Showing papers by "Robert N. Baldassano published in 2021"

Remodeling of the maternal gut microbiome during pregnancy is shaped by parity.

Abstract: The maternal microbiome has emerged as an important factor in gestational health and outcome and is associated with risk of preterm birth and offspring morbidity. Epidemiological evidence also points to successive pregnancies—referred to as maternal parity—as a risk factor for preterm birth, infant mortality, and impaired neonatal growth. Despite the fact that both the maternal microbiome and parity are linked to maternal-infant health, the impact of parity on the microbiome remains largely unexplored, in part due to the challenges of studying parity in humans. Using synchronized pregnancies and dense longitudinal monitoring of the microbiome in pigs, we describe a microbiome trajectory during pregnancy and determine the extent to which parity modulates this trajectory. We show that the microbiome changes reproducibly during gestation and that this remodeling occurs more rapidly as parity increases. At the time of parturition, parity was linked to the relative abundance of several bacterial species, including Treponema bryantii, Lactobacillus amylovorus, and Lactobacillus reuteri. Strain tracking carried out in 18 maternal-offspring “quadrads”—each consisting of one mother sow and three piglets—linked maternal parity to altered levels of Akkermansia muciniphila, Prevotella stercorea, and Campylobacter coli in the infant gut 10 days after birth. Collectively, these results identify parity as an important environmental factor that modulates the gut microbiome during pregnancy and highlight the utility of a swine model for investigating the microbiome in maternal-infant health. In addition, our data show that the impact of parity extends beyond the mother and is associated with alterations in the community of bacteria that colonize the offspring gut early in life. The bacterial species we identified as parity-associated in the mother and offspring have been shown to influence host metabolism in other systems, raising the possibility that such changes may influence host nutrient acquisition or utilization. These findings, taken together with our observation that even subtle differences in parity are associated with microbiome changes, underscore the importance of considering parity in the design and analysis of human microbiome studies during pregnancy and in infants.

Tofacitinib Therapy in Children and Young Adults With Pediatric-onset Medically Refractory Inflammatory Bowel Disease

Abstract: Objectives Tofacitinib, a selective Janus kinase inhibitor, effectively induces and maintains remission in adults with inflammatory bowel disease (IBD), but data are limited in children. This study aimed to evaluate the efficacy and safety of tofacitinib for medically refractory pediatric-onset IBD. Methods This single-center retrospective study included subjects ages 21 years and younger who started tofacitinib for medically refractory IBD. Clinical activity indices, clinical response, steroid-free remission, biochemical response, and adverse events (AEs) were evaluated over 52 weeks. Results Twenty-one subjects, 18 with ulcerative colitis or indeterminate IBD, received tofacitinib. At the end of the 12-week induction period, 9 out of 21 (42.9%) subjects showed clinical response and 7 out of 21 (33.3%) were in steroid-free remission. Of evaluable subjects at 52 weeks, 7 out of 17 (41.2%) showed clinical response and were in steroid-free remission. Of those remaining on tofacitinib at 1 year, none required concomitant systemic corticosteroids. Tofacitinib was discontinued in 8 subjects because of refractory disease, including 8 who ultimately underwent colectomy, and in 1 subject who developed a sterile intra-abdominal abscess. There were no instances of thrombi, zoster reactivation, or clinically significant hyperlipidemia, all of which were AEs of interest. Conclusions There is limited experience with tofacitinib in pediatric IBD. In this cohort, tofacitinib induced rapid clinical response with sustained efficacy in nearly half of subjects. This study provides encouraging evidence for the efficacy and safety of tofacitinib as part of the treatment paradigm for young individuals with moderate-to-severe IBD. Larger, well-powered, prospective studies are warranted.

Stratification of Risk of Progression to Colectomy in Ulcerative Colitis using Measured and Predicted Gene Expression

Abstract: SUMMARY An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes Between 5% and 10% of ulcerative colitis (UC) patients require colectomy within five years of diagnosis, but polygenic risk scores (PRS) utilizing findings from GWAS are unable to provide meaningful prediction of this adverse status By contrast, in Crohn’s disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a Transcriptional Risk Score (TRS) Here we demonstrate that both measured (TRS) and polygenic predicted gene expression (PPTRS) identify UC patients at 5-fold elevated risk of colectomy with data from the PROTECT clinical trial and UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with transcriptome-wide association studies to stratify risk of disease complications

Decreased Intestinal Microbiome Diversity in Pediatric Sepsis: A Conceptual Framework for Intestinal Dysbiosis to Influence Immunometabolic Function.

Abstract: Objectives The intestinal microbiome can modulate immune function through production of microbial-derived short-chain fatty acids We explored whether intestinal dysbiosis in children with sepsis leads to changes in microbial-derived short-chain fatty acids in plasma and stool that are associated with immunometabolic dysfunction in peripheral blood mononuclear cells Design Prospective observational pilot study Setting Single academic PICU Patients Forty-three children with sepsis/septic shock and 44 healthy controls Measurements and main results Stool and plasma samples were serially collected for sepsis patients; stool was collected once for controls The intestinal microbiome was assessed using 16S ribosomal RNA sequencing and alpha- and beta-diversity were determined We measured short-chain fatty acids using liquid chromatography, peripheral blood mononuclear cell mitochondrial respiration using high-resolution respirometry, and immune function using ex vivo lipopolysaccharide-stimulated whole blood tumor necrosis factor-α Sepsis patients exhibited reduced microbial diversity compared with healthy controls, with lower alpha- and beta-diversity Reduced microbial diversity among sepsis patients (mainly from lower abundance of commensal obligate anaerobes) was associated with increased acetic and propionic acid and decreased butyric, isobutyric, and caproic acid Decreased levels of plasma butyric acid were further associated with lower peripheral blood mononuclear cell mitochondrial respiration, which in turn, was associated with lower lipopolysaccharide-stimulated tumor necrosis factor-α However, neither intestinal dysbiosis nor specific patterns of short-chain fatty acids were associated with lipopolysaccharide-stimulated tumor necrosis factor-α Conclusions Intestinal dysbiosis was associated with altered short-chain fatty acid metabolites in children with sepsis, but these findings were not linked directly to mitochondrial or immunologic changes More detailed mechanistic studies are needed to test the role of microbial-derived short-chain fatty acids in the progression of sepsis

Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression.

Abstract: Summary An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a transcriptional risk score (TRS). Here, we demonstrate that a measured TRS based on bulk rectal gene expression in the PROTECT inception cohort study has a positive predictive value approaching 50% for colectomy. Single-cell profiling demonstrates that the genes are active in multiple diverse cell types from both the epithelial and immune compartments. Expression quantitative trait locus (QTL) analysis identifies genes with differential effects at baseline and week 52 follow-up, but for the most part, differential expression associated with colectomy risk is independent of local genetic regulation. Nevertheless, a predicted polygenic transcriptional risk score (PPTRS) derived by summation of transcriptome-wide association study (TWAS) effects identifies UC-affected individuals at 5-fold elevated risk of colectomy with data from the UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with TWASs for stratification of risk of disease complications.