R01DK131581

Project Summary/Abstract

Metabolic Syndrome (MS), characterized by a cluster of conditions including dyslipidemia, central abdominal obesity, insulin resistance, and high blood pressure, is prevalent in people living with HIV (PLWH), and puts them at greater risk of cardiovascular events. MS and related metabolic derangements have been strongly correlated with gut microbiome activity outside the context of HIV but has not been deeply explored in HIV infected or uninfected men who have sex with men (MSM), who have a highly altered gut microbiome composition.

Intestinal dysbiosis, compromised intestinal barrier integrity, and associated inflammation have been linked with MS in certain populations, but whether this is a driving factor of high levels of MS in HIV+ MSM has not been deeply explored, even though increased bacterial translocation and associated systemic inflammation is known to occur in PLWH.

In our ongoing studies of factors that influence metabolic disease across HIV+ and HIV negative MSM, we found elevated plasma lipopolysaccharide binding protein (LBP) to be the most important predictor of poor metabolic health, with network analysis showing that LBP formed a hub joining correlated microbial and immune predictors of poor metabolic health. Our results suggest a central role of inflammatory processes linked with barrier dysfunction in the development of MS in HIV+ MSM, but further mechanistic studies are needed to fully understand how barrier function is compromised, including a potential role for gut bacteria and bacterial-derived metabolites, which are well known to influence barrier.

One key finding of our ongoing work was a negative correlation between plasma LBP levels and butyrate-producing bacteria; butyrate has a well-characterized protective influence on intestinal epithelial integrity. We also observed a positive correlation between LBP and a microbe that degrades sialic acids on mucus glycoproteins, which has also been linked with intestinal barrier dysfunction and inflammatory processes in PLWH previously.

Thus, we hypothesize that intestinal dysbiosis impacts gut barrier function in HIV+ MSM, and that this promotes MS via the translocation of microbial products including LPS. To test this hypothesis, we will perform three coordinated specific aims.

In Aim 1, we will determine whether intestinal barrier dysfunction is higher in HIV+ and negative MSM with MS compared to without MS and related to deficiency in butyrate-production and/or activity of mucolytic bacteria in the gut microbiome.

In Aims 2 and 3, we will verify the relationship between HIV/MS-associated gut microbes and barrier dysfunction using enteroids and gnotobiotic mice, and explore the role of microbial production of butyrate and degradation of mucus glycoproteins in these processes.

Taken together, this work will produce a mechanistic understanding of the relationship between gut microbiome dysbiosis, barrier function, and MS in HIV-infected individuals and will have broader implications as well, since intestinal barrier dysfunction has been linked with chronic inflammation and many associated co-morbidities in PLWH.

The Regents Of The University Of Colorado

NOT APPLICABLE

93.847 - Diabetes, Digestive, and Kidney Diseases Extramural Research

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [HHS - NIH]

Aurora, Colorado 800452537 United States

Single Zip Code

Toward ElucidAting MechanismS of HIV Pathogenesis within the Mission of the NIDDK (Pathogenesis TEAMS) (R01 Clinical Trial Optional) (RFA-DK-20-022)

Amendment Since initial award the total obligations have increased 396% from $690,739 to $3,426,065.