The Department of Defense has awarded a three-year, $2 million grant to Laura Nagy, PhD, and Carol de la Motte, PhD, staff members in the Department of Inflammation and Immunity, to evaluate how HA35, a small form of hyaluronic acid, may protect against obesity and Western diet-induced metabolic syndrome in preclinical models.
More than 7 in 10 veterans who receive care through the Department of Veterans Affairs are obese or overweight, which is a strong risk factor for complications of metabolic syndrome, including insulin resistance, type 2 diabetes, dyslipidemia, cardiovascular disease and non-alcoholic fatty liver disease. High risk for metabolic syndrome among this population underscores the significant need for novel prevention and/or treatment approaches.
Drs. de la Motte and Nagy previously identified HA35 as a potential therapeutic agent for intestinal bacterial infections and alcohol-associated liver disease. Alcohol-associated liver disease, like obesity and metabolic syndrome, is characterized by intestinal microbiome imbalance (dysbiosis) and impaired barrier integrity, which is known to have downstream effects on the immune system and cause chronic, low-grade inflammation (metaflammation).
“The results of our studies in preclinical models of alcohol-associated liver disease were promising, revealing a profound protective effect of HA35 on gut integrity and reduction of liver inflammation,” said Dr. Nagy. “The significant benefit we saw in that study strongly supports moving forward to test the therapeutic effects of HA35 in the context of metabolic syndrome, which shares a lot of disease pathology with alcohol-associated liver disease.”
This new study will explore if and how HA35 may protect against and/or treat the gut and liver injury, adipose (fat cell) inflammation and insulin resistance common of Western diet-induced obesity and metabolic syndrome. Gaining a mechanistic understanding of how HA35 may help to reduce inflammation and maintain intestinal integrity will be important in identifying therapeutic targets for treating obesity and pre-diabetes in patients.
“Just last year, results published from our early clinical safety study of HA35 showed dietary HA35 is safe and tolerable in lean and obese patients,” said Dr. de la Motte. “Should we see HA35 has benefits in preclinical models of obesity and metabolic syndrome, as well, the translation from this preclinical work to clinical studies in veterans will be fast tracked.”
Nagy and de la Motte began collaborating as a result of their shared interest in understanding inter-organ cross-talk between the gut and immune system, providing a dovetailing of expertise between Nagy’s research into preclinical models of metabolic liver diseases, including high fat diet- and ethanol-induced liver injury and de la Motte’s focus on preclinical models of colitis, hyaluronan biology and intestinal cellular physiology. The results of their National Institutes of Health-funded human study can be found here.
Image: In preclinical models, dietary HA35 transits through the intestine and induces anti-microbial peptide expression at colon epithelial cell surfaces. [biotinylated HA35 (green) and β-defensin (red), co-localized (yellow) as detected in proximal colon]