Introduction: Fecal virome dysbiosis was reported in obese subjects with type 2 diabetes (ObT2). We aimed to characterize the changes in gut virome composition and viral-bacterial transkingdom interaction in ObT2 patients following feacal microbiota transplantation (FMT) and the association of virome change with host metabolic profiles.

Methods: In this double-blind, randomized, placebo-controlled trial, 61 ObT2 subjects were randomized to three parallel groups: FMT with lifestyle intervention (FMT with LSI), FMT alone, or sham transplantation with LSI every 4 weeks for up to week 12. FMT solution was prepared from six healthy lean donors. Fecal virus-like particles (VLP) for virome and whole DNA extraction for bacteriome were performed at baseline, weeks 4, 16 and 24. Outcomes include (1) the proportion of subjects achieving ≥20% lean-associated virome from lean donors; (2) change in viral species abundance and virome-bacterial transkingdom interactions after intervention; and (3) viral species associated with response in low density lipoprotein (LDL-responder, defined by ≥ 0.5mmol/L reduction of serum LDL level) and liver steatosis (liver controlled attenuation parameter score, CAP-responder, defined by ≥30 reduction in CAP score).

Result: 53 subjects had both stool bacterial and viral sequencing at baseline and week 24. At baseline, Caudovirales spp. were enriched in donors compared to FMT recipients (P < 0.05, LDA score > 2). Significantly more recipients treated with FMT (100%) or FMT with LSI (88%) achieved ≥20% lean-associated viral contigs from donor than LSI group (33%) (P < 0.05) at week 24. FMT led to closer resemblance of gut virome composition to lean donors at week 24 (P < 0.0001) compared to LSI alone group, regardless of LSI. Most of the viral species enriched after FMT with LSI treatment were Caudovirales, including, Arthrobacter phage, Klebsiella phage, Natrialba phage and Propionibacterium phage (P < 0.05, LDA score > 2). Transkingdom ecological analysis revealed these viral species correlated positively with butyrate producing bacteria including, Faecalibacterium prausnitzii, Anaerostipes hadrus, and several Eubacterium spp. Lactococcus phage was enriched in both LDL and CAP non-responders at week 24 (P < 0.05, LDA score > 2), and its abundance inversely correlated with Leuconostoc mesenteroides, a bacterium shown to alleviate liver steatosis in mice. (R < –0.5, P < 0.05).

Conclusion: Repeated FMTs led to sustained engraftment of lean-associated viruses and more resemblance to lean virome composition. Lactococcus phage was associated with unfavorable response after FMT.

Funding:
This study was funded by InnoHK, The Government of Hong Kong, Special Administrative Region of the People’s Republic of China; seed fund from Centre for Gut Microbiota Research, Faculty of Medicine, The Chinese University of Hong Kong

Keli Yang

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