Bachelor of Science, King Saud University (2006)
Doctor of Philosophy, McMaster University (2014)
The gastrointestinal microbiota controls cancer cell intrinsic mechanisms to promote the progression of acute lymphoblastic leukemia.
AMER ASSOC CANCER RESEARCH. 2020: 58–59
View details for Web of Science ID 000526057000081
Strain-resolved microbiome sequencing reveals mobile elements that drive bacterial competition on a clinical timescale.
2020; 12 (1): 50
Populations of closely related microbial strains can be simultaneously present in bacterial communities such as the human gut microbiome. We recently developed a de novo genome assembly approach that uses read cloud sequencing to provide more complete microbial genome drafts, enabling precise differentiation and tracking of strain-level dynamics across metagenomic samples. In this case study, we present a proof-of-concept using read cloud sequencing to describe bacterial strain diversity in the gut microbiome of one hematopoietic cell transplantation patient over a 2-month time course and highlight temporal strain variation of gut microbes during therapy. The treatment was accompanied by diet changes and administration of multiple immunosuppressants and antimicrobials.We conducted short-read and read cloud metagenomic sequencing of DNA extracted from four longitudinal stool samples collected during the course of treatment of one hematopoietic cell transplantation (HCT) patient. After applying read cloud metagenomic assembly to discover strain-level sequence variants in these complex microbiome samples, we performed metatranscriptomic analysis to investigate differential expression of antibiotic resistance genes. Finally, we validated predictions from the genomic and metatranscriptomic findings through in vitro antibiotic susceptibility testing and whole genome sequencing of isolates derived from the patient stool samples.During the 56-day longitudinal time course that was studied, the patient's microbiome was profoundly disrupted and eventually dominated by Bacteroides caccae. Comparative analysis of B. caccae genomes obtained using read cloud sequencing together with metagenomic RNA sequencing allowed us to identify differences in substrain populations over time. Based on this, we predicted that particular mobile element integrations likely resulted in increased antibiotic resistance, which we further supported using in vitro antibiotic susceptibility testing.We find read cloud assembly to be useful in identifying key structural genomic strain variants within a metagenomic sample. These strains have fluctuating relative abundance over relatively short time periods in human microbiomes. We also find specific structural genomic variations that are associated with increased antibiotic resistance over the course of clinical treatment.
View details for DOI 10.1186/s13073-020-00747-0
View details for PubMedID 32471482
Mimicking the human environment in mice reveals that inhibiting biotin biosynthesis is effective against antibiotic-resistant pathogens.
To revitalize the antibiotic pipeline, it is critical to identify and validate new antimicrobial targets1. In Mycobacteria tuberculosis and Francisella tularensis, biotin biosynthesis is a key fitness determinant during infection2-5, making it a high-priority target. However, biotin biosynthesis has been overlooked for priority pathogens such as Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa. This can be attributed to the lack of attenuation observed for biotin biosynthesis genes during transposon mutagenesis studies in mouse infection models6-9. Previous studies did not consider the 40-fold higher concentration of biotin in mouse plasma compared to human plasma. Here, we leveraged the unique affinity of streptavidin to develop a mouse infection model with human levels of biotin. Our model suggests that biotin biosynthesis is essential during infection with A. baumannii, K. pneumoniae and P. aeruginosa. Encouragingly, we establish the capacity of our model to uncover in vivo activity for the biotin biosynthesis inhibitor MAC13772. Our model addresses the disconnect in biotin levels between humans and mice, and explains the failure of potent biotin biosynthesis inhibitors in standard mouse infection models.
View details for DOI 10.1038/s41564-019-0595-2
View details for PubMedID 31659298
Large-Scale Analyses of Human Microbiomes Reveal Thousands of Small, Novel Genes.
Small proteins are traditionally overlooked due to computational and experimental difficulties in detecting them. To systematically identify small proteins, we carried out a comparative genomics study on 1,773 human-associated metagenomes from four different body sites. We describe >4,000 conserved protein families, the majority of which are novel; 30% of these protein families are predicted to be secreted or transmembrane. Over 90% of the small protein families have no known domain and almost half are not represented in reference genomes. We identify putative housekeeping, mammalian-specific, defense-related, and protein families that are likely to be horizontally transferred. We provide evidence of transcription and translation for a subset of these families. Our study suggests that small proteins are highly abundant and those of the human microbiome, in particular, may perform diverse functions that have not been previously reported.
View details for DOI 10.1016/j.cell.2019.07.016
View details for PubMedID 31402174
Long term but not short term exposure to obesity related microbiota promotes host insulin resistance.
2018; 9 (1): 4681
The intestinal microbiota and insulin sensitivity are rapidly altered after ingestion of obesogenic diets. We find that changes in the composition of the fecal microbiota precede changes in glucose tolerance when mice are fed obesogenic, low fiber, high fat diets (HFDs). Antibiotics alter glycemia during the first week of certain HFDs, but antibiotics show a more robust improvement in glycemic control in mice with protracted obesity caused by long-term feeding of multiple HFDs. Microbiota transmissible dysglycemia and glucose intolerance only occur when germ-free mice are exposed to obesity-related microbes for more than 45 days. We find that sufficient host exposure time to microbiota derived from HFD-fed mice allows microbial factors to contribute to insulin resistance, independently from increased adiposity in mice. Our results are consistent with intestinal microbiota contributing to chronic insulin resistance and dysglycemia during prolonged obesity, despite rapid diet-induced changes in the taxonomic composition of the fecal microbiota.
View details for PubMedID 30409977