Intestinal microbiota and pectin in non-alcoholic steatohepatitis

La stéatose hépatique non alcoolique (NAFLD) est la manifestation hépatique du syndrome métabolique. Elle suit l’épidémie d’obésité et affecte un quart de la population mondiale. Son évolution croissante en fait un enjeu sociétal majeur tant d’un point de vue de santé publique que par l’impact économique qu’elle engendre. Actuellement, aucune thérapeutique n’est spécifiquement approuvée pour le traitement de la NAFLD. L’urgence est donc à la compréhension des mécanismes impliqués dans la pathogenèse de la NAFLD dans l’optique de développer des solutions thérapeutiques optimales. Le microbiote intestinal est un cofacteur primordial de la pathogenèse de la NAFLD et intervient dans la susceptibilité individuelle à la maladie. Le microbiote intestinal peut notamment être modulé par les fibres alimentaires telles que la pectine considérée comme prébiotique. L’objectif de ce travail était dans un premier temps d’asseoir les liens entre microbiote intestinal, pectine et l’impact sur les acteurs de la NAFLD dont le foie et les tissus adipeux. Dans un deuxième temps nous souhaitions évaluer si la modification du microbiote intestinal par la pectine suffisait à améliorer et restaurer les lésions hépatiques induites par un régime gras dans un modèle murin de NAFLD. A faible dose, une supplémentation en pectine atténue les lésions délétères induites par un régime gras chez la souris. L’effet protecteur de la pectine est liée à une modulation du microbiote. Cette modification impacte les fonctionnalités des tissus adipeux via la libération de métabolites bactériens dont les acides gras à chaîne courte (AAGC). Ce travail de thèse montre que le microbiote intestinal et ses métabolites sont une cible thérapeutique potentielle dans la stéatose hépatique non-alcoolique. L’utilisation des AAGC couplé à l’utilisation de probiotiques pourraient s’avérer des pistes intéressantes chez l’homme et ce en association avec des mesures diététiques visant à réintroduire des fibres alimentaires au sein du régime.Nonalcoholic fatty liver disease (NAFLD) corresponds to the hepatic manifestation of the metabolic syndrome and affects a quarter of general population which leads to dramatic economic and health issues. So far, no approved pharmacotherapy is available for NAFLD. Among overweighed/obese patients, only a subset of individuals will develop severe liver lesions. It has been demonstrated that intestinal microbiota plays a major role in the individual susceptibility of patients to develop NAFLD. The Western-style diet, enriched in fat and sugar and low in fibers contribute at least in part to depletion of specific bacterial taxa in the IM. Thus, if the establishement of a bacterial signature in NAFLD is important for the follow-up of patients, change the IM to restore a “healthy” IM could be relevant. Indeed, impact of dietary fiber on gut microbiota is clearly established. It has been shown that fibers prevent liver injury depending of the type of fiber. In the current study, we addressed the role of fiber in the prevention of liver injury during a diet induced obesity (DIO) by adding fiber in a high fat diet (HFD). Then, we studied the role of IM in the protective effect of pectin in DIO mice. To this end, the IM from DIO mice treated with pectin was transplanted in DIO mice both before or after the development of obesity. Moreover, we analyzed the effect of the addition of pectin in a HFD pectin after the establishment of obesity. We were able to confirm the beneficial role of pectin in the pathogenesis of NAFLD. Pectin supplementation modulates intestinal microbiota composition and bacterial metabolites like short-chain fatty acids (SCFAs). Together, this actors influence the functionality of white and brown adipose tissues. In the future, the use of bacterial metabolites as SCFAs and specific probiotics could be proposed in the management of NAFLD in addition to dietary measures with fibers supplementation

Implications du microbiote intestinal et de la pectine dans la stéato-hépatite non-alcoolique

Nonalcoholic fatty liver disease (NAFLD) corresponds to the hepatic manifestation of the metabolic syndrome and affects a quarter of general population which leads to dramatic economic and health issues. So far, no approved pharmacotherapy is available for NAFLD. Among overweighed/obese patients, only a subset of individuals will develop severe liver lesions. It has been demonstrated that intestinal microbiota plays a major role in the individual susceptibility of patients to develop NAFLD. The Western-style diet, enriched in fat and sugar and low in fibers contribute at least in part to depletion of specific bacterial taxa in the IM. Thus, if the establishement of a bacterial signature in NAFLD is important for the follow-up of patients, change the IM to restore a “healthy” IM could be relevant. Indeed, impact of dietary fiber on gut microbiota is clearly established. It has been shown that fibers prevent liver injury depending of the type of fiber.In the current study, we addressed the role of fiber in the prevention of liver injury during a diet induced obesity (DIO) by adding fiber in a high fat diet (HFD). Then, we studied the role of IM in the protective effect of pectin in DIO mice. To this end, the IM from DIO mice treated with pectin was transplanted in DIO mice both before or after the development of obesity. Moreover, we analyzed the effect of the addition of pectin in a HFD pectin after the establishment of obesity. We were able to confirm the beneficial role of pectin in the pathogenesis of NAFLD. Pectin supplementation modulates intestinal microbiota composition and bacterial metabolites like short-chain fatty acids (SCFAs). Together, this actors influence the functionality of white and brown adipose tissues. In the future, the use of bacterial metabolites as SCFAs and specific probiotics could be proposed in the management of NAFLD in addition to dietary measures with fibers supplementation.La stéatose hépatique non alcoolique (NAFLD) est la manifestation hépatique du syndrome métabolique. Elle suit l’épidémie d’obésité et affecte un quart de la population mondiale. Son évolution croissante en fait un enjeu sociétal majeur tant d’un point de vue de santé publique que par l’impact économique qu’elle engendre. Actuellement, aucune thérapeutique n’est spécifiquement approuvée pour le traitement de la NAFLD. L’urgence est donc à la compréhension des mécanismes impliqués dans la pathogenèse de la NAFLD dans l’optique de développer des solutions thérapeutiques optimales. Le microbiote intestinal est un cofacteur primordial de la pathogenèse de la NAFLD et intervient dans la susceptibilité individuelle à la maladie. Le microbiote intestinal peut notamment être modulé par les fibres alimentaires telles que la pectine considérée comme prébiotique. L’objectif de ce travail était dans un premier temps d’asseoir les liens entre microbiote intestinal, pectine et l’impact sur les acteurs de la NAFLD dont le foie et les tissus adipeux. Dans un deuxième temps nous souhaitions évaluer si la modification du microbiote intestinal par la pectine suffisait à améliorer et restaurer les lésions hépatiques induites par un régime gras dans un modèle murin de NAFLD. A faible dose, une supplémentation en pectine atténue les lésions délétères induites par un régime gras chez la souris. L’effet protecteur de la pectine est liée à une modulation du microbiote. Cette modification impacte les fonctionnalités des tissus adipeux via la libération de métabolites bactériens dont les acides gras à chaîne courte (AAGC). Ce travail de thèse montre que le microbiote intestinal et ses métabolites sont une cible thérapeutique potentielle dans la stéatose hépatique non-alcoolique. L’utilisation des AAGC couplé à l’utilisation de probiotiques pourraient s’avérer des pistes intéressantes chez l’homme et ce en association avec des mesures diététiques visant à réintroduire des fibres alimentaires au sein du régime

Multikinase inhibitor-induced liver injury in patients with cancer: A review for clinicians

International audienceBACKGROUND: Multikinase inhibitors (MKI) are targeted molecular agents that have revolutionized cancer management. However, there is a paucity of data concerning MKI-related liver injury risk and clinical guidelines for the management of liver toxicity in patients receiving MKI for cancer are scarce. DESIGN: We conducted a PubMed search of articles in English published from January 2000 to December 2018 related to hepatotoxicity of the 29 FDA-approved MKIs at doses used in clinical practice. The search terms were the international non-proprietary name of each agent cross-referenced with «hepatotoxicity», «hepatitis», «hepatic adverse event», or «liver failure», and «phase II clinical trial», «phase III clinical trial», or «case report». RESULTS: Following this search, 140 relevant studies and 99 case reports were considered. Although asymptomatic elevation of aminotransferase levels has been frequently observed in MKI clinical trials, clinically significant hepatotoxicity is a rare event. In most cases, the interval between treatment initiation and the onset of liver injury is between one week and two months. Liver toxicity is often hepatocellular and less frequently mixed. Life-threatening MKI-induced hepatic injury has been described, involving fulminant liver failure or death. Starting from existing data, a description of MKI-related liver events, grading of hepatotoxicity risk, and recommendations for management are also given for various MKI molecules. CONCLUSION: All MKIs can potentially cause liver injury, which is sometimes irreversible. As there is still no strategy available to prevent MKI-related hepatotoxicity, early detection remains crucial. The surveillance of liver function during treatment may help in the early detection of hepatotoxicity. Furthermore, the exclusion of potential causes of hepatic injury is essential to avoid unnecessary MKI withdrawal

Gut Microbiota Reshaped by Pectin Treatment Improves Liver Steatosis in Obese Mice

Pectin, a soluble fiber, improves non-alcoholic fatty-liver disease (NAFLD), but its mechanisms are unclear. We aimed to investigate the role of pectin-induced changes in intestinal microbiota (IM) in NAFLD. We recovered the IM from mice fed a high-fat diet, treated or not with pectin, to perform a fecal microbiota transfer (FMT). Mice fed a high-fat diet, which induces NAFLD, were treated with pectin or received a fecal microbiota transfer (FMT) from mice treated with pectin before (preventive FMT) or after (curative FMT) being fed a high-fat diet. Pectin prevented the development of NAFLD, induced browning of adipose tissue, and modified the IM without increasing the abundance of proteobacteria. Preventive FMT also induced browning of white adipose tissue but did not improve liver steatosis, in contrast to curative FMT, which induced an improvement in steatosis. This was associated with an increase in the concentration of short-chain fatty acids (SCFAs), in contrast to preventive FMT, which induced an increase in the concentration of branched SCFAs. Overall, we show that the effect of pectin may be partially mediated by gut bacteria

Microbiota tryptophan metabolism induces aryl hydrocarbon receptor activation and improves alcohol-induced liver injury

International audienceObjective: Chronic alcohol consumption is an important cause of liver-related deaths. Specific intestinal microbiota profiles are associated with susceptibility or resistance to alcoholic liver disease in both mice and humans. We aimed to identify the mechanisms by which targeting intestinal microbiota can improve alcohol-induced liver lesions.Design: We used human associated mice, a mouse model of alcoholic liver disease transplanted with the intestinal microbiota of alcoholic patients and used the prebiotic, pectin, to modulate the intestinal microbiota. Based on metabolomic analyses, we focused on microbiota tryptophan metabolites, which are ligands of the aryl hydrocarbon receptor (AhR). Involvement of the AhR pathway was assessed using both a pharmacological approach and AhR-deficient mice.Results: Pectin treatment modified the microbiome and metabolome in human microbiota-associated alcohol-fed mice, leading to a specific faecal signature. High production of bacterial tryptophan metabolites was associated with an improvement of liver injury. The AhR agonist Ficz (6-formylindolo (3,2-b) carbazole) reduced liver lesions, similarly to prebiotic treatment. Conversely, inactivation of the ahr gene in alcohol-fed AhR knock-out mice abrogated the beneficial effects of the prebiotic. Importantly, patients with severe alcoholic hepatitis have low levels of bacterial tryptophan derivatives that are AhR agonists.Conclusions: Improvement of alcoholic liver disease by targeting the intestinal microbiota involves the AhR pathway, which should be considered as a new therapeutic target