Maternal HIV infection influences the microbiome of HIV-uninfected infants

We read with great interest the recent publication by Bender et al; ”Maternal HIV infection influences the microbiome of HIV-uninfected infants” 1. As HIV-uninfected infants born by HIV-infected mothers have twice the mortality of matched unexposed infants, identifying potential triggering factors is of utmost importance. The microbiome could be one such factor, as the infant microbiome is to a large degree inherited from the mother.
The authors report that HIV-uninfected infants born by HIV-infected mothers have a dysbiotic gut microbiome, with reduced biodiversity compared to the microbiome of unexposed infants. Interestingly, they find the lowest alpha diversity in infants delivered by the mothers with the lowest CD4+ T cell count, and those with a detectable viral load despite antiretroviral therapy (ART), suggesting a link between infant dysbiosis and maternal immunodeficiency. The authors also propose a link to differences in the composition of the mothers' breast milk.
These findings are of potential interest from a translational perspective, strengthening the case of dysbiosis as a potential driver of immune dysfunction, and also from a clinical perspective, as the gut microbiome is a potential therapeutic target. Hence, the interpretation of these data is important, and we would like to add some potentially contributing factors to the discussion.
1. Mode of delivery. Although not significantly different (p=0.10), there was a numerical increase in caesarean section (24%) in the HIV-exposed group compared to the non-exposed group (4%). An effect of mode of delivery on gut microbiome is generally observed at least up to 6 months of age, strongest at earliest stages 2. Reduced alpha diversity has been observed after caesarean section 3, suggesting that mode of delivery in part could be a confounder, along with a stronger contribution of vaginal microbiome to the stool microbiome in the HIV-unexposed group and stronger contribution of areola microbiome (skin) in the exposed group.
2. The gut microbiome of the mother. As discussed by the authors, stool microbiome of the mother was unfortunately not investigated. During the first year, the gut microbiome of infants become increasingly similar to the gut microbiome of their mother's 4. It could be speculated that a significant proportion of the "unknown" source of the infants' stool microbiome (>70%, Figure 4b) could be the mother's gut. Importantly, low diversity of gut microbiome has been reported in several HIV cohorts, in part associated with immune dysfunction and use of ART 5-9 . The authors discuss maternal ART as a contributing factor, and it is noteworthy that we reported decreased alpha diversity and reduction in Prevotella few months after ART initiation 7, the same findings as reported in HIV-exposed children in the present study.
3. Infant factors. The gut microbiome of the infant during the first year is highly dynamic. The differences in median age at sampling (48 vs 72 days) are therefore potentially of importance. While the children did not receive antibiotics, no data are presented on prophylactic ART to the infants, as normally given as part of the prevention of mother to child transmission (PMTCT) program. For example zidovudine (AZT), an antiretroviral drug which is usually part of this regime, has been shown to exert antibacterial effect 10.
Whatever the causes, the potential consequences of the dysbiosis in HIV-exposed infants should be thoroughly studied in prospective large scale studies, powered for clinical end points and accounting for the factors noted above. If infant dysbiosis is proven to be clinically relevant, breast feeding, modes of delivery and ART exposure are potentially modifiable practices. In addition, microbiota-directed therapies, including dietary interventions, prebiotics and fecal microbiome transfer could be tested in clinical trials.  
Reference List

(1) Bender JM, Li F, Martelly S et al. Maternal HIV infection influences the microbiome of HIV-uninfected infants. Sci Transl Med 2016 July 27;8(349):349ra100.
(2) Rutayisire E, Huang K, Liu Y, Tao F. The mode of delivery affects the diversity and colonization pattern of the gut microbiota during the first year of infants' life: a systematic review. BMC Gastroenterol 2016;16(1):86.
(3) Jakobsson HE, Abrahamsson TR, Jenmalm MC et al. Decreased gut microbiota diversity, delayed Bacteroidetes colonisation and reduced Th1 responses in infants delivered by caesarean section. Gut 2014 April;63(4):559-66.
(4) Nuriel-Ohayon M, Neuman H, Koren O. Microbial Changes during Pregnancy, Birth, and Infancy. Front Microbiol 2016;7:1031.
(5) Dillon SM, Lee EJ, Kotter CV et al. An altered intestinal mucosal microbiome in HIV-1 infection is associated with mucosal and systemic immune activation and endotoxemia. Mucosal Immunol 2014 July;7(4):983-94.
(6) Dinh DM, Volpe GE, Duffalo C et al. Intestinal microbiota, microbial translocation, and systemic inflammation in chronic HIV infection. J Infect Dis 2015 January 1;211(1):19-27.
(7) Nowak P, Troseid M, Avershina E et al. Gut microbiota diversity predicts immune status in HIV-1 infection. AIDS 2015 November 28;29(18):2409-18.
(8) Vazquez-Castellanos JF, Serrano-Villar S, Latorre A et al. Altered metabolism of gut microbiota contributes to chronic immune activation in HIV-infected individuals. Mucosal Immunol 2015 July;8(4):760-72.
(9) Vujkovic-Cvijin I, Dunham RM, Iwai S et al. Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism. Sci Transl Med 2013 July 10;5(193):193ra91.
(10) Doleans-Jordheim A, Bergeron E, Bereyziat F et al. Zidovudine (AZT) has a bactericidal effect on enterobacteria and induces genetic modifications in resistant strains. Eur J Clin Microbiol Infect Dis 2011 October;30(10):1249-56.