Microbiome in Human Health and Disease

The objective of this RFA was to solicit proposals that will promote a greater understanding of the role(s) microbiomes play in the maintenance of normal human physiology and in the manifestation and treatment of human disease. For this opportunity, the microbiome encompasses viruses, bacteria, and fungi as they relate to human physiology and/or illness. There was no restriction on the area of human health to be investigated in the proposal. Applicants were encouraged to think broadly about the interactions between microbiomes and human physiology and ecology in formulating their proposals.

Five pilot grants were awarded in amounts up to $50,000 for each one-year project starting June 1, 2019

Microbiome in Human Health and Disease Awardees

Georg Gerber: Predicting C. difficile recurrence from the microbiome using interpretable machine learning models

Predicting C. difficile recurrence from the microbiome using interpretable machine learning models

Principal Investigator: Georg Gerber, MD PhD. Brigham and Women's Hospital

Clostridioides difficile infection (CDI) is the most common cause of hospital-acquired infection in the U.S., responsible for ~500,000 cases of severe diarrhea and ~15,000 deaths annually. First-line treatment is ineffective in ~25% of CDI patients, creating substantial unnecessary morbidity with costs to the healthcare system of ~$2.8 billion. There is thus an urgent need for accurate diagnostics to identify patients at risk for recurrent CDI in order to provide effective initial treatment. A causal relationship has been established between CDI and an impaired gut microbiome, suggesting a microbiome-based test could predict CDI recurrence. However, there are few prior studies and these suffer from serious shortcomings, including inadequate cohort sizes, limited longitudinal sampling, and no measurements of microbiome metabolic activities. In addition, due to the complexities of large, dynamic and multi-dimensional microbiome datasets, computational approaches are essential that can derive predictors from these data that are not only accurate, but also produce outputs that clinicians can understand. We therefore propose to take critical steps toward developing a microbiome-based diagnostic test for CDI recurrence by: (a) scaling up a novel human-interpretable machine learning approach that we have developed, to enable analysis of large multi-‘omics datasets, and (b) applying our method to derive CDI-recurrence predictor models from our ongoing study that collects sequence-based and metabolome microbiome data from longitudinal fecal samples of 150 participants with CDI. This work is expected to provide critical preliminary results needed to obtain funding to develop and validate a diagnostic test for CDI recurrence.

 

Kate Jeffrey: Distinguishing immunomodulatory capacity of the enteric virome in healthy and diseased intestine

Distinguishing immunomodulatory capacity of the enteric virome in healthy and diseased intestine

Principal Investigator, Kate Jeffrey, PhD. Massachusetts General Hospital

Although the microbiome has been established as an important regulator of homeostasis, the role of commensal viruses that inhabit human intestine (collectively, the virome) is largely unknown. The fecal virome is altered in inflammatory bowel disease (IBD) suggesting a role for virome dysbiosis. How the virome contributes to host homeostasis or how changes in virome composition impacts gut inflammation is unknown. To advance our knowledge of the virome-intestine relationship, a critical step is to move beyond correlation and toward identifying specific immunoregulatory viruses and mechanisms of virome immunomodulation. Mammalian cells detect viral nucleic acids via receptors RIG-I and MDA-5, triggering canonical antiviral defense pathways. How host viral sensors distinguish from, and achieve divergent responses toward pathogenic viruses and viral symbionts is a fundamental and unanswered question in mucosal immunity. We recently demonstrated interaction between certain commensal viruses with RIG-I in mouse intestine. The overall objective of the present proposal is to identify immunomodulatory virome constituents of healthy and diseased human intestine and elucidate the host immune response that ensues. We will elucidate global RIG-I/MDA-5-virome interaction maps in healthy and diseased intestinal tissue using a crosslinking immunoprecipitation (CLIP) technique in fresh intestinal resections from non-IBD and IBD patients. As a second aim, we will determine the immunomodulatory capacity of viruses isolated from healthy versus IBD intestinal tissue or ileostomies. Determination of the precise viral components that interact with the host will help in understanding the role of the virome in regulating immune homeostasis and how commensal viruses may contribute to IBD.

Caroline Mitchell: Role of the reproductive tract microbiota in fertility

Role of the reproductive tract microbiota in fertility

Principal Investigator, Caroline Mitchell, MD, Massachusetts General Hospital

The human reproductive tract microbiota is unique: no other species has a commensal Lactobacillus- dominant microbiota. Microbes in the vagina, cervix and uterus are associated with pregnancy and fertility outcomes, but the exact mechanism and optimal composition are not well described. We hypothesize that a particular Lactobacillus species, L. crispatus, is associated with optimal reproductive outcomes, compared to the other most common Lactobacillus species (L. iners) or non-Lactobacillus microbes. We propose a pilot study of 60 women presenting for in vitro fertilization treatment: 30 with male factor infertility (normal uterus, tubes and ovarian function) and 30 with idiopathic infertility (normal evaluation of uterus and tubes, normal ovarian function but no conception after 1 year of trying). We will collect vaginal swabs, the embryo transfer catheter (to sample intrauterine microbiota influencing pregnancy implantation) and a stool sample. We will perform 16S rRNA sequencing of the microbial community in each sample, and will measure pro-inflammatory cytokines in the vaginal swab eluate. We will compare the microbial community between 1) women with idiopathic infertility vs. male factor controls and 2) women who achieve pregnancy and those who do not. We will compare vaginal markers of inflammation between women who do and do not achieve pregnancy, and will assess whether the impact of the reproductive tract microbiota is dependent on the host mucosal immune response. Finally, the gut microbiota will be compared between women with idiopathic vs. male factor infertility to identify broader differences in microbial colonization outside the reproductive tract.

Victor Neel: Characterization of the skin microbiome during acute wound healing following surgery

Characterization of the skin microbiome during acute wound healing following surgery

Principal Investigator, Victor Neel, MD. Massachusetts General Hospital

The abstract for this grant award has not been published at the request of the Principal Investigator.

George Whitesides: Antibiotic susceptibility testing of clinically relevant bacteria using density-based live/dead separation

Antibiotic susceptibility testing of clinically relevant bacteria using density-based live/dead separation

Principal Investigator, George Whitesides, PhD. Harvard University Faculty of Arts and Sciences

The abstract for this grant award has not been published at the request of the Principal Investigator.