Bacteria in our gut affects HIV—is there a solution?

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BETA is reporting from the 2016 Conference on Retroviruses and Opportunistic Infections (CROI) this week in Boston—bringing you the latest news, updates, and research on HIV treatment and prevention.

Across our bodies—on our skin, in our mouth and nose, inside our intestines, on our genitalia, and in other places—colonies of microorganisms flourish. We call these colonies of bacteria, viruses and fungi that live in and on our bodies the microbiota, or the microbiome. The largest microbiome colony lives in our gastrointestinal tract—our gut—and in healthy people, helps us do things like digest carbohydrates, produce vitamins and prevent harmful pathogens from flourishing. When there’s a disruption to our gut microbiome, problems can arise.

Now, researchers are investigating how HIV and the microbiome are linked. At CROI 2016, and at a recent San Francisco General Hospital HIV Grand Rounds presentation, research was presented about how HIV and other things change the gut microbiome—and if things like fecal microbial transplantation and probiotics can make it healthy again.

A bit of background about the microorganisms in our gut

A huge variety of bacteria, viruses and fungi take up residence in the mucous linings of our gastrointestinal tract starting from the time we’re born. Our diet, lifestyle and environment play a huge role in the type and diversity of microorganisms that a find a home in our gut. For instance, infants who are breastfed develop different gut microbiomes than those fed on formula. In general, people develop a gut microbiome “steady-state” that’s normal, healthy and functions without issue. That’s why we don’t notice the estimated three extra pounds of microorganisms that we carry around with us every day.

Things that disrupt a healthy microorganism balance can cause problems. Antibiotics—used to kill off disease-causing pathogens—also kill off healthy gut bacteria. When this happens, disease-causing bacteria have the opportunity and real estate to set up shop in our gut. The bacteria C. difficile, which is sometimes spread in hospitals and other healthcare settings, can cause life-threatening illness in people whose gut microbiomes are destroyed by antibiotics.

A change in diet, lifestyle factors, and infection—including HIV—can also change the composition of your microbiome.

How HIV changes the gut microbiome

“We know that HIV-positive people not on antiretroviral therapy have different gut microbiomes than people who are HIV-negative,” said Ma Somsouk, MD, MAS, an associate professor at the University of California San Francisco during a San Francisco General HIV grand rounds presentation. Here’s why.

CD4 cells in the gut are more susceptible to the HIV virus than CD4 cells circulating in the blood because a larger percentage of gut CD4 cells have a protein on their surface, called CCR5, that the virus can use to bind and enter the cell. One type of CD4 cell in the gut that HIV enters and kills off, called Th17 cells, normally work to maintain the intestinal barrier and control intestinal bacteria. Destruction of these Th17 CD4 cells by HIV leads to something referred to as “microbial translocation”—the leaking of harmful bacterial products into the blood stream.

While the total number of gut bacteria doesn’t differ between HIV-negative and HIV-positive people, the composition of the microorganisms changes with HIV infection.

At CROI, Jesus Luevano, from Ragon Institute of MGH, MIT and Harvard shared results from a study of the microbial communities analyzed from fecal samples in 137 participants. His team found samples taken from people with HIV tended to have higher proportions of a type of bacteria called Prevotella and lower proportions of a type of bacteria called Firmicutes. In addition, Luevano shared that samples taken from HIV-negative participants had greater bacteria “richness” (or greater diversity in the types of bacteria that were detected).

Differences in men who have sex with men

Muntsa Rocafort, from IrsiCaixa Institute for AIDS Research, presented an unexpected finding at the CROI microbiome session. In her study, men who have sex with men (MSM) had distinct microbiomes from other men. Fecal samples from the MSM in her team’s study had higher proportions of Prevotella, while other men had higher proportions of Bacteroides. This was true for both HIV-negative and HIV-positive men in the study.

“We didn’t expect these results,” said Rocafort. “So it was quite surprising for us to find this difference between MSM and non-MSM. We did not have a specific variable that measured sexual practices, so we don’t know the mechanism [that was responsible for this effect].”

What are the consequences?

Some people with HIV on antiretrovirals regain a normal gut microbiome, but many do not. Luevano reported that among his study participants, the microbiomes of people with HIV changed, even if they were on antiretroviral therapy.

Some scientists think that an altered gut microbiome may contribute to the inflammation that people living with HIV experience, since studies have found that people with HIV who have altered gut microbiomes are more likely to have higher levels of inflammatory markers such as IL-6 in the blood. While these findings suggest a relationship, more research is needed to determine if the gut microbiome is responsible for the increased inflammation seen.

Stephanie Dillon, PhD, of University of Colorado Anschutz Medical Campus, presented research at CROI showing a possible link between the gut microbiome and a worsening of HIV disease. She found that some gut bacteria—notably, the type of bacteria found in higher proportions in people living with HIV—can impact the infectiousness of immune system cells.

She found that gram-negative bacteria enhanced CCR5 expression (a protein on the surface of CD4 cells) which can increase the ability of HIV to actively infect immune system cells. “It suggests that this might be a novel mechanism which potentially links the intestinal microbiome to HIV associated mucosal pathogenesis.”

“Really, we don’t know [if the altered microbiome of people with HIV causes health consequences],” said Somsouk. “But there are some observations that suggest increased inflammation depending on the microbial community that you harbor.”

New treatment approaches

Ingesting probiotics is a direct way to change the gut microbiome and improve health. Probiotics containing strains of Lactobacilli are a common therapy that may help decrease inflammation in the gut. One study, with 30 men living with HIV on antiretroviral therapy, found that drinking one bottle of fermented milk with the probiotic Lactobacillus casei Shirota twice a day for four weeks increased T cells, and decreased the level of inflammatory markers.

Jennifer Manuzak, from the University of Washington, presented results at CROI from a macaque study with a probiotic treatment that lasted for 80 days. The probiotic treatment appeared to enhance immune system functioning in the macaques (who were also infected with a virus similar to HIV). After 28 days, immune system cells (B cells and T follicular helper cells) increased in the colon and lymph node.

A more complicated therapy, called fecal microbial transplantation (FMT), involves taking a fecal preparation from a healthy donor and transplanting it into the colon of another person. The theory is that the “healthy” microorganisms in the sample from the donor may populate the gut of the other person.

Dr. Somsouk said his research has focused on determining if this method is safe for people with HIV, if it works to change the unhealthy microbial community, and if this can reduce HIV-related inflammation. In a small pilot study, he delivered FMT by colonoscopy to six people living with HIV and took multiple follow-up measurements 1, 2, 4, 8 and 24 weeks afterward.

None of the participants experienced any serious adverse events, and the transplants modestly altered the compositions of the microbial community. “The recipient microbial community drifted towards the donor community,” said Somsouk, “but it did not move very much.”

He did not find any evidence that the FMT procedure reduced inflammation. Next steps, he said, include improving the “engrafting” procedure that’s part of FMT, and seeing if effects can be enhanced with antibiotics or FMT in the form of oral pills.

“There has been much interest in the role of the microbiome, but anecdotes and hopes related to the role of the microbiome in health and disease need to be supported by evidence,” he concluded.

Selected sources:

Dillon, S. Altered gut microbes enhance mucosal CD4 T cell infection and depletion ex vivo. CROI, 2016. Session TD-8.

Falasca, K. and others. Effect of probiotic supplement on cytokine levels in HIV-infected individuals: A preliminary study. Nutrients. 2015.

Lozupone, C. A. and others. Alterations in the gut microbiota associated with HIV-1 infection. Cell Host Microbe. 2013.

Luevano, J. Impact of HIV-associated changes in the gut microbiome on disease progression. CROI, 2016. Session TD-8.

Manuzak, J. Enhancement of microbiota in macaques leads to beneficial immune function modulation. CROI, 2016. Session TD-8.

Pop, M. We are what we eat: How the diet of infants affects their gut microbiome. Genome Biology. 2012.

Rocafort, M. Distinct gut microbiota composition in gay men. CROI, 2016. Session TD-8.

Somsouk, M. Fecal microbial transplantation: Safety and engraftment during treated HIV infection. CROI, 2016. Session TD-8.

Vyboh, K. and others. HIV and the gut microbiota, partners in crime: Breaking the vicious cycle to unearth new therapeutic targets. Journal of Immunology Research. 2015.