Human Milk Oligosaccharide (2'-FL) Modifies the Gut Microbiome in Children after Bone Marrow Transplant

Dysbiosis after allogeneic hematopoietic stem cell transplant (allo-HSCT) predisposes to acute gastrointestinal (GI) graft-versus-host disease (GVHD). Human milk oligosaccharides (HMOs) are prebiotics that establish a favorable intestinal microbiome. We hypothesized that peri-transplant HMOs would reduce dysbiosis, and conducted a prospective phase I/II study (NCT04263597 Clinicaltrials.gov) in which 70 patients received oral, daily 2'-fucosyllactose (2'-FL), the most abundant HMO, from start of conditioning through day +30. Primary phase I and phase II endpoints were safety and tolerability of 2'-FL and longitudinal preservation of microbiome diversity, respectively. Phase I and phase II patients with ³60% adherence were evaluated by correlative analyses. Twenty-nine age-matched patients with available samples in our institutional biorepository served as contemporary controls. 2'-FL was safe and well-tolerated on the phase I study, which established dosing for the phase II study. Shannon diversity was preserved in 2'-FL recipients and declined from baseline to day +30 in controls (p=0.04). Generalized linear mixed model analysis revealed higher association of Bifidobacteria and Blautia with 2'-FL (adjusted p<0.05). Higher fecal isoleucine (p=0.005), tyrosine (p=0.05), and taurine (p=0.04) were observed in 2'-FL recipients, all associated with protection and regeneration of intestinal epithelium. Lower plasma reg3a (p=0.053) and ST2 levels (p=0.038) were observed in 2'-FL recipients compared to controls. Incidence of grade II-IV acute GI GVHD was 0% in 2'-FL recipients compared to 17% in controls (p=0.009). Adenovirus reactivation was 0% in 2'-FL recipients compared to 17% in controls (p=0.009). 2'-FL is safe and modifies the gut microbiome in children following allo-HSCT.