USA 2019 American National Call for Project

ANNUAL THEME

Microbiota-directed therapies in chronic intestinal disease

SUPPORTED PROJECT

Foundation_USA_national-grant

Dr Arpana Gupta, Regents University of California

Novel mechanisms and new pharmacological targets within the BGMI axis with the long-term goal of improving treatment strategies for MetS.

PROJECT DESCRIPTION

The prevalence of Metabolic Syndrome (MetS) and its complications continues to rise in the US and around the world. MetS is the biggest driver of preventable chronic diseases and has become one of the most expensive healthcare problems. Many of the MetS-associated adverse health outcomes can be prevented by early detection and treatment, mainly through changes in diet and exercise.

This proposal addresses questions of clinical and scientific importance as a way to overcome the current lack of effective and long-lasting treatment options for MetS by: 1. Using a systems biology approach to identify the interactions within the nervous system, the gut microbiome, the circulating metabolites, and the immune system (i.e. the brain-gut microbiome-immune axis, [BGMI]) in females with MetS. 2. Evaluating the efficacy of a fasting-mimicking diet (FMD; ProMet) intervention in reducing biological alterations within the BGMI axis in order to improve health outcomes such as disinhibited ingestive behaviors, appetite, cravings, and weight loss in females with MetS. This pilot study is limited to females since they have higher prevalence rates of MetS, gain more weight, and have difficulties implementing weight loss treatments. The proposal includes a data driven analysis in which changes in BGMI interactions will be measured in women with MetS on the FMD compared to age-matched women with MetS on the placebo diet.

The proposed research will generate insights into novel mechanisms and identify new pharmacological targets within the BGMI axis with the long-term goal of improving treatment strategies for MetS.

The lack of effective and long-lasting treatments for metabolic syndrome (MetS) can be attributed to various factors. For example, traditional drug-based MetS treatments are based on molecules that decrease appetite and/or energy expenditure, but this approach lacks sustained efficacy. Only a handful of FDA drugs are approved for weight loss and are regulators of hormonal satiety signals. However, these drugs induce only modest weight loss in a fraction of individuals and are associated with safety concerns that significantly limit their clinical use. In addition, most research in MetS has focused on one biological system (e.g. genetics, proteomics), so the goal of this application is to develop a systems biological understanding of brain-gut microbiome immune (BGMI) alterations in MetS. It is expected that the proposed studies will fill a void in knowledge about the underlying mechanisms associated with MetS in altering the BGMI axis at baseline and after a specified diet intervention.

The insights from these studies could offer a non-pharmacological and cost-efficient intervention that can be quickly and safely expanded once demonstrated to be safe, feasible, and effective in humans. Should the proposed studies be successful, could lead to a significant impact on clinical practice with the possibility of personalized therapies for individuals with metabolic syndrome, new biomarkers and diagnostic tests.

In summary, prior conducted studies, together with my future goals has allowed me to create a programmatic line of research, focused on investigating the bidirectional interactions between the brain and periphery (immune, metabolomics) and how those interactions are modified by vulnerability (early adversity, stress, socioeconomic status, diet, sex, race) and protective (resilience, exercise) factors in contributing to the underlying pathophysiology of ingestive behaviors, metabolic syndrome, and obesity. In order to provide new mechanistic insights into these disorders, large-scale computational pipelines and sophisticated bioinformatic analyses are needed. My research has begun to demonstrate the power of multivariate methods in characterizing and testing alterations in brain-gut microbiome alterations associated with these disorders, while accounting for the influence of psychosocial environmental factors, sex, and clinical data. Overall, this will result in a better understanding of the underlying mechanisms of metabolic syndrome, obesity and ingestive behaviors, and possibly identify specific targets for the development of a novel class of pharmacological and non-drug based treatments.