Biology subjects

Xavier, R. J.

Publications and source records attributed to Xavier, R. J..

3 recordsLinked to original sources

bioRxiv2017

T helper cells modulate intestinal stem cell renewal and differentiation

In the small intestine, a cellular niche of diverse accessory cell types supports the rapid generation of mature epithelial cell types through self-renewal, proliferation, and differentiation of intestinal stem cells (ISCs). However, not much is known about interactions between immune cells and ISCs, and it is unclear if and how immune cell dynamics affect eventual ISC fate or the balance between self-renewal and differentiation. Here, we used single-cell RNA-seq (scRNA-Seq) of intestinal epithelial cells (IECs) to identify new mechanisms for ISC-immune cell interactions. Surprisingly, MHC class II (MHCII) is enriched in two distinct subsets of Lgr5+ crypt base columnar ISCs, which are also distinguished by higher proliferation rates. Using co-culture of T cells with intestinal organoids, cytokine stimulations, and in vivo mouse models, we confirm that CD4+ T helper (Th) cells communicate with ISCs and affect their differentiation, in a manner specific to the Th subtypes and their signature cytokines and dependent on MHCII expression by ISCs. Specific inducible knockout of MHCII in intestinal epithelial cells in mice in vivo results in expansion of the ISC pool. Mice lacking T cells have expanded ISC pools, whereas specific depletion of Treg cells in vivo results in substantial reduction of ISC numbers. Our findings show that interactions between Th cells and ISCs mediated via MHCII expressed in intestinal epithelial stem cells help orchestrate tissue-wide responses to external signals.

immunology↗

bioRxiv2017

Comprehensive analysis of mobile genetic elements in the gut microbiome reveals a phylum-level niche-adaptive gene pool

Mobile genetic elements (MGEs) drive extensive horizontal transfer in the gut microbiome. This transfer could benefit human health by conferring new metabolic capabilities to commensal microbes, or it could threaten human health by spreading antibiotic resistance genes to pathogens. Despite their biological importance and medical relevance, MGEs from the gut microbiome have not been systematically characterized. Here, we present a comprehensive analysis of chromosomal MGEs in the gut microbiome using a method called Split Read Insertion Detection (SRID) that enables the identification of the exact mobilizable unit of MGEs. Leveraging the SRID method, we curated a database of 5600 putative MGEs encompassing seven MGE classes called ImmeDB (Intestinal microbiome mobile element database) (https://immedb.mit.edu/). We observed that many MGEs carry genes that confer an adaptive advantage to the gut environment including gene families involved in antibiotic resistance, bile salt detoxification, mucus degradation, capsular polysaccharide biosynthesis, polysaccharide utilization, and sporulation. We find that antibiotic resistance genes are more likely to be spread by conjugation via integrative conjugative elements or integrative mobilizable elements than transduction via prophages. Additionally, we observed that horizontal transfer of MGEs is extensive within phyla but rare across phyla. Taken together, our findings support a phylum level niche-adaptive gene pools in the gut microbiome. ImmeDB will be a valuable resource for future fundamental and translational studies on the gut microbiome and MGE communities.

bioinformatics↗

bioRxiv2017

Adaptive evolution within the gut microbiome of individual people

Individual bacterial lineages stably persist for years in the human gut microbiome1-3. However, the potential of these lineages to adapt during colonization of healthy people is not well understood2,4. Here, we assess evolution within individual microbiomes by sequencing the genomes of 602 Bacteroides fragilis isolates cultured from 12 healthy subjects. We find that B. fragilis within-subject populations contain substantial de novo nucleotide and mobile element diversity, which preserve years of within-person evolutionary history. This evolutionary history contains signatures of within-person adaptation to both subject-specific and common selective forces, including parallel mutations in sixteen genes. These sixteen genes are involved in cell-envelope biosynthesis and polysaccharide utilization, as well as yet under-characterized pathways. Notably, one of these genes has been shown to be critical for B. fragilis colonization in mice5, indicating that key genes have not already been optimized for survival in vivo. This lack of optimization, given historical signatures of purifying selection in these genes, suggests that varying selective forces with discordant solutions act upon B. fragilis in vivo. Remarkably, in one subject, two B. fragilis sublineages coexisted at a stable relative frequency over a 1.5-year period despite rapid adaptive dynamics within one of the sublineages. This stable coexistence suggests that competing selective forces can lead to B. fragilis niche-differentiation even within a single person. We conclude that B. fragilis adapts rapidly within the microbiomes of individual healthy people, providing a new route for the discovery of key genes in the microbiome and implications for microbiome stability and manipulation.

evolutionary biology↗