A Novel Probiotic with The Potential for Long-term Management of Obesity and Insulin Resistance

PROJECT SUMMARY/ABSTRACT: Obesity is a major public health problem in the United States. It is linked to insulin resistance and type 2 diabetes, two devastating diseases that affect millions of Americans. Current treatments for obesity have largely failed to achieve long-term success, highlighting the need for new, long-term sustainable strategies. Our goal is to develop a preventive and complementary nutritional intervention for obesity and its associated insulin resistance that is non-invasive, long-lasting, and low-cost. We are particularly interested in the potential of Clostridium cochlearium 2316 (CC), a proprietary bacterial strain that has demonstrated significant and consistent activities in reducing obesity and insulin resistance. CC is a spore-forming anaerobic bacterium that has been found in the gut of many mammals, including humans. Unlike certain known pathogenic Clostridium species, CC is considered safe for humans, as it is classified as a Biological Safety Level (BSL)-1 bacterium. Our preliminary studies have illuminated CC's potential. Dietary supplementation with CC led to substantial alterations in the gut microbiome and resulted in a 22% reduction in body weight gain among high-fat diet- induced obese (DIO) mice, all without impacting food intake. Moreover, CC intake led to a significant 47% reduction in insulin resistance and complete restoration of glucose homeostasis in obese mice. Notably, CC displayed no toxicity, and no traces of antibiotic-resistant genes or virulence factors were detected. These consistent findings substantiate the potential nutraceutical application of CC in obesity management. In this Phase I proposal, we are seeking support for critical toxicity and safety assessments of CC for long-term dietary interventions, as mandated for IND-required studies preceding clinical trials. Specifically, our aims are twofold: Aim 1: To elucidate the pharmacokinetics and pharmacodynamics of acute CC ingestion in DIO mice, a crucial step towards ensuring the safe and effective use of CC. Aim 2: To determine the long-term efficacy and safety of CC treatment in mitigating obesity and insulin resistance in DIO mice. These findings hold utmost importance as they set the stage for subsequent transformative research endeavors in clinical evaluation. Following the confirmation of its long-term safety and efficacy in this study, CC is poised to pursue FDA Generally Recognized as Safe (GRAS) status. Such a designation would enable CC's inclusion as a food ingredient or additive within legal bounds, thereby enabling its formulation as a dietary supplement. Our study will open a new avenue using a novel probiotic as a safe, low cost, and long-term sustainable dietary supplement/medical food for obesity management. This study is significant because it will not only provide mechanistic insights into how CC reduces diet-induced obesity, but will also provide long-term safety and efficacy data to be readily used for clinical trials to further confirm its effects on obesity and metabolic outcomes, which if shown to be efficacious, would have an immediate and strong impact on public health given the obesity epidemic in the United States.