Toxicological impact of food contaminants at the intestinal and hepatic levels

Cette thèse examine les effets toxicologiques de contaminants alimentaires au niveau intestinal et hépatique sur des modèles murins.Dans le premier chapitre, une revue de la littérature détaille l'organisation et les fonctions du système digestif, en mettant particulièrement l'accent sur l'intestin et le foie, ainsi que sur certaines pathologies associées. Cette exploration s'accompagne d'une description de l'omniprésence des contaminants dans notre alimentation et de leur impact sur notre santé.Dans un deuxième chapitre, l'attention est portée sur la mycotoxine déoxynivalénol, un contaminant fréquent des produits céréaliers, et son impact sur l'inflammation intestinale et le cancer colorectal. Les résultats montrent que le déoxynivalénol aggrave l'entérite induite par l'indométacine et favorise le développement du cancer colorectal associé à la colite. De plus, des altérations du microbiote intestinal et du métabolisme bactérien sont observées.Le troisième chapitre se concentre sur les effets des microplastiques de polyéthylène, qui représentent l'un des contaminants alimentaires émergents de ces dernières années. Les résultats indiquent que ces microplastiques altèrent la composition du microbiote intestinal ainsi que les réponses inflammatoires de l'intestin. Au niveau hépatique, les microplastiques exacerbent les processus inflammatoires et fibrotiques, notamment dans le contexte de la fibrose hépatique induite par le tétrachlorure de carbone.En résumé, cette thèse met en évidence les effets néfastes de certains contaminants alimentaires sur l'intestin et le foie. Ces résultats soulignent l'importance de prévenir et de gérer les risques associés aux contaminants alimentaires afin de préserver la santé gastro-intestinale et hépatique chez l'homme.This thesis examines the toxicological effects of dietary contaminants on the intestinal and hepatic levels using murine models.In the first chapter, a literature review details the organization and functions of the digestive system, with a particular focus on the intestine and the liver, as well as certain associated pathologies. This exploration is accompanied by a description of the omnipresence of contaminants in our diet and their impact on our health.In the second chapter, attention is focused on the mycotoxin deoxynivalenol, a common contaminant in cereal products, and its impact on intestinal inflammation and colorectal cancer. The results demonstrate that deoxynivalenol exacerbates indomethacin-induced enteritis and promotes the development of colorectal cancer associated with colitis. Additionally, alterations in the intestinal microbiota and bacterial metabolism are observed. The third chapter centers on the effects of polyethylene microplastics, which represent one of the emerging dietary contaminants in recent years. The results indicate that these microplastics alter the composition of the intestinal microbiota as well as the inflammatory responses in the intestine. At the hepatic level, microplastics exacerbate inflammatory and fibrotic processes, particularly in the context of carbon tetrachloride-induced hepatic fibrosis. In summary, this thesis highlights the adverse effects of certain dietary contaminants on the intestine and the liver. These findings emphasize the importance of preventing and managing the risks associated with dietary contaminants to preserve gastrointestinal and hepatic health in humans

Impact toxicologique de contaminants alimentaires au niveau intestinal et hépatique

This thesis examines the toxicological effects of dietary contaminants on the intestinal and hepatic levels using murine models.In the first chapter, a literature review details the organization and functions of the digestive system, with a particular focus on the intestine and the liver, as well as certain associated pathologies. This exploration is accompanied by a description of the omnipresence of contaminants in our diet and their impact on our health.In the second chapter, attention is focused on the mycotoxin deoxynivalenol, a common contaminant in cereal products, and its impact on intestinal inflammation and colorectal cancer. The results demonstrate that deoxynivalenol exacerbates indomethacin-induced enteritis and promotes the development of colorectal cancer associated with colitis. Additionally, alterations in the intestinal microbiota and bacterial metabolism are observed. The third chapter centers on the effects of polyethylene microplastics, which represent one of the emerging dietary contaminants in recent years. The results indicate that these microplastics alter the composition of the intestinal microbiota as well as the inflammatory responses in the intestine. At the hepatic level, microplastics exacerbate inflammatory and fibrotic processes, particularly in the context of carbon tetrachloride-induced hepatic fibrosis. In summary, this thesis highlights the adverse effects of certain dietary contaminants on the intestine and the liver. These findings emphasize the importance of preventing and managing the risks associated with dietary contaminants to preserve gastrointestinal and hepatic health in humans.Cette thèse examine les effets toxicologiques de contaminants alimentaires au niveau intestinal et hépatique sur des modèles murins.Dans le premier chapitre, une revue de la littérature détaille l'organisation et les fonctions du système digestif, en mettant particulièrement l'accent sur l'intestin et le foie, ainsi que sur certaines pathologies associées. Cette exploration s'accompagne d'une description de l'omniprésence des contaminants dans notre alimentation et de leur impact sur notre santé.Dans un deuxième chapitre, l'attention est portée sur la mycotoxine déoxynivalénol, un contaminant fréquent des produits céréaliers, et son impact sur l'inflammation intestinale et le cancer colorectal. Les résultats montrent que le déoxynivalénol aggrave l'entérite induite par l'indométacine et favorise le développement du cancer colorectal associé à la colite. De plus, des altérations du microbiote intestinal et du métabolisme bactérien sont observées.Le troisième chapitre se concentre sur les effets des microplastiques de polyéthylène, qui représentent l'un des contaminants alimentaires émergents de ces dernières années. Les résultats indiquent que ces microplastiques altèrent la composition du microbiote intestinal ainsi que les réponses inflammatoires de l'intestin. Au niveau hépatique, les microplastiques exacerbent les processus inflammatoires et fibrotiques, notamment dans le contexte de la fibrose hépatique induite par le tétrachlorure de carbone.En résumé, cette thèse met en évidence les effets néfastes de certains contaminants alimentaires sur l'intestin et le foie. Ces résultats soulignent l'importance de prévenir et de gérer les risques associés aux contaminants alimentaires afin de préserver la santé gastro-intestinale et hépatique chez l'homme

Recent Progress in Intestinal Toxicity of Microplastics and Nanoplastics: Systematic Review of Preclinical Evidence

The tremendous plastic production and poor post-use management are current and future sources of environmental and human contamination due to their degradation products: microplastics and nanoplastics (MNPLs). Methodological developments have allowed MNPLs to be detected in an increasing variety of human foods, as well as in stool and colonic mucosa. It was suggested early that the direct contact between MNPLs and intestinal tissues could represent a potential risk for human health. In order to assess this, over the last 3 years, numerous studies have evaluated the impact of MNPL ingestion on intestinal homeostasis in rodents. This comprehensive review reports the preclinical studies published between January 2021 and January 2024, and analyzes their contributions as well as their shortcomings. It shows that evidence is accumulating of the intestinal toxicity of spherical MNPLs, which lead to pro-inflammatory, pro-oxidative, barrier-disruptive and dysbiotic effects. However, the available literature has addressed only a minor part of the potential health issues of MNPLs. Many parameters contributing to MNPL toxicity need to be better taken into account in future studies. Particular attention should be paid to improve the representativeness of MNPLs, as well as to better consider the susceptibility factors of MNPL toxicity, generated especially by an underlying pathology or pathological imprinting

Aluminum Ingestion Promotes Colorectal Hypersensitivity in RodentsSummary

Background & Aims: Irritable bowel syndrome (IBS) is a multifactorial disease arising from a complex interplay between genetic predisposition and environmental influences. To date, environmental triggers are not well known. Aluminum is commonly present in food, notably by its use as food additive. We investigated the effects of aluminum ingestion in rodent models of visceral hypersensitivity, and the mechanisms involved. Methods: Visceral hypersensitivity was recorded by colorectal distension in rats administered with oral low doses of aluminum. Inflammation was analyzed in the colon of aluminum-treated rats by quantitative PCR for cytokine expression and by immunohistochemistry for immune cells quantification. Involvement of mast cells in the aluminum-induced hypersensitivity was determined by cromoglycate administration of rats and in mast cell-deficient mice (KitW-sh/W-sh). Proteinase-activated receptor-2 (PAR2) activation in response to aluminum was evaluated and its implication in aluminum-induced hypersensitivity was assessed in PAR2 knockout mice. Results: Orally administered low-dose aluminum induced visceral hypersensitivity in rats and mice. Visceral pain induced by aluminum persisted over time even after cessation of treatment, reappeared and was amplified when treatment resumed. As observed in humans, female animals were more sensitive than males. Major mediators of nociception were up-regulated in the colon by aluminum. Activation of mast cells and PAR2 were required for aluminum-induced hypersensitivity. Conclusions: These findings indicate that oral exposure to aluminum at human dietary level reproduces clinical and molecular features of IBS, highlighting a new pathway of prevention and treatment of visceral pain in some susceptible patients. Keywords: Visceral Hypersensitivity, Risk Factors, Mast Cells, PAR

The RAGE signaling pathway is involved in intestinal inflammation and represents a promising therapeutic target for Inflammatory Bowel Diseases.

International audienceInflammatory Bowel Diseases (IBD) are chronic inflammatory conditions of the intestinal tract. IBD are believed to result from an inappropriate immune response against the intestinal flora in genetically predisposed patients. The precise etiology of these diseases is not fully understood, therefore treatments rely on the dampening of symptoms, essentially inflammation, rather than on the cure of the disease. Despite the availability of biologics, such as anti-TNF antibodies, some patients remain in therapeutic failure and new treatments are thus needed. The multiligand receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor implicated in inflammatory reactions and immune system activation. Here, we investigated the role of RAGE in intestinal inflammation and its potential as a therapeutic target in IBD. We showed that RAGE was upregulated in inflamed tissues from IBD patients compared to controls. Rage(-/-) mice were less susceptible to intestinal and colonic inflammation development than WT mice. WT mice treated with the RAGE-specific inhibitor FPS-ZM1 experienced less severe enteritis and colitis. We demonstrated that RAGE could induce intestinal inflammation by promoting oxidative stress and endothelial activation which were diminished by FPS-ZM1 treatment. Our results revealed the RAGE signaling pathway as a promising therapeutic target for IBD patients

New FAAH inhibitors based on 3-carboxamido-5-aryl-isoxazole scaffold that protect against experimental colitis

Growing evidence suggests a role for the endocannabinoid (EC) system, in intestinal inflammation and compounds inhibiting anandamide degradation offer a promising therapeutic option for the treatment of inflammatory bowel diseases. In this paper, we report the first series of carboxamides derivatives possessing FAAH inhibitory activities. Among them, compound 39 displayed significant inhibitory FAAH activity (IC(50)=0.088 μM) and reduced colitis induced by intrarectal administration of TNBS

Benzo[d]thiazol-2(3H)-ones as new potent selective CB2 agonists with anti-inflammatory properties.

International audienceThe high distribution of CB receptors in immune cells suggests their important role in the control of inflammation. Growing evidence offers this receptor as an attractive therapeutic target: selective CB agonists are able to modulate inflammation without triggering psychotropic effects. In this work, we report a new series of selective CB agonists based on a benzo[d]thiazol-2(3H)-one scaffold. This drug design project led to the discovery of compound 9, as a very potent CB agonist (K = 13.5 nM) with a good selectivity versus CB. This compound showed no cytotoxicity, acceptable ADME-Tox parameters and demonstrates the ability to counteract colon inflammatory process in vivo

O-GlcNAcylation Links Nutrition to the Epigenetic Downregulation of UNC5A during Colon Carcinogenesis

International audienceWhile it is now accepted that nutrition can influence the epigenetic modifications occurring in colorectal cancer (CRC), the underlying mechanisms are not fully understood. Among the tumor suppressor genes frequently epigenetically downregulated in CRC, the four related genes of the UNC5 family: UNC5A, UNC5B, UNC5C and UNC5D encode dependence receptors that regulate the apoptosis/survival balance. Herein, in a mouse model of CRC, we found that the expression of UNC5A, UNC5B and UNC5C was diminished in tumors but only in mice subjected to a High Carbohydrate Diet (HCD) thus linking nutrition to their repression in CRC. O-GlcNAcylation is a nutritional sensor which has enhanced levels in CRC and regulates many cellular processes amongst epigenetics. We then investigated the putative involvement of O-GlcNAcylation in the epigenetic downregulation of the UNC5 family members. By a combination of pharmacological inhibition and RNA interference approaches coupled to RT-qPCR (Reverse Transcription-quantitative Polymerase Chain Reaction) analyses, promoter luciferase assay and CUT&RUN (Cleavage Under Target & Release Using Nuclease) experiments, we demonstrated that the O-GlcNAcylated form of the histone methyl transferase EZH2 (Enhancer of Zeste Homolog 2) represses the transcription of UNC5A in human colon cancer cells. Collectively, our data support the hypothesis that O-GlcNAcylation could represent one link between nutrition and epigenetic downregulation of key tumor suppressor genes governing colon carcinogenesis including UNC5A

Effects of urban coarse particles inhalation on oxidative and inflammatory parameters in the mouse lung and colon

International audienceBackground: Air pollution is a recognized aggravating factor for pulmonary diseases and has notably deleterious effects on asthma, bronchitis and pneumonia. Recent studies suggest that air pollution may also cause adverse effects in the gastrointestinal tract. Accumulating experimental evidence shows that immune responses in the pulmonary and intestinal mucosae are closely interrelated, and that gut-lung crosstalk controls pathophysiological processes such as responses to cigarette smoke and influenza virus infection. Our first aim was to collect urban coarse particulate matter (PM) and to characterize them for elemental content, gastric bioaccessibility, and oxidative potential; our second aim was to determine the short-term effects of urban coarse PM inhalation on pulmonary and colonic mucosae in mice, and to test the hypothesis that the well-known antioxidant N-acetyl-L-cysteine (NAC) reverses the effects of PM inhalation.Results: The collected PM had classical features of urban particles and possessed oxidative potential partly attributable to their metal fraction. Bioaccessibility study confirmed the high solubility of some metals at the gastric level. Male mice were exposed to urban coarse PM in a ventilated inhalation chamber for 15 days at a concentration relevant to episodic elevation peak of air pollution. Coarse PM inhalation induced systemic oxidative stress, recruited immune cells to the lung, and increased cytokine levels in the lung and colon. Concomitant oral administration of NAC reversed all the observed effects relative to the inhalation of coarse PM.Conclusions: Coarse PM-induced low-grade inflammation in the lung and colon is mediated by oxidative stress and deserves more investigation as potentiating factor for inflammatory diseases