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Changes in Gut Bacteria May Promote Inflammation and HIV Disease Progression

Changes in intestinal bacteria may contribute to disease progression and development of non-AIDS conditions in people with HIV, even those on effective antiretroviral therapy (ART), according to a report in the July 10, 2013, issue of Science Translational Medicine.

A growing body of evidence indicates that chronic HIV infection is associated with greater risk and earlier development of non-AIDS conditions such as cardiovascular disease, which are linked to persistent inflammation and ongoing immune activation.

Ivan Vujkovic-Cvijin, Susan Lynch, Joseph McCune, and colleaguesfrom University of California at San Francisco compared populations of gut bacteria in treated and untreated people with HIV infection and healthy HIV negative individuals.

HIV infection is characterized by dysregulation of the intestinal immune barrier and translocation -- or spilling out of the gut -- of bacteria and microbial products that stimulate ongoing immune activation and a state of chronic systemic inflammation, the researchers noted as background.

"We thought the gut microbiome might be different in HIV-infected individuals, and that the high degree of immune activation in the patients might be associated with and possibly due to the presence of specific members of the bacterial community," Lynch explained in a UCSF news release.

The authors collected rectal tissue biopsy samples from 6 untreated HIV positive people with active infection, 1 HIV positive long-term non-progressor, 18 people with HIV on ART with undetectable plasma viral load and varying degrees of immunological recovery, and 9 HIV negative individuals matched for other health risks. All were men.

Results

• Total levels of intestinal bacteria were similar regardless of HIV status.
• High-resolution bacterial genetic profiling identified "a dysbiotic mucosal-adherent community," or abnormal population of bacteria on the intestinal mucosa, in untreated HIV positive individuals, which contained more Proteobacteria but fewer Bacteroidiaand Clostridia species.
• In particular, people with HIV had more pro-inflammatory and opportunistic bacteria including Salmonella, Escherichia (i.e., E. coli), Serratia, Shigella, Klebsiella, Staphylococcus, Pseudomonas, and Campylobacter species.
• Bacterial "dysbiosis" was evident even among HIV positive people on suppressive ART.
• Changes in bacterial populations in people with HIV were not strongly associatedwith CD4 T-cell counts or levels of HIV RNA or DNA in the gut.
• However, these changes were associated with elevated T-cell activation, mucosal disruption (including levels of indoleamine 2,3-dioxygenase, an enzyme that can impair the gut's ability to act as a barrier), and plasma biomarkers of inflammation.
• Among HIV positive people on ART, the extent of dysbiosis correlated with tryptophan catabolism through the kynurenine pathway and plasma concentrations of the inflammatory cytokine interleukin 6, which are 2 established markers of disease progression. 

"These observations demonstrate a link between mucosal-adherent colonic bacteria and immunopathogenesis during progressive HIV infection that is apparent even in the setting of viral suppression during [ART]," the authors concluded. "This link suggests that gut-resident microbial populations may influence intestinal homeostasis during HIV disease."

These findings point to a vicious cycle in which gut inflammation leads to bacterial abnormalities, which in turn promote chronic systemic inflammation, as previously seen in mice.

The researchers do not believe there is a single bacterial species responsible for disrupting intestinal integrity, nor do they propose specific probiotic therapies to restore a healthy gut, according to the UCSF release, though Lynch said manipulating bacterial populations is a promising idea.

"It appears that changes in the microbiome perpetuate a vicious cycle that drives inflammation in HIV-infected patients," she said. "We are considering a restoration ecology approach to restore appropriate microbial colonization patterns and healthy functioning of the gut microbiome."

"Our dream is to be able to make the virus go away, allowing HIV-infected people to lead longer lives without the need for life-long therapy," McCune added. "Perhaps restoring the microbiome to normal will be one strategy to make that happen."

7/24/13

Reference

I Vujkovic-Cvijin, RM Dunham, S Iwai, JM McCune, et al.Dysbiosis of the Gut Microbiota Is Associated with HIV Disease Progression and Tryptophan Catabolism. Science Translational Medicine 5(193):193ra91. July 10, 2013.

Other Sources

J Norris. Intestinal Bacteria May Fuel Inflammation and Worsen HIV Disease. UCSF news. July 10, 2013.

AAAS. Gut Microbes May Worsen HIV. Science Translational Medicine press package for 10 July 2013.