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Dr. Cristoforo Silvestri's projects

Here you will find all the projects on which Dr. Cristoforo Silvestri and his team are working.

Northern populations have an increased incidence of vitamin D deficiency and use of antipsychotic drugs. Both vitamin D status, mental health disorders and subsequent use of antipsychotic drugs are associated with alterations in the gut microbiome: commensal microbes that are critical to several aspects of health, especially metabolic health. Gut microbiome alterations associated with vitamin D deficiency and antipsychotic drug use correlate with the development of aspects of metabolic syndrome such as weight gain and glucose and lipid dysregulation. However, how pre-existing perturbations of the gut microbiome, such as those associated with vitamin D deficiency, modulates the onset/severity of antipsychotic drug metabolic side effects is not known. Further, vitamin D supplementation seems to mitigate these side effects, though the role of the gut microbiome in this remains to be determined. We will examine the effects of vitamin D status (deficiency or supplementation) and antipsychotic drug exposure on the gut microbiome and the development of metabolic perturbations in a rodent model, with the eventual aim of developing microbiome-based regimens to counter antipsychotic drug metabolic side effects.

The endocannabinoidome system (ECBome) and gut microbiome (µB) dysregulation is a key player in the pathology of white adipose tissue expansion, inflammation and obesity. We study the underlying molecular mechanisms of the anti-adipogenic ECBome mediator prostamide F2α, and the effects of dysbiotic µB endotoxic bacterial wall component LPS on this system in white fat. We utlize murine cellular models and human adipose tissue explants.

This project is being carried out in collaboration with Nature's Decision, a Quebec-based leader in hemp production, and is supported by a Mitacs grant. With a shift from traditional to modern life-styles, there is an increasing consumption of mass produced foods, which has shifted the balance of omega-3 and omega-6 fatty acids and is associated with poor cardiometabolic health. Whole hemp (Cannabis sativa) seeds are of exceptional nutritional value, being very rich in essential fatty acids (EFAs) and other polyunsaturated fatty acids (PUFAs), high quality protein and fibre. Hemp seeds represent a potentially important food crop for northern populations that may impart healthful benefits to those who consume it, especially to individuals with low consumption rates of omega 3 fatty acids and fiber.  We are assessing the effects of dietary supplementation of whole hemp seeds on the development of obesity and related complications in a diet-induced obesity mouse model and determine its effects on the gut microbiome-endocannabinoidome axis.

This project will test the effectiveness of natural extracts on inflammation using the DSS model of colitis and to determine the relationship with the endocannabinoidome. The ultimate goal is for SiliCycle to better understand the biological potential of its products.

The bidirectional comunication between the brain and the gut microbiota, named "microbiota-gut-brain axis" comprises small molecule messaging systems to update health status and possibly regulate brain activity and behavior. Among the underlying molecular mechanisms of this cross-talk, we hypothesize a possible role for the endocannabinoidome (eCBome) which has important functions in neuronal activity, metabolism and immune response. We are therefore utilizing germ free mice, which have never had microbial colonization, as a tool to parse the link between microbiota and the eCBome in gut-brain signaling and examinging the effect of introducing a functional microbiome through fecal microbiota transfer (FMT) to gain evidence of crosstalk with the eCBome and its potential involvement in neurobiology of the brain psychiatric conditions such as anxiety- and stress-related disorders.

The Liver-expressed antimicrobial peptide 2 (Leap2) encodes a 40 animo acid peptide that was recently found to be upregulated after a vertical sleeve gastrectomy and acts as an endogenous antagonist of the ghrelin receptor. Mainly known for its antimicrobial activity, the physiological function and mechanism of action is not well understood. Ghrelin is an orexigenic hormone that regulates food intake through the endocannabinoid system (ECS). The ECS and its extension, the endocannabinoidome, are important in the regulation cardiometabolic health and metabolism, which are dysregulated in obesity. The gut microbiome is also altered in association with obesity. Studies suggest that eCBome molecules and gut microbiota bidirectionally influence each other, with implications in energy balance and cardiometabolic health. Given the interconnection, we hypothesize that Leap2 is dysregulated in obesity, dysbiosis and in metabolic endotoxaemia, perhaps via the eCBome signaling. To assess to our hypothesis, we use hepatocyte, intestinal cell lines and intestinal organoids treated with phamracological modifiers of eCBome related receptors and enzymes to see the possible role of the ECS in regulating Leap2, investigate its expression in the liver and small intestine of mice lacking of microbiota as well as those fed with an obesogenic diet and  in rats that undergo different bariatric surgeries.

This project is carried out in colaboration with Paul De Koninck of CERVO. The gut microbiota, through the gut-brain axis is believed to influence locomotion, stress, feeding behavior, and some neurological diseases. This project aims to better understand the communication between the dopaminergic system and the endocannabinoidome system (eCBome) and their role in regulating the gut-brain axis. By modulating the eCBome in zebrafish under different microbial conditions (i.e. conventionally raised, germ-free, and microbially reconstituted), we aim to examine interactions between these systems and their effects on behavior, metabolic activity and their pathological malfunctioning.