2021 Spring TUMI Pilot and Feasibility Grant Awardees Announced!
The TransUniversity Microbiome Initiative is excited to announce the second round of Awardees for the Spring 2021 (Round 2) TUMI Pilot and Feasibility Grants. Nine investigators submitted applications and TUMI assembled a panel of over twenty reviewers to assess and select our finalists. Below you will find brief summaries of each of the six funded projects. TUMI looks forward to supporting this research over the coming months, and we are unbelievably excited by the creative microbiome research proposed across grounds. Selecting only a handful to fund was not an easy task. Our next funding opportunity for TUMI Pilot and Feasibility Grants will be announced in June 2021. Stay tuned for microbiome research updates from each of these investigators!!
The detection of a ketogenic diet-induced metabolic signature in a cohort of relapsing multiple sclerosis patients
PI: James "Nick" Brenton, M.D.
Key Personnel: Maureen Carey and Brett Moreau (Data Scientists)
Summary: Multiple sclerosis (MS) is an autoimmune neurodegenerative disorder and its course is influenced by environmental factors. Dietary intake is one environmental factor that modulates disease via direct influences on an individual’s immune profile and function – including shaping of the gut microbiome, development of the host immune system, protection against pathogenic organisms, and maintenance of the immunologic response. There has been a strong interest in therapeutic diet interventions for MS, yet the evidence base for a particular “MS diet” is currently lacking. One of the oldest diet interventions – a low carbohydrate, high fat diet known as the ketogenic diet (KD) –has several key characteristics that make it an ideal diet-based approach for disease modification in MS – including its anti-inflammatory properties and its ability to attenuate oxidative stress and enhance mitochondrial biogenesis. On a KD, MS subjects experience significant reduction in serum pro-inflammatory adipokines and exhibit significant clinical improvements in MS-related neurologic disability, fatigue, and depression. However, there remains a knowledge gap as to the mechanism(s) by which these benefits are promoted and sustained – including the impact of this diet on the human MS metabolome. This pilot project will take the first critical step in defining potential metabolomics mechanism(s) of a KD in patients living with MS. Identifying how a diet intervention could impact the disease process in MS patients - potentially by way of correcting a dysregulated metabolome - will provide great insight into the impact on the dietary and/or lifestyle management in MS patients.
Metabolic and microbial signatures associated with Cryptosporidium infection and diarrhea
Key Personnel: Catalina Alvarez (BME graduate student) and Carol Gilchrist, Bill Petri, and Rashidul Haque (Collaborators)
Summary: Cryptosporidium parasites are a leading cause of childhood diarrhea, but can also cause subclinical infections without enteric symptoms. We recently identified an association between the microbiome and diarrhea during Cryptosporidium infection. Specifically, we observed that Cryptosporidium diarrhea was inversely associated with the presence of Megasphaera, both prior to and at the time of infection, in a cohort of Bangladeshi infants. If the microbiome confers protection, it may act via altering the intestinal metabolome or host response, or by directly interacting with the parasite. We hypothesize that children with and without diarrhea during cryptosporidiosis have metabolic differences induced by the microbiota. This work will establish a putative metabolic mechanism for microbiome-mediated protection and garner further support for the role of Megasphaera in the subclinical phenotype.
Investigating the role of microbiota-driven intestinal immune responses in oral vaccine failure during undernutrition
Key Personnel: Jasmine Cano, B.A. and Yadeliz A. Serrano (graduate student)
Summary: Undernutrition and linear growth stunting in the first 1,000 days of life perturb metabolic and immune programming, with lifelong implications for health and productivity. This syndrome is multifactorial and intergenerational; mothers who experience growth stunting are more likely to give birth to stunted children. Intestinal pathogens are also common in undernourished communities and contribute to poor child growth. Rotavirus (RV) is the number one cause of childhood deaths from diarrhea, and oral Rotavirus vaccination (ORV) is significantly less effective in undernourished populations than in developed areas. The gut microbiota plays a pivotal role in shaping the development of both intestinal and systemic immune responses, and stunted children are known to have altered microbial communities and mucosal immunity. Preliminary data from our lab demonstrate that colonization of gnotobiotic murine breeding pairs with microbiota from a severely stunted infant transmits alterations in immune development to resulting pups (relative to offspring of animals with microbiota from a healthy child).
We propose to test the hypothesis that stunted offspring have reduced intestinal barrier integrity, leading to dysregulated IgA targeting of the microbiota and poor oral vaccine efficacy. The goal of this proposal is to determine the extent to which development of a successful oral vaccine response is influenced by mucosal immune recognition of the gut microbiota in early life, setting the stage for future investigation into bacterial functions and host pathways that regulate oral vaccine efficacy. This work is significant because improving oral vaccine efficacy offers an enormous opportunity to reduce deaths from childhood diarrhea. It is innovative because it leverages a new model of intergenerational undernutrition to investigate the influence of human microbial communities on host immunity, and translational by identifying potential microbial targets to enhance oral vaccine efficacy.
Metabolite-mediated progression of colorectal cancer by Enterotoxigenic Bacteroides fragilis
PIs: Todd Fox, Ph.D. and Mark Kester, Ph.D.
Key Personnel:
Summary: The long-term goal of this project is to develop better therapeutics strategies for colorectal cancer (CRC). CRC is the second most common cause of cancer-related mortality in the United States with the lifetime risk of developing CRC at 1 in 20. CRC development can be caused by a combination of host- and microbiota- dependent mechanisms. Symbiosis between the host and the gut microbiome is critical for intestinal health. Evidence supports that alterations in the microbiome contribute to the development of CRC. A key mediator in this may be the bacteria enterotoxigenic Bacteroides fragilis (ETBF). ETBF is a molecular subset of B. fragilis distinguished by the secretion of a pathogenic factor, the B. fragilis toxin (BFT). Increased detection of ETBF has been reported in patients with inflammatory bowel disease and in those with CRC. Evidence supports that ETBF induces CRC in mice through a BFT-dependent activation of inflammation and disruption of epithelial cell- cell interactions. However, there is much unknown about how ETBF leads to colon tumor formation. The objective of this proposal is to fill in gaps in this knowledge through (1) delineating the role of EBTF-induced glycosphingolipids (GSLs) metabolism on CRC in mice and (2) identifying the metabolic perturbations that correspond to ETBF-induced tumorigenesis in the colon. Drs. Fox and Kester have formed a synergistic team to complete the proposed studies and have extensive experience in metabolism and sphingolipid biology. This team is augmented by the expertise of Dr. Sears (John Hopkins), an expert in ETBF and CRC, as well as the resources of the TransUniversity Microbiome Initiative. The public health significance of this work is substantial as understanding the mechanism of how ETBF alters cellular and lipid metabolism will lead to the identification of novel drugable targets to combat CRC.
Microbial dysbiosis as a driver of neuroinflammation and pathology in Alzheimer’s disease
Key Personnel: Carrie Cowardin PhD, Carol Manning MD, Hannah Ennerfelt (NGP Graduate Student), Coco Holliday (Undergraduate Student)
Summary: Mounting evidence indicates that imbalances in microbiota composition (also known as dysbiosis) are major hallmarks of most human neurodegenerative diseases including Alzheimer’s disease (AD). While there have been exciting recent findings demonstrating that dysbiosis occurs in AD, it still remains to be determined if changes in microbiota landscape are a cause or consequence of AD. Therefore, the first major goal of this proposal is to directly interrogate a role for AD-associated dysbiosis in neurodegenerative disease progression. We also currently lack knowledge of how alterations in microbiota diversity can contribute to neurodegenerative disease at the mechanistic level. Recent studies in other non-AD models of neurological disease have begun to reveal that the microbiome can influence disease pathogenesis by modulating immune responses and/or metabolite production (i.e. the metabolome). Despite this, the impact of the dysbiosis seen in AD patients on immune responses and the metabolome has yet to be fully investigated. Therefore, we will next leverage cutting-edge single-cell RNA-sequencing (scRNA-seq) and metabolomics approaches to provide a comprehensive and unbiased assessment of how AD-associated dysbiosis affects immune responses and the metabolome in our human microbiota transplantation system. Our overarching hypothesis is that dysbiosis in AD patients causes dysregulation of immune responses and the metabolome and that this can ultimately lead to exacerbated neurodegenerative disease progression.
Successful completion of the proposed research directions will define to what extent AD-associated dysbiosis contributes to neurodegenerative disease pathogenesis and will also begin to reveal prospective factors underpinning the effects of the human AD microbiota on disease progression. If our overarching hypothesis is proven correct, this work would then be of translational significance, as microbiota targeting approaches such as fecal transplantation and probiotics could offer safe and cost-effective strategies to delay and/or treat AD.
Deep characterization of microbiota structure and function in kidney disease
Key Personnel: Jennie Ma, Pankaj Kumar, Binu Sharma, Shirin Pourafshar, Pao-Hwa Lin (Duke)
Summary: Kidney disease is a global health epidemic and one of the few non-communicable diseases rising in morbidity and mortality globally. The current standard to prevent kidney disease includes control of blood sugar, blood pressure, and body weight. The gastrointestinal (GI) microbiota is known to contribute to each of these risk factors, but its role in development of kidney disease is not well understood. Our goal is to evaluate the GI microbiota in individuals with mild-moderate kidney disease to identify candidate communities and functions that may contribute to pathogenesis. To achieve this goal we have established a pilot study cohort enriched with participants who have kidney disease. In this year-long longitudinal cohort, participants provide stool samples for microbiota characterization seasonally, dietary interviews throughout the year, health and medication information, and measurement of a variety of clinically important, kidney-related traits (blood pressure, body mass index, waist circumference, and glycemia). We will use stool shotgun metagenomic sequencing and LC-MS/MS metabolomics to identify candidate species and functions associated with kidney function and kidney-related traits to design a larger longitudinal follow up study.