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Evaluation of Endoscopic Bariatric Metabolic Therapies (EBMTs) in the setting of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): from human clinical trials to translational studies

par Hadefi, Alia
Président du jury Remmelink, Myriam
Promoteur Trepo, Eric
Co-Promoteur Garcia, Marie-Isabelle
Publication Non publié, 2024-10-21

Thèse de doctorat

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Résumé :

Metabolic-dysfunction associated steatohepatitis (MASH) is a progressive liver diseasethat can lead to advanced fibrosis, cirrhosis, and hepatocellular carcinoma. Weight loss remains a fundamental treatment for MASH, yet many patients struggle to achieve and maintain the significant weight reduction necessary for histological improvements. This challenge underscores the necessity to expand and diversify therapeutic approaches.Endoscopic bariatric and metabolic therapies (EBMTs) present promising alternatives,potentially effective through mechanisms that are both dependent and independent of weight loss. These therapies, encompassing interventions targeting the gastric or small bowel, could provide new avenues for treatment. Moreover, the gut-liver axis plays a crucial role in the onset and progression of MASH.Although much of the current understanding is derived from murine models, the specific molecular and cellular mechanisms at the gut epithelium level in humans remain largely unexplored. Investigating these mechanisms could be extremely valuable, offering insights that might lead to the discovery of novel gut-based therapeutic options for MASH. In this thesis, we aimed to evaluate several potential therapeutic strategies for MASH. Specifically, we focused on:i) Assessing the therapeutic potential of targeting the duodenum/jejunal mucosa to reduce insulin resistance, a key pathogenic component of MASH, and evaluating its viability as a treatment option.ii) Investigating whether gut epithelium homeostasis is disrupted in MASH by using the organoid model.iii) Exploring the effectiveness of endoscopic gastric remodeling (EGR) procedures that induce weight loss, to determine if they could serve as a viable treatment approach for patients with MASH.In the first part of this thesis, we sought to study the impact of an endoscopic duodenal mucosal resurfacing (DMR) procedure on patients with MASH. We found that this procedure was not associated with improvements in MASH resolution nor in metabolic parameters, such as glycated hemoglobin or insulin resistance markers, independently of weight loss. However, these parameters were improved in another study, including type 2 diabetes patients, that was associated with significant weight loss. Overall, there is still a knowledge gap in our understanding of the underlying mechanisms of action of DMR and also whether weight loss acts synergistically with DMR. One of the drawbacks of the DMR endoscopic procedure is the inhomogeneity of treated zones. Therefore, we also evaluated an alternative procedure for duodenal mucosal ablation using cold atmospheric plasma (CAP). CAP is a partially or totally ionized gas that exerts its cytotoxic effects and anti-tumoral activity through generation of reactive oxygen and nitrogen intermediates, and promotion of apoptosis. In this pre-clinical study, we used a mouse ex-vivo model to investigate whether an endoscopic helium CAP jet treatment was toxic to healthy tissues and to determine whether this treatment was potentially more effective on mouse tumor-derived organoids. Our results suggested higher CAP sensitivity in healthy cells as compared to tumoral organoid cells. However, further studies are needed to investigate whether this technique could be effective in decreasing insulin resistance and if this procedure would be safe in humans.In the second part of this thesis, we performed a pilot translational study that assessed the duodenal epithelium of biopsy-proven MASH patients. For this purpose, we also used the organoid model. We found that MASH-derived duodenal epithelial organoids (MDEOs) exhibited an altered digestive homeostasis characterized by transcriptomic, protein, and structural alterations of the intestinal barrier and deregulated lipid metabolism. However, no increased intestinal permeability was observed in MDEO susing FITC-dextran 4kDa and transepithelial electrical resistance investigations. Taken together, these findings provide evidence of persistent digestive alterations in MDEOs. Nevertheless, further studies are needed to confirm these results and assess how these alterations occur across the metabolic-dysfunction associated steatotic liver disease (MASLD) spectrum.In the final part of this thesis, we conducted a comprehensive systematic review andmeta-analysis assessing the benefits and potential risks associated with currently available EBMTs used for treating obesity. Although the majority of the included studies did not specifically assess the effect of EBMTs on MASH, analyzing critical endpoints such as percentage of total body weight loss provided substantial insights because weight loss is the most important predictor for improvement in obesity-related comorbidities such as MASLD/MASH.Overall, all of the medical devices used to perform these procedures were safe, and specifically EGR were associated with the most substantial weight loss sustained over time. However, the current evidence for the efficacy of EGR therapies in the setting of MASH is insufficient due to high heterogeneity in study designs. Therefore, we designed a randomized, controlled, multicentric trial (RCT) to evaluate whether using EGR,performed with the Endomina® device in addition to a hypocaloric Mediterranean diet, might improve liver histology one year after the treatment in biopsy-proven MASH patients. To date, 50 patients of the 100 planned to be enrolled have been included.In conclusion, our findings suggest that DMR procedure, in the absence of weight loss, appears to be inefficient for treating MASH. The mechanisms of action, particularly its impact on insulin resistance, remain unclear, indicating the need for further research to elucidate these processes. Considering alternative endoscopic procedure using CAP might be a promising approach. Nevertheless, future pre-clinical studies should focus on assessing the efficacy of CAP in reducing insulin resistance and confirming its safety profile.Moreover, the use of duodenal-derived organoids from MASH patients has revealed disruptions in digestive homeostasis, regardless of other confounding factors contributing to the disease, such as luminal nutrient and microbial content, and the surrounding stromal compartment. This pilot study validates this model as a valuable tool for deepening our understanding of gut-level alterations and testing the effectiveness of targeted interventions.Finally, the anticipated results from forthcoming results of our ongoing RCT will be crucial in determining whether EGR should be recommended as a viable treatment option for MASLD.