Nocca, D. | Search bioRxiv

bioRxiv2024

Obesity induces phenotypic switching of gastric smooth muscle cells through the activation of the PPARD/PDK4/ANGPTL4 pathway

ObjectiveClinical research has identified stomach dysmotility as a common feature of obesity. However, the specific mechanisms driving gastric emptying dysfunction in patients with obesity remain largely unknown. In this study, we investigated potential mechanisms by focusing on the homeostasis of gastric smooth muscle, using tissue samples from both patient and mice, as well as human cell culture system. DesignTissue samples were collected from patients who underwent sleeve gastrectomy for obesity, as well as from control subjects with standard weight who were undergoing treatment for gastric or esophageal carcinoma. Stomach tissues were harvested from mice after 12 weeks on a High-Fat Diet (HFD). Differentiated human gastric smooth muscle cells (SMCs) were treated with lipids, siRNA-peptide-based nanoparticles and/or pharmaceutical compounds. All experimental conditions were analyzed for their effects on SMC differentiation using stage-specific smooth muscle markers. Additionally, lipidomic and RNA sequencing analyses were performed on human gastric SMC cultures. The findings were assessed in patients with obesity to evaluate their clinical relevance. ResultsThe smooth muscle layers in gastric tissue from both patients with obesity and mice fed on a HFD exhibited altered differentiation status. Treatment of differentiated human gastric SMCs with lipids phenocopies these alterations and is associated with increased expression of PDK4 and ANGPTL4. Inhibition of PDK4 or ANGPTL4 upregulation prevents these lipid-induced modifications. Mechanistically, lipid treatment activates PPARD, which regulates PDK4 and ANGPTL4 upregulation, leading to SMC dedifferentiation. Notably, PDK4 and ANGPTL4 levels correlate with immaturity and alteration of gastric smooth muscle in patients with obesity. ConclusionObesity triggers a phenotypic change in gastric SMCs, driven by the activation of the PPARD/PDK4/ANGPTL4 pathway. These mechanistic insights offer potential biomarkers for diagnosing stomach dysmotility in patients with obesity.

physiology↗

bioRxiv2018

Laparoscopic Roux-en-Y gastric bypass profoundly changes gut microbiota compared to laparoscopic sleeve gastrectomy: a metagenomic comparative analysis

BackgroundBariatric surgery is an effective therapeutic procedure for morbidly obese patients as it induces sustained weight loss. The two most common interventions are Laparoscopic Sleeve Gastrectomy (LSG) and Laparoscopic Roux-en-Y Gastric Bypass (LRYGB).\n\nObjectiveCharacterizing the gut microbiota changes induced by LSG and LRYGB.\n\nDesign89 and 108 patients who underwent LSG and LRYGB respectively, were recruited from three countries: USA, France and Switzerland. Stools were collected before and 6 months after surgery. Microbial DNA was analysed with shotgun metagenomic sequencing (SOLiD 5500xl Wildfire). MSPminer, a novel innovative tool to characterize new in silico biological entities, was used to identify 715 Metagenomic Species Pan-genome (MSPs). 148 functional modules were analysed using GOmixer and KEGG database.\n\nResultsBoth interventions resulted in a similar increase of Shannons diversity index and gene richness of gut microbiota, in parallel with weight loss, but the changes of microbial composition were different. LRYGB led to higher relative abundance of aero-tolerant bacteria, such as Escherichia coli and buccal species, such as Streptococcus and Veillonella spp. In contrast, anaerobes such as Clostridium were more abundant after LSG, suggesting better conservation of anaerobic conditions in the gut. Function-level changes included higher potential for bacterial use of supplements such as vitamin B12, B1 and iron upon LRYGB. Moreover, after LRYGB, potential for nitrate and Trimethylamine oxidized (TMAO) respiration was detected.\n\nConclusionMicrobiota changes after bariatric surgery depend on the nature of the intervention. LRYGB induces greater taxonomic and functional changes in gut microbiota than LSG and may lead to a more dysbiotic microbiome. Possible long-term health consequences of these alterations remain to be established.\n\nSignificance of this studyO_ST_ABSWhat is already known on this subject?C_ST_ABSPrevious studies have reported changes of microbial composition after bariatric surgery with shotgun metagenomics, but lacked statistical power to document the changes. Important shifts in gut microbiome have been observed after LRYGB and LSG with an increase of aerotolerants from buccal microbiota. However, it is not clear how different the changes are between LRYGB and LSG although both procedures induce quite similar results with respect to weight loss, comorbidities remission and global glycaemic improvement outcomes.\n\nWhat are the new findings?LSG and LRYGB have specific but different impacts on gut microbial composition 6 months after bariatric surgery. The changes could be related to specific physiological effects. LRYGB promotes an important invasion of oral colonizers with Veillonella and Streptococcus genera. In contrast, these changes were less important after LSG. Moreover, microbial transportation potential of iron and vitamin B12 were also higher after LRYGB than LSG. We concluded that the type of surgery leads to different gut microbiome and functional profiles.\n\nHow might it impact on clinical practice in the foreseeable future?Microbiome composition and functional profiles are not altered to the same extent by LRYGB and LSG 6 months after surgery. This difference should be considered when advising the patient on the type of bariatric surgery or post op diet.

microbiology↗