Editors' ChoiceInfectious Disease

HIV-associated anaerobes ferment TB risk

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Science Translational Medicine  10 May 2017:
Vol. 9, Issue 389, eaan3781
DOI: 10.1126/scitranslmed.aan3781

Abstract

Short-chain fatty acids produced by anaerobic bacteria increase the risk of TB in HIV-infected, antiretroviral drug–treated people.

HIV and tuberculosis (TB) are a lethal combination. One-third of deaths in people with HIV are due to TB, and HIV increases the risk of developing TB 20-fold. A major reason why HIV predisposes to TB is that it depletes CD4+ T cells, which are critical in maintaining control of Mycobacterium tuberculosis, the causative agent of TB. Even when treatment with antiretroviral therapy (ART) restores CD4+ T cell numbers, HIV-infected individuals remain at increased risk of TB; the continued immune dysfunction is not well understood.

Now, Segal and colleagues raise the interesting possibility that a third party is also involved. Recent work demonstrated that HIV-infected, ART-treated individuals have more anaerobic bacteria in their lower airways than uninfected people. Anaerobes produce short chain fatty acids (SCFA), such as butyrate, propionate, and acetate, as a byproduct of fermentation. In the gut, other studies have shown that SCFAs induce regulatory T cells (Tregs), an immunosuppressive population of T cells that can impair TB control. Segal and colleagues also show that butyrate inhibits lymphocyte production of interferon-γ (IFN-γ) and interleukin-17 (IL-17), key cytokines in controlling M. tuberculosis. Putting these pieces together, the authors hypothesized that lower airway anaerobes and their fermentation products might promote TB in HIV patients who are high-risk even though they are on ART. To test this, they followed a cohort of such individuals in South Africa and compared baseline characteristics in patients who developed TB with those who did not. Interestingly, increased TB susceptibility was associated with higher serum butyrate and propionate and reduced serum IFN-γ and IL-17. Samples from the lungs of HIV-infected individuals on ART also revealed elevated propionate, which was associated with an enrichment of anaerobes and induction of FoxP3-expressing Tregs.

These provocative findings will require validation in additional populations. Future investigation will need to evaluate whether the elevated serum SCFAs are from a pulmonary source and whether they play a causative role or reflect immune dysregulation. Nonetheless, these studies raise the intriguing possibility that oral anaerobes collude with HIV to increase TB risk and, furthermore, that prophylactic treatment might reduce that risk. It will be interesting to see whether anaerobes and their fermentation products also contribute to pulmonary infections in additional patient populations.

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