Dottore di ricerca

ciclo: XXXIV

Titolo della tesi: “Obesity and post-bariatric surgery: searching for predictive biomarkers”

Abstract Background: Obesity and metabolic disorders are multifactorial diseases resulting from the interaction between genetic and environmental factors. A systemic low grade of chronic inflammation, oxidative stress and mitochondrial dysfunction are the main common traits in obese people. In the last years, the relationship between gut microbiota and obesity has been extensively documented. Both animal and human studies have highlighted the role of the gut microbiota and its functional products as environmental factors able to modulate the energy harvest from the diet and fat storage affecting the host metabolism. While lifestyle modifications, a combination of diet, physical activity and behavior therapy are the cornerstones of weight management and prevention of cardiovascular risk factors, these are usually not enough to treat severe obesity, especially to prevent the obesity-related comorbidities onset. In this case, bariatric surgery seems to be the most effective tool in weight loss and reduction of risk of metabolic syndrome development. Several studies, carried out both in animal models and in humans, have shown that bariatric surgery can modify the gut microbiota leading to a “healthier” community. The oral microbiome is the second most complex microbial community in the human body and plays an important role in maintaining a normal oral physiological environment, thus affecting the host health. Nevertheless, the molecular mechanisms that underlie this positive impact of bariatric surgery on the clinical and metabolic profile of morbid obese subjects are still unknown. Materials and methods: In our longitudinal study, 36 severe obese subjects (mean body mass index, BMI= 44.3) who underwent bariatric surgery and subsequent weight loss (mean BMI= 29.8), were enrolled. Stool, saliva and blood samples were collected pre-surgery and up to 1-year post-surgery. A complete panel of clinical and anthropometric parameters has been collected during the follow up. The gut and oral microbiota have been analyzed by 16S rRNA metagenomics sequencing in stool and saliva samples, respectively. The gene expression levels of Sirtuin 3 (SIRT3), the transcriptional co-activator peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1-α) and the dynamin-related protein 1 (Drp1), as mitochondrial molecular players, have been analyzed by real time (RT-PCR) in peripheral blood samples and the mitochondrial DNA copy number (mtDNA-CN) in peripheral blood mononuclear cell (PBMC) has also been measured by droplet digital PCR (ddPCR). All these analyses have been carried out at the different time of the follow up. Results: The beneficial effect of the bariatric surgery is testified by a significant recovery of a normal clinical profile also associated to the decrease of the anthropometric parameters. A reduction of plasmatic levels of interleukin-6 (IL6), C-reactive protein, tumor necrosis factor‐alpha (TNF-α), C-peptide and leptin has been also observed confirming that the intervention is able to reduce the inflammatory status of treated subjects. These changes are associated to a reduction of several obesity-related comorbidities. The 16s metagenomics studies show a significant increase of alpha and beta diversity and specific changes of microbial composition leading to the restoration of eubiosis. The molecular analysis of mitochondrial players shows a higher expression level of SIRT3, PGC1-α and Drp1 both after six (T1) months and one year (T2) after the intervention. Lastly, a significant reduction of mitochondrial DNA copy number (mtDNA-CN) at the end of the follow up is also observed. Discussion and conclusion: The clinical-anthropometric healthier profile associated to the gut eubiosis and the restoration of the mitochondrial homeostasis, observed in our cohort after bariatric surgery, strongly suggest a potential microbiota-mitochondria interplay. Interestingly, a bidirectional crosstalk between gut microbiota and mitochondria have been recently proposed. Gut microbiota, by its metabolites, modulates the gene expression levels of proteins implicated in the mitochondrial biogenesis and metabolism as well as the mitochondria concur to guarantee redox balance and gut barrier integrity. This study, focused on the association between gut/oral microbiota and mitochondrial function, explores the potential use of mitochondrial players as key biomarkers for the development of therapeutic strategies to prevent obesity-related comorbidities.

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