Highly active antiretroviral therapy (HAART) has become so efficient that it leaves HIV-infected people with undetectable viral loads, allowing them to lead almost normal lives. Their lifespan, however, is still about ten years shorter than that of uninfected people. One major reason for this is that they suffer from chronic inflammation, much of it due to poor gut health, which can result in the translocation of bacteria into the blood.
Now a study suggests that probiotics, the harmless bacteria found in foods like yogurt, can improve gut immunity in pigtail macaques on HAART that are infected with simian immunodeficiency virus (SIV), the monkey equivalent of HIV (J. Clin. Invest. doi:10.1172/JCI66227). The study, led by Jason Brenchley of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health in Bethesda, Maryland, shows that when such animals are given probiotics, they have less inflammation-induced scarring and more CD4+ T cells and antigen presenting cells in their gut than animals treated with HAART alone.
“It’s the first study where the effects of probiotics have been looked at in SIV-infected nonhuman primates,” Brenchley says. Previous studies in HIV-infected humans have shown that probiotics modestly boost the number of CD4+ T cells in the blood, but this is the first that shows such an effect on the gastrointestinal (GI) tract. If the findings hold true in humans, Brenchley says, probiotics could be used to reduce the chronic inflammation-related mortality in HIV-infected individuals on HAART.
Brenchley and colleagues infected 11 pigtail macaques with the SIV strain mac239. A hundred days later, they began giving seven of them a twice-daily pill containing a cocktail of nine different probiotic strains, which have been shown to improve gut health in humans with other diseases where microbial translocation is thought to play a role, such as Crohn’s disease. Sixty days later, the researchers put all 11 animals on a five-month-long ART regimen, which reduced viral replication to undetectable levels below 50 copies per milliliter blood in all but one animal.
At the end of the five-month-long ART, they checked for any differences between the animals treated with ART and probiotics and with ART alone. One of the earliest and most dramatic effects of SIV and HIV infection is the depletion of CD4+ T cells in the GI tract, and it was there where the probiotics had the most pronounced effect. Animals treated with ART and probiotics had more than twice as many CD4+ T cells (about 80% of healthy levels), compared to animals that received ART alone. “I was quite surprised to see the significant reconstitution of CD4+ T cells,” Brenchley said, adding that even in humans who have been on HAART for years, any rise in CD4+ T cell numbers in the gut is very difficult to achieve. “I think that was better than anything we were hoping for.”
The GI tract of the animals treated with ART and probiotics also contained about 30% more antigen presenting cells (APCs), which are also depleted by SIV and HIV infection. These additional cells likely include those that induce Th17 cells, a subset of CD4+ T helper cells that are important for antibacterial defenses and the maintenance of the structural barrier of the GI tract. Brenchley now plans to examine which types of APCs are more common in the animals treated with probiotics, and whether these additional APCs really induce more Th17 cells in the gut of these animals.
The animals treated with probiotics and ART also had only half the amount of inflammation-induced fibrosis (scar formation) in the lymphoid tissue surrounding the gut, Brenchley said. This change could make it easier for immune cells to enter the GI tract and interact with each other to improve immune responses, and could explain the larger number of CD4+ T cells and APCs in the animals treated with probiotics.
The probiotic treatment had a less pronounced effect in the blood, resulting in only a slight reduction in chronic inflammation markers, and no difference in markers of bacterial translocation. One possible reason, Brenchley says, is that changes in the blood are harder to measure than changes in the GI tract. “There is more noise,” he says, adding that a longer study and a larger experimental cohort of monkeys might better elucidate effects in the blood.
In a commentary that appeared in the same journal, Martin Wolff, Michael Poles and Judith Aberg of the New York University School of Medicine, who were not involved in the study, call the results “intriguing.” Should further research support its findings, they add, “the use of probiotics may be an inexpensive, noninvasive, and generally well-tolerated adjunctive treatment for HIV.”
Indeed, Brenchley says, all studies so far have shown that the probiotics used in the study are safe for human use. What’s more, they can be easily bought in the supermarket or online, and a treatment similar to the one used in the study just costs a few dollars a day. Still, further studies are needed to find out which bacterial strains are the most effective. “There are hundreds of formulations of probiotics, and every maker of a probiotic strain claims that theirs is the best,” he says.