NIH – Advancing Mechanistic Probiotic/Prebiotic and Human Microbiome Research (R01 Clinical Trial Not Allowed)

August 1, 2018 by School of Medicine Webmaster

The purpose of this funding opportunity announcement (FOA) is twofold: (1) to stimulate basic and mechanistic science that facilitates the development of effective probiotics or pre-/probiotic combinations of relevance to human health and disease; and (2) determine biological outcomes for the evaluation of efficacy of pre/probiotics in appropriate test systems and animal models. This FOA encourages basic and mechanistic studies using in vitro, in vivo, ex vivo, and in silico models that focus on prebiotic/probiotic strain selectivity, interaction, and function. It will also encourage inter and multidisciplinary collaborations among scientists in a wide range of disciplines including nutritional science, immunology, microbiomics, genomics, other ‘-omic’ sciences, biotechnology, and bioinformatics.


Probiotics are defined as “live microorganisms which, when administered in adequate amounts confer a health benefit on the host”. This definition is sufficiently inclusive of a broad range of microbes and applications, and captures the essence of probiotics (microbial; viable; and beneficial to health). Prebiotics are considered as “non-viable food component that confers a health benefit on the host associated with modulation of the microbiota”. Despite the exponential growth in the marketing of prebiotic/probiotic products, fundamental knowledge gaps regarding their health benefits remain, including the understanding of their molecular mechanisms of action, long-term effects and their potential interactions with the host physiology. For example, to design therapeutic/preventive manipulations of the gut microbiota, it is critical to understand the evolutionary and ecologic interplay among the GI microbiota and host physiology. This FOA will support the generation of valid and reliable evidence to show that prebiotic/probiotics as singular or combination formulations can stimulate specific measurable and beneficial functions of the host microbiota. The study of biochemical and genomic expression pathways and host-microbial interactions among prebiotic compounds, probiotic strains and the host microbiota will provide a sound basis for developing effective singular or combination pre/probiotic applications for enhancing or restoring functional health.

Many events can shape or alter microbial communities.  For example, human/microbial co-evolution is uniquely selected for coupling structure-specific nutrient (prebiotic) substrates with (probiotic) strain-specific functions to promote growth of a ‘healthy’ microbiota in breast-fed infants. Diet may potentially serve as the primary modulator of mammalian microbiota for infant growth and development. However, competing selective pressures (e.g., from exposures to xenobiotics or broad-spectrum antibiotics) disturb the normal ecological balance of host-microbial interactions. Current knowledge of the molecular interface between pre/probiotic factors and host-specific interactions with resident microbes is limited. Therefore, omics-based and other novel approaches are needed for elucidating the functional effects of pre/probiotic singular or combination formulations and microbial metabolites on the host and for the study of the taxonomic composition of the microbiome. Well characterized probiotic strains (e.g., selected lactobacillus; bifidobacterium) secrete a variety of signaling molecules that can modify inter-bacterial signaling (quorum sensing) and potentially suppress the expression of virulence genes and pathogenic-strain growth patterns. Thus, there is a need for identifying the functional roles of bacterially derived low molecular weight (LMW) bioactive molecules including bacteriocins and others that affect human health.

The LMW microbial metabolites and signal molecules in human physiologic fluids may have diagnostic value or provide key information to design products with specific nutritional and medicinal effects. Because in vivo production of bioactive small molecules of human and microbial origin is often connected with prebiotic secondary metabolism, there is much interest in developing the rational basis for conducting mechanistic studies of specific pre/probiotic singular or combination formulations for nutritional and medical purposes for specific health functions in the host.

A wide variety of concepts and technologies can guide research in this area to include:

  • Structure/function relationships within endogenous microbial populations – Metagenomic reconstruction of community metabolism has shown that similar metabolic networks are common among individual strains suggesting functional redundancy within microbial consortia. Systems-level approaches can be utilized to determine microbial community function particularly at the metagenomic, and chemical and biological levels in diverse communities.
  • Functional Omics-based Technologies and Biologic Signatures of Host-Microbial Interactions – High dimensional methods including meta-omic approaches that provide qualitative and quantitative information on genes, transcripts, proteins and metabolites present in microbial communities at specific points in space and time. Such approaches will highlight the intricate cross-feeding and signaling pathways between the human and microbial ecosystems by deciphering differential gene expression profiles, microbial biotransformation pathways, host epigenetic patterns and protein functions for development and safety testing of pre/probiotics in the future.
  • Modeling Microbial-Host Metabolite Interactions – To better understand the complexity of interactions of pre/probiotics and/or their combinations in different host anatomical sites, host-microbial modeling will require further development and refinement to include:
  • Basic Modeling – Robust in vivo, in vitro and ex vivo models, used singly or in combination, which will allow high-throughput first-pass experiments aimed at proving cause-and-effect relationships prior to hypothesis testing in animal models.
  • Animal Modeling – Use of animal models (germ free, gnotobiotic or others such as CONV-R treated with antibiotics) to understand the causal relationship between microbiota and host interactions.
  • Systems Biology Modeling – In silico models in combination with in vitro, ex vivo and in vivo experimental data are promising approaches to predict metabolic interactions between gut microbes and their host in both diseased and healthy states.

Specific Objectives and Scope of this FOA

Research areas of interest may include, but not limited to and not in any order of priority, the following:

Accelerating Mechanistic Studies to Feed the Translational Pipeline

  1. Study the effect of prebiotics/probiotics on: microbial composition and function, microbial-host interactions and co-metabolism, interactions with diet, dietary supplements or dietary components, changes in microenvironment (i.e. pH, toxin production), local and systemic inflammatory response, pathogenic control.
  2. Identification of bacterial strains and bacteriophage types and characterization of the underlying mechanisms of robustness of prebiotic/probiotic formulation and microbial resilience to prevent or treat human diseases (e.g., caries, gingivitis, periodontitis, necrotizing enterocolitis, inflammatory bowel disease, cancer, hematological disease, enteric bowel infections.
  3. Characterization of commensal microbes, including probiotic strain(s) or a prebiotic compound/consortia of strains, that secrete a variety of signaling molecules that can affect microbial community dynamics and human metabolic and signaling pathways by: (a) modifying inter-bacterial signaling (e.g., quorum sensing) mechanisms and optimizing the composition and function of indigenous microbiota; (b) regulating metabolic and/or behavior reactions; (c) suppressing the expression of virulence genes in pathogens; (d) stimulating the growth of beneficial endogenous microorganisms; and (e) elucidating possible functional redundancy and synergy among the human microbiota and probiotic strains.
  4. Identification of low molecular weight bioactives (both chemical and biological molecules) and characterization of their functional role in human health and disease risk.
  5. Development of potential microbial starter cultures of human origin as a platform for meta-biotic production. This culture could be used for synthesis of structural and excreted bioactive substances participating in or regulating pathways associated with metabolism of carbohydrates, fat, and cholesterol; effect on the immune, hormone, and nervous systems; metagenome and epigenome stability; and gene expression regulation.
  6. Development and validation of animal models and characterizing their ability to recapitulate the microbial ecology of a particular body site.
  7. Characterization of mechanisms of probiotic action on host phenotypes or diseases such as IBD, chronic pulmonary, cardiac, and renal diseases, or metabolic/endocrine diseases; study the impact of the microbiome and pre/probiotic interventions on immune function, inflammation, or chronic immune activation and potential effect on therapy. These studies may, for example, implicate mechanisms of adhesion to various body surfaces; competition with pathogens for receptor binding, nutrients and colonization; enhancement of mucosal barrier function; promotion of innate and adaptive immune responses; elaboration of bacteriocins and antimicrobial action; and modulation of cell kinetics.
  8. Analysis of probiotic modulation of cell kinetics through effects on cell proliferation and apoptosis by examining the importance to homeostasis of cell death and reproduction (i.e. the ability of certain probiotics to promote normal cell propagation and concurrently inhibit abnormal cell apoptosis).
  9. Study of the mechanisms by which bacterial products interact with or affect host pathways related to intestinal barrier function, differentiation and regulation of immune cell function, regulation of intestinal regeneration and repair, and modulation of electrolyte and nutrient transport.
  10. Use of novel probiotic approaches as mucosal adjuvants to enhance vaccine immunogenicity and derived antimicrobials that provide alternatives to conventional antibiotics that are refractory to resistance development.
  11. Study the effects of substances of abuse (narcotics/opiates, alcohol, tobacco) on the efficacy of pre/probiotics and intestinal microbiome/microflora in populations with co-occurring infections including HIV, HCV and others; study if manipulation of the microbiome/human virome would alter the pathogenesis of complications of drug use such as HIV, HCV-related disease, and interactions with pre/probiotics.

New Innovative Methods and Experimental Approaches

  1. Identification, development and validation of diagnostic test assays for microbial metabolites and signal molecules produced by microorganisms in human physiological fluids.
  2. Characterization of singular or combined meta-biotic prebiotic/probiotic food and drug applications targeted to host microbiota or to indigenous microflora associated host functions, metabolic and behavior reactions.
  3. Characterization of microbial O- and N-glycans to identify possible glycosylated proteins released from probiotics and their effects on glycan-mediated signaling pathways in response to disease or under normal health conditions.
  4. Development of nutritional and pharmacologic pre/probiotic strategies: Systems biology methods and tools to study pre/probiotic associated changes in microbial ecology.
  5. Study of optimal diet against specific pathogenic bacteria related to disease prevention and characterization of the underlying mechanisms.
  6. Developing novel intervention methods including narrow-spectrum antimicrobials and probiotics that selectively target pathogenic organisms while avoiding killing of beneficial microbiota.

New Technology and Database Platforms

  1. Development and validation of rapid in vitro simulated organ systems, organoid systems, and other tissue/organ-on-a-chip systems, in the context of probiotic/prebiotic (commensal) targets and host-microbial co-metabolism.
  2. Biovalidation of high throughput screening models for preclinical toxicity testing or to ensure virulence traits are not present in candidate probiotics: testing, cataloguing, multi-omic development of standards and approaches to reduce variability.
  3. Development of integrative biology approaches for nutrigenomics and/or pharmacogenomics of prebiotic/probiotics and host-microbial co-metabolism.
  4. Development of tools and technologies that enable identification, quantification and characterization of temporal dynamics establishing causative links between external stimuli (i.e. probiotic strains, microbial bioactives or prebiotics) and the imbalance or rebalance of the human microbiota.
  5. Development of computational models that enable the generation of hypothesis testing from multi-omic data to elucidate the molecular (including small molecules) underpinnings in microbe-microbe and microbe-host interactions.
  6. Development of novel computational approaches e.g., ecological principles with predictive and therapeutic algorithms.
  7. Development of tools and technologies to program bacteria to sense and manipulate the local environment for a controlled therapeutic response.

The National Cancer Institute (NCI) encourages research on the microbiome and cancer, including the influence of pre/probiotics on functional and molecular profiles in cancer prevention, development and treatment. The Division of Cancer Biology at the NCI is interested in basic/mechanistic studies that seek to understand probiotic’s underlying molecular mechanisms of action related to tumor etiology, their interactions with host cells or other resident microbes as it relates to their effects on host cell signaling, physiology or metabolism.  Within the scope of the Division of Cancer Prevention, the NCI encourages research to understand how pre/probiotics compete with pathogens associated with cancer, modulate the production of metabolites and/or reduce the production of pro-carcinogens relevant to key well known risk factors or pre-neoplastic lesions. Studies concerning the effect of probiotics on biofilm composition and luminal vs. mucosal-associated functional changes related to cancer prevention would also be encouraged. Since food plays a critical role in maintaining and/or changing the gut microbiota, diet and nutrition should be considered in conjunction with pre/probiotic studies, i.e. nutrient-microbial interaction, the dose and strain of probiotics, the effect from/on underlying medical conditions (i.e. obesity, inflammatory bowel disease) and the linkages to those outcomes and cancer risk. The Division of Cancer Treatment and Diagnosis at the NCI encourages research focused on xenobiotic metabolism and the effects of probiotics and microbial metabolism on the bioavailability of anticancer agents; on the role of probiotics on immunotherapeutic interventions or cancer vaccine efficacy; and the development of molecular signatures of the biome at all stages of cancer, how that signature changes with treatment, and whether those changes predict response or resistance.

The National Institute on Drug Abuse (NIDA) supports basic, pre-clinical, clinical, and epidemiologic research on drugs of abuse and co-occurring infections (e.g., HIV, HCV) and associated consequences including the impact on human microbiome. Active drug use (opiates, alcohol, tobacco) and natural opiate and cannabinoid receptors have potential effects on the microbiome indirectly through alterations in gut motility, a known influence on the subpopulations of gut microflora.  The bloodborne viral infections also occur at increased rates in injection drug users.  The primary intestinal CD4 depletion that accompanies HIV infection is associated with alterations in intestinal microflora.  Although, transmission of HIV, hepatitis B virus, and hepatitis C virus are the best studied, the effects of successful CD4 recovery with cART on the microbiome are incompletely understood.  It is likely that the human virome is different in injection drug users.  Since the composition of the human virome has been reported to affect HIV pathogenesis, it is plausible that injection drug use affects HIV pathogenesis by alteration in the virome. Thus, NIDA is interested in research on areas that may include, but not limited to: (i) the direct impact of narcotic/opiate abuse on composition of the intestinal microbiome; the impact of alterations on associated disease conditions; (ii) the effects of HIV disease on the intestinal microflora and determine what implications does this have for immune activation; (iii) the interaction of active injection drug use with HIV in regard to their collective impact on the microbiome; (iv) whether successful cART have on restitution of the microbiome; does this restitution  have a beneficial effect on systemic immune activation, (v) what effect does the composition of the microbiome have on liver disease related to complications of substance abuse, including co-occurring infections such as HCV, HBV, and fatty liver disease; and (vi) does manipulation of the microbiome alter the pathogenesis of complications of drug use such as HIV and HCV related disease.

The National Institute of Dental and Craniofacial Research (NIDCR) encourages projects that pertain to the microbiota of the human oral cavity (specifically those communities composed of dentally-relevant archaea, bacteria, and fungi). Likewise, dental pre/probiotics are defined here as those agents/formulations/combinations targeting the human oral cavity and under study to treat dental diseases or to improve dental, oral, and craniofacial health.

The National Institute of Arthritis Musculoskeletal and Skin Diseases (NIAMS) encourages applications that address immune or non-immune mechanisms by which a) the skin microbiome interacts with the skin at homeostasis, and b) the microbiome modulates pathogenesis of the skin, rheumatic and musculoskeletal diseases and conditions at preclinical, clinical onset and chronic phases. Examples of mechanistic studies include: 1) Characterization of microbiome-host molecular and cellular interactions. 2) Characterization of the signaling pathways that affect the dynamics of the relevant microbial communities. 3) Characterization of microbiome changes during therapy for skin, rheumatic and musculoskeletal diseases and conditions. 4) Studies of the impact of the prebiotic/probiotic interventions. Examples of skin, rheumatic and musculoskeletal diseases and conditions of interest to the NIAMS in the context of this FOA include but are not limited to: chronic skin wounds, atopic dermatitis, psoriasis, alopecia areata, vitiligo, acne, pemphigus vulgaris, rosacea, systemic sclerosis, rheumatoid arthritis, systemic lupus erythematous, inflammatory myopathies, autoinflammatory diseases, osteoarthritis, and osteoporosis.

The mission of the Office of Dietary Supplements (ODS) is to strengthen knowledge and understanding of dietary supplements, including prebiotics and probiotics, by evaluating scientific information, stimulating and supporting research, disseminating research results, and educating the public to foster an enhanced quality of life and health for the U.S. population.  ODS is interested in research investigating the role of prebiotics and probiotics on health maintenance and disease prevention.  Research interests of ODS are not limited to specific health conditions, organ systems or population groups.

Deadlines:  standard dates and standard AIDS dates apply


Filed Under: Funding Opportunities