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Study Reveals Nature of Gut Microbiome Shifts During HIV Progression

NEW YORK (GenomeWeb News) – Microbial communities in the human gut shift in response to HIV infection-related changes in intestinal immunity and inflammation, potentially reinforcing and contributing to some of these symptoms, a new study suggests.

As they reported online today in Science Translational Medicine, researchers from the University of California at San Francisco and elsewhere used array-based 16S ribosomal RNA gene profiling to profile gut microbial communities in dozens of men with or without HIV infection.

In the HIV-infected individuals, the team found gut microbial communities characterized by especially high levels of bacteria from the phylum Proteobacteria, as well as bugs capable of dismantling the amino acid tryptophan via a pathway previously linked to other aspects of HIV-associated gut inflammation. The disease-associated gut communities also showed a dip in representation by apparently beneficial bacteria from the Bacteroidia class.

The presence of certain members of the disease-associated gut microbiome seemed to correspond with HIV progression and the presence of other inflammatory symptoms in the gut, the team noted, even in individuals whose viral loads had been successfully suppressed with highly active antiretroviral therapy, or HAART.

"Although the mechanistic relationships defining the observed associations are not fully understood," UCSF researchers Susan Lynch and Joseph McCune, the study's co-senior authors, and their colleagues wrote, "a complex cross talk between gut immune states and the microbiome in the context of HIV disease progression and treatment is tenable."

"A re-envisioning of the pathogenic mechanisms associated with HIV disease progression may … include dysregulation of the balance between homeostasis-promoting versus gut barrier-disrupting microbes," they added, "contributing to weakened mucosal immune function, microbial translocation, and subsequent chronic infection."

Previous research has revealed a range of changes in the gut during progressive HIV infection, the study authors noted, from a waning barrier to infection by the intestinal mucosa itself to a rise in inflammation and immune T cell activity in the gut.

Such gut changes not only bump up the number of microbes that make their way from the intestine into the bloodstream, but also affect immune capabilities of the gut. For instance, some studies have described an HIV-associated jump in tryptophan breakdown through a so-called kynurenine pathway, which produces metabolites that interfere with the proper differentiation of certain T cells.

In a study published in Cell last fall, a Washington University and Beth Israel Deaconess Medical Center-led team presented a series of experiments that revealed a rise in gut viruses in rhesus macaques infected with simian immunodeficiency virus, as the SIV marched towards full-fledged AIDS.

Even so, there's still much to be learned about the microbial consequences and contributors to gut glitches in humans with HIV, authors of the latest study explained, especially since some of these gut symptoms can stick around even while some aspects of HIV infection are kept in check with HAART.

With that in mind, the team tested colon biopsy samples from half a dozen men with untreated HIV, 18 HIV-infected men who had achieved HIV viral load suppression while on HAART, and one individual with a long-term HIV infection that had not progressed. They also tested samples from nine risk-matched men who weren't infected with the virus.

With these samples, the researchers characterized microbial members present in each individual's gut community using Second Genome's G3 PhyloChip microarray, which targets variable stretches of the 16S rRNA gene. Blood samples from the same participants were also assessed to get a peek at the individuals' immune cell profiles.

"Because HIV disease is characterized by pronounced disruptions to mucosal immunity as well as a sustained chronic inflammatory state," McCune, Lynch, and colleagues wrote, "we sought to understand whether the gut microbiota is altered during HIV infection, and to assess relationships between these assemblages and characteristic immunological state of HIV disease progression."

In individuals with or without HIV infection, the investigators saw similar numbers of gut microbiome bacteria. But the identity of those bugs differed depending on infection status and other factors, they reported.

In general, gut communities from untreated men with HIV tended to have an over-representation of opportunistic pathogens and/or bacteria implicated in inflammation, obesity, and other disease states, for instance, including many representatives from the Proteobacteria phylum.

Compared to the HIV-negative individuals, the gut microbiomes in individuals from the untreated, HIV-positive group also showed lower-than-usual levels of bacteria from at least two potentially helpful bacterial genera.

Gut microbial community differences turned up within the group of HIV-positive men treated with HAART, too, the team found.

Though viral loads were under control in all of the participants in the HAART-treated group, some had gut microbial community profiles that were quite similar to those found in infected but untreated individuals, while others had gut microbiomes more closely resembling those who weren't infected with HIV at all.

Because certain microbes in the disease-related gut communities tended to coincide with not only disease progression, but also unusual tryptophan catabolism and the presence inflammatory markers in the blood, the study's authors speculated that there might eventually be a therapeutic benefit to tackling some of the troublesome intestinal features of HIV infection by targeting gut microbes.

"Further efforts to determine the mechanistic processes underlying the complex relationships between the gut microbiome and its host will be critical toward developing the potential of gut community modulation as a therapeutic strategy," they concluded, "and may lead to new approaches for the management of HIV disease as well as of other chronic inflammatory conditions."