ido1, Nos2, Duox2). These signatures are observed in samples from Crohn's disease patients, distinguishing active from inactive inflammation. Thus, mitochondrial perturbation of the epithelium causes microbiota-dependent injury with discriminative inflammatory gene profiles relevant for IBD.

After birth, the development of secondary lymphoid tissues (SLTs) in the colon is dependent on the expression of the aryl hydrocarbon receptor (AhR) in immune cells as a response to the availability of AhR ligands. However, little is known about how AhR activity from intestinal epithelial cells (IECs) may influence the development of tertiary lymphoid tissues (TLTs). As organized structures that develop at sites of inflammation or infection during adulthood, TLTs serve as localized centers of adaptive immune responses, and their presence has been associated with the resolution of inflammation and tumorigenesis in the colon. Here, we investigated the effect of the conditional loss of AhR activity in IECs in the formation and immune cell composition of TLTs in a model of acute inflammation. In females, loss of AhR activity in IECs reduced the formation of TLTs without significantly changing disease outcomes or immune cell composition within TLTs. In males lacking AhR expression in IECs, increased disease activity index, lower expression of functional-IEC genes, increased number of TLTs, increased T-cell density, and lower B- to T-cell ratio were observed. These findings may represent an unfavorable prognosis when exposed to dextran sodium sulfate (DSS)-induced epithelial damage compared with females. Sex and loss of IEC AhR also resulted in changes in microbial populations in the gut. Collectively, these data suggest that the formation of TLTs in the colon is influenced by sex and AhR expression in IECs.NEW & NOTEWORTHY This is the first research of its kind to demonstrate a clear connection between biological sex and the development of tertiary lymphoid tissues (TLT) in the colon. In addition, the research finds that in a preclinical model of inflammatory bowel disease, the expression of the aryl hydrocarbon receptor (AhR) influences the development of these structures in a sex-specific manner.

Intestinal eosinophils express the aryl hydrocarbon receptor (AHR), an environmental sensor and ligand-activated transcription factor that responds to dietary or environmental ligands. AHR regulates tissue adaptation, survival, adhesion, and immune functions in intestinal eosinophils. The AHR repressor (AHRR) is itself induced by AHR and believed to limit AHR activity in a negative feedback loop. We analyzed gene expression in intestinal eosinophils from wild-type and AHRR knockout mice and found that AHRR did not suppress most AHR-dependent genes. Instead, AHRR limited the expression of a distinct small set of genes involved in the innate immune response. These included S100 proteins, antimicrobial proteins, and alpha-defensins. Using bone marrow-derived eosinophils, we found that AHRR knockout eosinophils released more reactive oxygen species upon stimulation. This work shows that the paradigm of AHRR as a repressor of AHR transcriptional activity does not apply to intestinal eosinophils. Rather, AHRR limits the expression of innate immune response and antimicrobial genes, possibly to maintain an anti-inflammatory phenotype in eosinophils when exposed to microbial signals in the intestinal environment.

Early studies have shown that the gut microbiota is a critical target during cadmium exposure. The prebiotic activity of epigallocatechin-3-gallate (EGCG) plays an essential role in treating intestinal inflammation and damage. However, the exact intestinal barrier protection mechanism of EGCG against cadmium exposure remains unclear. In this experiment, four-week-old mice were exposed to cadmium (5 mg kg-1) for four weeks. Through 16 S rDNA analysis, we found that cadmium disrupted the gut microbiota and inhibited the indole metabolism pathway of tryptophan (TRP), which serves as the principal microbial production route for endogenous ligands to activate the aryl hydrocarbon receptor (AhR). Additionally, cadmium downregulated the intestinal AhR signaling pathway and harmed the intestinal barrier function. Treatment with EGCG (20 mg kg-1) and the AhR agonist 6-Formylindolo[3,2-b] carbazole (FICZ) (1 μg/d) significantly activated the AhR pathway and alleviated intestinal barrier injury. Notably, EGCG partially restored the gut microbiota and upregulated the TRP-indole metabolism pathway to increase the level of indole-related AhR agonists. Our findings demonstrate that cadmium dysregulates common gut microbiota to disrupt TRP metabolism, impairing the AhR signaling pathway and intestinal barrier. EGCG reduces cadmium-induced intestinal functional impairment by intervening in the intestinal microbiota to metabolize AhR agonists. This study offers insights into the toxic mechanisms of environmental cadmium and a potential mechanism to protect the intestinal barrier with EGCG.