Gastroesophageal reflux and PPI exposure alter gut microbiota in very young infants.

Importance: Infants with symptomatic Gastroesophageal reflux are treated with pharmacological therapy that includes proton pump inhibitors (PPI) with clinical improvement. The alterations to gut microbiome profiles in comparison to infants without reflux is not known. Objective: To determine the effect of PPI therapy on gut bacterial richness, diversity, and proportions of specific taxa in infants when compared to infants not exposed to acid suppressive therapy. Design setting and participants: This cohort study was conducted at the Stony Brook Hospital in Stony Brook, NY between February 2016, and June 2019. Infants meeting inclusion criteria were enrolled in a consecutive fashion. Results: A total of 76 Infants were recruited and 60 were enrolled in the study, Twenty nine infants met clinical criteria for reflux and were treated with PPI therapy: median [IQR] gestation: 38.0 weeks [34.7-39.6 weeks]; median [IQR] birthweight: 2.95 Kg [2.2-3.4]; 14 [46.7%] male) and 29 infant were healthy controls median [IQR] gestation: 39.1 weeks [38-40 weeks]; median [IQR] birthweight: 3.3 Kg [2.2-3.4]; 17 [58.6%] male); 58 stool samples from 58 infants were analyzed. There were differences in Shannon diversity between the reflux and control groups. The reflux group that was exposed to PPI therapy had increased relative abundance of a diverse set of genera belonging to the phylum Firmicutes. On the other hand, the control group microbiota was dominated by Bifidobacterium, and a comparatively lower level of enrichment and abundance of microbial taxa was observed in this group of infants. Conclusions and relevance: We observed significant differences in both α- and ß-diversity of the microbiome, when the two groups of infants were compared. The microbiome in the reflux group had more bacterial taxa and the duration of PPIs exposure was clearly associated with the diversity and abundance of gut microbes. These findings suggest that PPI exposure among infants results in early enrichment of the intestinal microbiome.

Metagenomic and bile acid metabolomic analysis of fecal microbiota transplantation for recurrent Clostridiodes difficile and/or inflammatory bowel diseases.

Background: Fecal microbiota transplantation (FMT) is an effective treatment of recurrent Clostridioides difficile infections (rCDI), but has more limited efficacy in treating either ulcerative colitis (UC) or Crohn's disease (CD), two major forms of inflammatory bowel diseases (IBD). We hypothesize that FMT recipients with rCDI and/or IBD have baseline fecal bile acid (BA) compositions that differ significantly from that of their healthy donors and that FMT will normalize the BA compositions. Aim: To study the effect of single colonoscopic FMT on microbial composition and function in four recipient groups: 1.) rCDI patients without IBD (rCDI-IBD); 2.) rCDI with IBD (rCDI+IBD); 3.) UC patients without rCDI (UC-rCDI); 4.) CD patients without rCDI (CD-rCDI). Methods: We performed 16S rRNA gene sequence, shotgun DNA sequence and quantitative bile acid metabolomic analyses on stools collected from 55 pairs of subjects and donors enrolled in two prospective single arm FMT clinical trials (Clinical Trials.gov ID NCT03268213, 479696, UC no rCDI ≥ 2x IND 1564 and NCT03267238, IND 16795). Fitted linear mixed models were used to examine the effects of four recipient groups, FMT status (Donor, pre-FMT, 1-week post-FMT, 3-months post-FMT) and first order Group*FMT interactions on microbial diversity and composition, bile acid metabolites and bile acid metabolizing enzyme gene abundance. Results: The pre-FMT stools collected from rCDI ± IBD recipients had reduced α-diversity compared to the healthy donor stools and was restored post-FMT. The α-diversity in the pre-FMT stools collected from UC-rCDI or CD-rCDI recipients did not differ significantly from donor stools. FMT normalized some recipient/donor ratios of genus level taxa abundance in the four groups. Fecal secondary BA levels, including some of the secondary BA epimers that exhibit in vitro immunomodulatory activities, were lower in rCDI±IBD and CD-rCDI but not UC-rCDI recipients compared to donors. FMT restored secondary BA levels. Metagenomic baiE gene and some of the eight bile salt hydrolase (BSH) phylotype abundances were significantly correlated with fecal BA levels. Conclusion: Restoration of multiple secondary BA levels, including BA epimers implicated in immunoregulation, are associated with restoration of fecal baiE gene counts, suggesting that the 7-α-dehydroxylation step is rate-limiting.

Thyrotoxic periodic paralysis associated with a mutation in the sodium channel gene SCN4A.

Thyrotoxic hypokalemic periodic paralysis (THypoKPP) is an uncommon disorder with an unknown etiology. We describe a family in which the proband presented with paralysis and thyrotoxicosis. Because of similarities between familial hypokalemic periodic paralysis (FHypoKPP) and THypoKPP, we sequenced exon 12 of the SCN4A gene, which is known to be mutated in FHypoKPP. We identified an Arg672Ser mutation in the proband and his affected father, as well as the proband's brother. As the brother has paralysis without thyrotoxicosis, our finding suggests that the genetic spectrum of FHypoKPP and THypoKPP overlap. We speculate that thyroid hormone may exert a threshold or permissive effect in hypokalemic periodic paralysis. Non-thyrotoxic family members of individuals with THypoKPP may have an unrecognized risk for paralysis.