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A Glimpse into the Gut: HiFi Sequencing Enables Strain-Level Study of Intestinal and Breastmilk Microbiota in Celiac Disease

Tuesday, December 29, 2020

SMRT Grant winner Ali R. Zomorrodi of Harvard Medical School

Celiac disease happens in the gut, but scientists still don’t fully understand the complex interplay between host genetics and the environmental factors that lead to the development of the autoimmune digestive disease.

Researchers at the Mucosal Immunology and Biology Research Center of MassGeneral Hospital for Children and Harvard Medical School are hoping to shed light on the ‘microbial dark matter’ in the breastmilk of mothers with celiac disease and in the intestine of celiac children using full-length 16S rRNA and metagenome sequencing — they will be supported in their efforts by the 2020 Microbial Genomics SMRT Grant.

Ali R. Zomorrodi (@arzomorrodi), the research center’s computational and systems biology lead and an Instructor of Pediatrics at Harvard Medical School, has teamed up with Alessio Fasano, a renowned celiac disease specialist, chief of Pediatric Gastroenterology and Nutrition at Massachusetts General Hospital and a Professor of Pediatrics at Harvard Medical School, to tackle these questions.

By leveraging a large-scale prospective birth cohort study referred to as the Celiac Disease Genomic, Environmental, Microbiome, and Metabolomic (CDGEMM) study, led by Dr. Fasano, they have a unique opportunity to delve more deeply into the role of microbiota in the etiology of the disease. The CDGEMM study has been banking stool, breastmilk and other biospecimens, as well as clinical metadata from ~500 infants with high risk of celiac disease from birth through childhood.

HiFi Sequencing for Strain-Level Resolution

In celiac disease, one of the most common forms of food intolerance worldwide, the ingestion of gluten-containing grains triggers an immune response that attacks and progressively damages the small intestine. It is a unique model of autoimmune diseases since it is the only such disease for which the environmental trigger (exposure to gluten) and genetic risk factors are well-characterized.

Research shows that 30% of the population are genetically susceptible for celiac disease and are exposed to gluten, yet only 2-3% of them develop the disease. Recent studies suggest a critical role for the gut microbiota in celiac disease pathogenesis, but how exposure to environmental risk factors other than gluten early in life may alter the engraftment of the gut microbiota in infants at risk of the disease is still poorly understood. So, one aspect of Zomorrodi’s project involves the investigation of the role breast milk may play on the engraftment of the gut microbiota in CDGEMM infants.

Zomorrodi and colleagues will use full-length 16S rRNA HiFi sequencing to see whether the composition of breast milk microbiota in mothers of CDGEMM infants with a history of celiac disease is different from those of mothers without the disease. They will also use this technology to study fecal microbiota from infants of these mothers and fecal microbiota of at-risk infants who consume formula, to explore whether the breast milk microbiota has any effects on the composition of the babies’ intestinal microbiota. While the conventional short-read 16S sequencing can identify microbes at genus or sometimes species level, the 16S HiFi sequencing would allow the team to profile the microbiota at strain-level resolution. This will enable researchers to gain deeper insights into the role of breast milk microbiota in shaping the intestinal microbiota of infants at risk of celiac disease.

A Deeper Understanding of the Intestinal Microbiome

In another project, Zomorrodi and his colleagues will be applying HiFi metagenomic sequencing to fecal samples from CDGEMM children who developed celiac disease and matched controls who did not. They hope to comprehensively characterize the intestinal microbiome composition of these subjects at strain-level resolution and to identify celiac-specific biomarkers in the microbiome.

“This is important, because we know that many diseases are driven by specific strains within the same species. Healthy people may carry the same species, but do not become ill. We want to know why,” Zomorrodi said.

Zomorrodi also wants to capture as much of the microbiome as possible using this innovative technology.

“A good proportion (up to 50%) of the short-read metagenomic data we collect cannot be mapped to any database during the taxonomic or functional profiling processes. This means that we are losing a significant portion of the data that could contain a lot of valuable information about the microbiome,” he said.

In addition to increasing the chance of identifying low-abundance microbes that may not be otherwise identified using short-read methods, the HiFi reads will enable a finer-level functional characterization of the microbiota and the assembly of closed genomes for novel microbial strains that do not exist in databases. These closed genomes can serve as a basis for downstream computational investigation of the microbiota function, such as constructing computational genome-scale models of metabolism.

“This study could go a long way towards finding celiac-specific biomarkers and designing targeted microbiota intervention strategies to treat celiac disease and other autoimmune diseases.”

Zomorrodi said he is looking forward to his first experience using PacBio long-read sequencing. Once a skeptic, he was sold on the value of full-length 16S rRNA and metagenomic HiFi sequencing after seeing data presented at a Cold Spring Harbor microbiome conference.

“It is really amazing,” he said. “I believe the field of the microbiome will be moving forward into using long-read technology. There are really lots of exciting opportunities that didn’t exist before at this level of resolution.”

 


We’re excited to support this research and look forward to seeing the results. Thank you to our co-sponsor and Certified Service Provider, Maryland Genomics, for supporting the 2020 Microbial Genomics SMRT Grant Program. Explore the 2020 HiFi For All – Collaborations SMRT Grant Program to apply to have your project funded.

 Learn more about using HiFi reads to explore microbiology and infectious disease.

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