Faculty Bibliography

Human microbiome is the collection of microbes living in and on the various parts of our body. The microbes living on our body in nature do not live alone. They act as integrated microbial community with massive competing and cooperating and contribute to our human health in a very important way. Most current analyses focus on examining microbial differences at a single time point, which do not adequately capture the dynamic nature of the microbiome data. With the advent of high-throughput sequencing and analytical tools, we are able to probe the interdependent relationship among microbial species through longitudinal study. Here, we propose a multivariate distance-based test to evaluate the association between key phenotypic variables and microbial interdependence utilizing the repeatedly measured microbiome data. Extensive simulations were performed to evaluate the validity and efficiency of the proposed method. We also demonstrate the utility of the proposed test using a well-designed longitudinal murine experiment and a longitudinal human study. The proposed methodology has been implemented in the freely distributed open-source R package and Python code.

To better characterize murine intestinal microbiota, a large number (187) of Gram-positive staining, rod- and coccoid-shaped facultative and strictly anaerobic bacteria were isolated from small and large intestinal contents from mice. Based on 16S rRNA gene sequencing, a total 115 isolates formed three phylogenetically distinct clusters located within the family Erysipelotrichaceae. Group 1, as represented by strain NYU-BL-A3T, was most closely related to Allobaculum stercoricanis, with 16S rRNA gene similarity values of 87.7%. A second group, represented by NYU-BL-A4T, was most closely related to Faecalibaculum rodentium, with 86.6% 16S rRNA gene similarity. A third group had a nearly identical 16S rRNA gene sequence (99.9%) compared to the recently described Faecalibaculum rodentium, also recovered from a laboratory mouse; however, this strain had a few differences in biochemical characteristics, which are detailed in an emended description. The predominant (>10%) cellular fatty acids of strains NYU-BL-A3T were C16:0, and C18:0 and for NYU-BL-A4T were C10:0, C16:0, C18:0 and C18:1 omega9c. The two groups could also be distinguished by multiple biochemical reactions, with the group represented by NYU-BL-A4T being considerably more active. Based on phylogenetic, biochemical and chemotaxonomic criteria, two novel genera are proposed. Ileibacterium valens gen. nov., sp. nov. with NYU-BL-A3T (ATCC TSD-63 = DSM 103668) as the type strain and Dubosiella newyorkensis gen. nov., sp. nov. with NYU-BL-A4T (ATCC TSD-64 = DSM 103457) as the type strain.

BACKGROUND: H. pylori colonizes the human stomach of approximately 50% of the world's population, and increases the risk of several gastric diseases. The goal of this study is to compare the gastric microbiota in pediatric patients with and without H. pylori colonization. METHODS: We studied 51 children that underwent gastric endoscopy due to dyspeptic symptoms (18 H. pylori-positive and 33 negative). Gastric biopsies were obtained for Rapid Urease Test, culture, histology and DNA extraction. H. pylori was quantified by qPCR and the gastric microbiome studied by V4-16S rRNA gene high-throughput sequencing. RESULTS: Bacterial richness and diversity of H. pylori-positive specimens were lower than those of negative and both groups were clearly separated according to beta diversity. Taxonomic analysis confirmed that H. pylori-positive subjects had a higher relative abundance of Helicobacter genus (66.3%) than H. pylori-negative subjects (0.45%). Four phyla (Proteobacteria, Bacteroidetes, Firmicutes, Actinobacteria) accounted for >97% of all reads in both groups. Within Proteobacteria, gamma- and beta-proteobacteria were the most abundant for H. pylori-negative patients, whilst epsilon-proteobacteria was for H. pylori positive. H. pylori-positive patients were associated with low Body Mass Index (BMI). In the group of underweight patients (BMI<18.5) there were 46.1% of H. pylori-positive patients compared with 24% in the non-underweight group (p=0.049). Patients with active superficial gastritis in H. pylori-positive patients had the lowest alpha diversity (p=0.035). CONCLUSIONS: We characterized the gastric microbiota for the first time in children with and without H. pylori and observed that when H. pylori is present, it tends to dominate the microbial community. In the H. pylori-negative patients, there was more relative abundance of Gamaproteobacteria, Betaproteobacteria, Bacteroidia and Clostridia classes and a higher bacterial richness and diversity.

Exposure of newborns to the maternal vaginal microbiota is interrupted with cesarean birthing. Babies delivered by cesarean section (C-section) acquire a microbiota that differs from that of vaginally delivered infants, and C-section delivery has been associated with increased risk for immune and metabolic disorders. Here we conducted a pilot study in which infants delivered by C-section were exposed to maternal vaginal fluids at birth. Similarly to vaginally delivered babies, the gut, oral and skin bacterial communities of these newborns during the first 30 d of life was enriched in vaginal bacteria-which were underrepresented in unexposed C-section-delivered infants-and the microbiome similarity to those of vaginally delivered infants was greater in oral and skin samples than in anal samples. Although the long-term health consequences of restoring the microbiota of C-section-delivered infants remain unclear, our results demonstrate that vaginal microbes can be partially restored at birth in C-section-delivered babies.

Helicobacter pylori is a late-in-life human pathogen with potential early-life benefits. Although H. pylori is disappearing from the human population, little is known about the influence of H. pylori on the host's microbiota and immunity. Studying the interactions of H. pylori with murine hosts over 6 months, we found stable colonization accompanied by gastric histologic and antibody responses. Analysis of gastric and pulmonary tissues revealed increased expression of multiple immune response genes, conserved across mice and over time in the stomach and more transiently in the lungs. Moreover, H. pylori infection led to significantly different population structures in both the gastric and intestinal microbiota. These studies indicate that H. pylori influences the microbiota and host immune responses not only locally in the stomach, but distantly as well, affecting important target organs.

Mammalian species have co-evolved with intestinal microbial communities that can shape development and adapt to environmental changes, including antibiotic perturbation or nutrient flux. In humans, especially children, microbiota disruption is common, yet the dynamic microbiome recovery from early-life antibiotics is still uncharacterized. Here we use a mouse model mimicking paediatric antibiotic use and find that therapeutic-dose pulsed antibiotic treatment (PAT) with a beta-lactam or macrolide alters both host and microbiota development. Early-life PAT accelerates total mass and bone growth, and causes progressive changes in gut microbiome diversity, population structure and metagenomic content, with microbiome effects dependent on the number of courses and class of antibiotic. Whereas control microbiota rapidly adapts to a change in diet, PAT slows the ecological progression, with delays lasting several months with previous macrolide exposure. This study identifies key markers of disturbance and recovery, which may help provide therapeutic targets for microbiota restoration following antibiotic treatment.

The intestinal microbiota can influence host metabolism. When given early in life, agents that disrupt microbiota composition, and consequently the metabolic activity of the microbiota, can affect the body mass of the host by either promoting weight gain or stunting growth. These effects are consistent with the role of the microbiota during development. In this Perspective, we posit that microbiota disruptions in early life can have long-lasting effects on body weight in adulthood. Furthermore, we examine the dichotomy between antibiotic-induced repression and promotion of growth and review the experimental and epidemiological evidence that supports these phenotypes. Considering the characteristics of the gut microbiota in early life as a distinct dimension of human growth and development, as well as comprehending the susceptibility of the microbiota to perturbation, will allow for increased understanding of human physiology and could lead to development of interventions to stem current epidemic diseases such as obesity, type 1 diabetes mellitus and type 2 diabetes mellitus.

Acquisition of the intestinal microbiota begins at birth, and a stable microbial community develops from a succession of key organisms. Disruption of the microbiota during maturation by low-dose antibiotic exposure can alter host metabolism and adiposity. We now show that low-dose penicillin (LDP), delivered from birth, induces metabolic alterations and affects ileal expression of genes involved in immunity. LDP that is limited to early life transiently perturbs the microbiota, which is sufficient to induce sustained effects on body composition, indicating that microbiota interactions in infancy may be critical determinants of long-term host metabolic effects. In addition, LDP enhances the effect of high-fat diet induced obesity. The growth promotion phenotype is transferrable to germ-free hosts by LDP-selected microbiota, showing that the altered microbiota, not antibiotics per se, play a causal role. These studies characterize important variables in early-life microbe-host metabolic interaction and identify several taxa consistently linked with metabolic alterations. PAPERCLIP: