Limited engraftment of donor microbiome via one-time fecal microbial transplantation in treated HIV-infected individuals

Abstract

Many HIV-infected individuals on antiretroviral therapy (ART) exhibit persistent systemic inflammation, which predicts morbidity and mortality. ART-treated subjects concurrently exhibit marked compositional alterations in the gut bacterial microbiota and the degree of dysbiosis correlates with systemic inflammation. Whether interventions to modulate the microbiome can affect systemic inflammation is unknown. An open-label fecal microbial transplantation (FMT) was delivered by colonoscopy to asymptomatic HIV-infected ART-suppressed individuals without antibiotic pre-treatment. Stool was assessed before and after FMT for engraftment of donor microbes, and peripheral blood was assayed for immune activation biomarkers. Six participants received FMT and 2 participants served as controls. No serious adverse effects occurred during 24 weeks of follow-up. At baseline, HIV-infected individuals exhibited microbiota profiles distinct from uninfected donors. During the 8 weeks post-FMT, recipients demonstrated partial engraftment of the donor microbiome (P < 0.05). Recipient microbiota remained significantly distant from donors, unlike that observed following FMT for treatment of C. difficile infection. Systemic inflammatory markers showed no significant change post-FMT. FMT was well-tolerated in ART-treated, HIV-infected individuals. Engraftment was detectable but modest, and appeared to be limited to specific bacterial taxa. Whether antibiotic conditioning can enhance engraftment and the capacity of microbiota to modulate inflammation remains to be investigated.

Keywords: HIV; Microbiota; engraftment; fecal microbiome transplant; fecal transplant; inflammation; microbiome engraftment.

Figure 1.

Flow diagram for recruitment of study participants. FMT, fecal microbiome transplant.

Figure 2.

Change in UniFrac distance over time in recipients and controls relative to donors. A) Significant shifts in the microbiome occur and persist post-FMT, but are diminished by week 8. Statistical significance of change in ecological distance to donor profiles before FMT as compared with after FMT was assessed statistically using linear mixed effects modeling. Control subjects (pink dotted line, average of 2 subjects) exhibited no significant changes in their microbiome relative to donors before and after colonoscopy. B) Proportions of shared OTUs between each recipient profile and its respective donor were calculated and plotted across time. Linear mixed effects was used to assess significance of difference in shared OTU proportions pre and post-FMT (P = 0.0019).

Figure 3.

Changes in relative abundance of key gut-resident bacterial genera after FMT. Selected genera shown are Faecalibacterium, an unclassified Rikenellaceae family member genus, and the Bulleidia genus within the Erysipelotrichaceae family (**, P = 0.005; †, P < 0.10). FMT, fecal microbiome transplant.

Figure 4.

Microbiome shifts much more pronounced in recurrent C. difficile infection (CDI) subjects than in HIV-infected subjects post-FMT. A) Principal coordinate analysis (PCoA) representing triplicate donor microbiota profiles and HIV-infected recipient microbiota community dynamics pre- and post-FMT was generated using the Unweighted Unifrac distance metric. After FMT, recipient microbiota profiles remain distinct from the donors. Points outlined in black are post-FMT time points, and shapes of recipient points reflect which donor material was infused by FMT (Donor 01, circles; Donor 37, triangles), while control subjects that received only bowel lavage over the same time period are shown as squares. Lines connect subject sample time points in a temporally linear fashion. B) Unweighted UniFrac distances were calculated as in Figure. 2 between each recipient stool microbiota profile time point and its respective donor, using data in the current study for HIV-infected subjects and the study by Weingarden et al. for CDI subjects. C) α diversity was calculated using the Faith's Phylogenetic Diversity metric for each sample in each category shown. D) PCoA plot of data from recurrent CDI subjects given FMT by Khoruts et al. reveals that CDI subjects differ greatly from donor samples pre-FMT and cluster closely with donor samples post-FMT. E) PCoA plot of data from recurrent CDI subjects given FMT and samples from the current study in HIV-infected subjects shows that movement of the microbiome toward the donor samples is much more dramatic for CDI subjects than for HIV-infected subjects as quantified discretely in panel B.