September 6, 2011
The effects of HIV and highly active antiretroviral therapy [HAART] on gut health were highlighted recently at the 13th International Workshop on Adverse Drug Reactions and Co-Morbidities in HIV in Rome, Italy.
There were two gut-related presentations that I'd especially like to make note of: One was given by Collin Ellis on gut bacteria changes before and after HAART initiation. The other was given by Michael Dubé, M.D., on the effect of microbial translocation on metabolic and body shape measures.
I have a special interest in this topic because, like many of my HIV-infected peers, I have not had a normal bowel movement since I got infected with HIV -- that's before I even started antiretrovirals. Digestive issues such as bloating, soft stools and gas are some of the other main complaints among many of us. In my case, these problems have not improved much, even after switching to protease inhibitor/ritonavir (Norvir)-free antiretroviral combinations.
Ellis, from the University of California-Davis, explained that we house more than 100 trillion microbes, most of which are bacteria and reside in the gut (researchers in this area refer to it as the "gut microbiome"). A normal gut is host to vast quantities of "friendly" bacteria that actually protect the surface of the gut from inflammation and unwelcome pathogens. These bacteria also break down complex carbohydrates (polysaccharides) into fatty acids and amino acids, synthesize vitamins and comprise 10% to 15% of the nutrients absorbed by humans. They also prevent the overgrowth of harmful yeast and bacteria that can cause disease. A healthy gut has a variety of bacteria in a healthy balance. Disease, antibiotics and diet can affect this balance.
We have heard from previous reports that leakage of microbial products from the gut into the blood stream (called microbial translocation), as a result of damage to the wall of the gut caused by inflammatory responses to HIV, may be one of the major causes of the immune activation that drives immune dysfunction even when HIV viral load is controlled with antiretrovirals. When this leaky-gut problem occurs, circulating levels of microbial products in the blood, such as lipopolysaccharides (LPS) and bacterial DNA, may increase. LPS have been linked to immune activation and dysfunction, metabolic disorders, bone disease and obesity.
Not all species of bacteria in the gut have been identified because most cannot be cultured. However, through the application of next-generation sequencing technology such as pyrosequencing -- and, specifically, an approach called 16S ribosomal RNA gene-targeted sequencing -- Ellis and his team have been able to characterize bacteria to determine if there are any gut microbes (microbiota) that increase or are depleted in HIV disease. Interestingly, they found a large number of unidentified bacteria in the guts of HIV-infected patients -- bacteria that, importantly, comprised only a small proportion of the microbiota in seronegative subjects.
Stool samples and biopsies were obtained from 14 HIV-infected patients by upper endoscopy before and nine months after they initiated HAART. Three control patients without HIV were included.
Compared to the controls, pre- and post-HAART stools had greater proinflammatory gammaproteobacteria (GP). These bacteria can cause inflammation of the gut lining, gastrointestinal issues and may be associated with increased microbial translocation, although Ellis' team will be looking for further proof of that as they proceed with more studies. HAART provided little restorative effect to return the microbiota to a healthy profile.
The dominating bacteria in all samples were in the G(+) Clostridia and G(-) Bacteroidetes species. In one person, increased cyanobacteria (blue-green algae) was found prior to starting HAART. These blue-green algae appear to have anti-HIV activity; Ellis postulated that the increased population may be an adaptation by the mutualistic microbiota to try to fight HIV infection in the gut.
The second gut-related presentation was given by Michael Dubé from the University of Southern California's Keck School of Medicine. He performed a study to determine if microbial translocation products such as LPS and soluble CD14 levels (a marker of monocyte immune activation) increased metabolic and body changes (fat and bone) in HIV disease before and after initiation of HAART. He found no strong association between these two parameters and increased metabolic issues, with the exception of a trend toward increased visceral fat and triglycerides in patients on prolonged HAART.
So, at least in Dubé's preliminary study, microbial translocation does not seem to be driving body and metabolic-related changes before and after starting HIV antiretrovirals. However, the jury is still out about the role of microbial translocation in immune system senescence (i.e., aging of the immune system) caused by years of hyperactive immune response to microbial products that enter the blood stream from the gut.
Now that this field is getting some attention in HIV, I encourage researchers to perform studies to determine if giving prebiotic and/or probiotic supplements to HIV-infected people improves friendly gut bacteria diversity and decreases inflammation and immune activation.
I am definitely looking forward to more presentations in the future on this fascinating area of the relationship between our bodies' health and the trillions of microbes that we carry inside of us.