The Human Microbiome Project (HMP) consortium established a unique population-scale framework which characterized the relationship between the human host and its microbial communities. These data provide strong initial evidence for host influences on microbial community structure and underscores the capacity for metagenomics and metabolomics to explore host-pathogen interactions in disease states. We will adopt such a systems biology approach to extend our published and preliminary findings as they relate to Clostridium difficile infection (CDI), antibiotic resistance and treatment outcome i children and adults. By comparisons with our pediatric and adult HMP reference datasets, we provide much needed insight into how antibiotics affect intestinal ecosystems over multiple life stages. Because young children are generally asymptomatic carriers of C. difficile whereas adults often become symptomatically infected, our proposed studies provide a developmental perspective of intestinal ecosystems that modulate C. difficile virulence and drug resistance. The novelty of our work is our discovery of an intestinal ecosystem that is refractory to frontline antibiotic therapy, the result of which is treatment failure in CDI patients. Our project goal is t identify microbes that regulate host susceptibility to C. difficile through characterization of newy-identified molecular and biochemical pathways. The combination of cutting edge multi-omics, coupled with real-time measurement of antibiotic resistance and clinical phenotyping in patients is expected to generate a valuable resource that provides new discovery into host susceptibility to CDI. To achieve these objectives we will pursue two aims:
Aim 1 : Unbiased longitudinal multi-omic studies of host-microbe interactions in CDI development.
Aim 2 : Targeted mechanistic studies of host-microbe interactions that affect treatment outcome in CDI. Through these longitudinal multi-omics studies, we expect to define host-microbe interactions that are predictive of antibiotic treatment failure in CDI patients and provide a rich array of resources - supported in part by our own ongoing CDI patient registry, the Texas Department of State Health Services, Autism Speaks, the TMC Digestive Disease Center and integrated microbiome centers (Center for Metagenomics and Microbiome Research (CCMR) and Texas Children's Microbiome Center (TCMC)).

Public Health Relevance

This work will use innovative multi-omic and bioinformatics approaches to develop new diagnostic and therapeutic concepts for Clostridium difficile infection, which causes widespread intestinal disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAI1)
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Shabman, Reed Solomon
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Baylor College of Medicine
Schools of Medicine
United States
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Koon, Hon Wai; Wang, Jiani; Mussatto, Caroline C et al. (2018) Fidaxomicin and OP-1118 Inhibit Clostridium difficile Toxin A- and B-Mediated Inflammatory Responses via Inhibition of NF-?B Activity. Antimicrob Agents Chemother 62:
Shrestha, Ritu; Sorg, Joseph A (2018) Hierarchical recognition of amino acid co-germinants during Clostridioides difficile spore germination. Anaerobe 49:41-47
Collins, J; Robinson, C; Danhof, H et al. (2018) Dietary trehalose enhances virulence of epidemic Clostridium difficile. Nature 553:291-294
Zhu, Duolong; Sorg, Joseph A; Sun, Xingmin (2018) Clostridioides difficile Biology: Sporulation, Germination, and Corresponding Therapies for C. difficile Infection. Front Cell Infect Microbiol 8:29
Bhattacharjee, Disha; Sorg, Joseph A (2018) Conservation of the ""Outside-in"" Germination Pathway in Paraclostridium bifermentans. Front Microbiol 9:2487
Peniche, Alex G; Spinler, Jennifer K; Boonma, Prapaporn et al. (2018) Aging impairs protective host defenses against Clostridioides (Clostridium) difficile infection in mice by suppressing neutrophil and IL-22 mediated immunity. Anaerobe 54:83-91
Dotson, Kierra M; Aitken, Samuel L; Sofjan, Amelia K et al. (2018) Outcomes associated with Clostridium difficile infection in patients with chronic liver disease. Epidemiol Infect 146:1101-1105
Shrestha, Ritu; Lockless, Steve W; Sorg, Joseph A (2017) A Clostridium difficile alanine racemase affects spore germination and accommodates serine as a substrate. J Biol Chem 292:10735-10742
Collins, James; Auchtung, Jennifer M (2017) Control of Clostridium difficile Infection by Defined Microbial Communities. Microbiol Spectr 5:
Luna, Ruth Ann; Oezguen, Numan; Balderas, Miriam et al. (2017) Distinct Microbiome-Neuroimmune Signatures Correlate With Functional Abdominal Pain in Children With Autism Spectrum Disorder. Cell Mol Gastroenterol Hepatol 3:218-230

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