NIH – Advancing Translational and Clinical Probiotic/Prebiotic and Human Microbiome Research (R01 Clinical Trial Optional)

August 20, 2018 by School of Medicine Webmaster

Probiotics and Prebiotics – marketing, consumption, and knowledge: Marketing and consumption of pro/prebiotic products is growing exponentially, despite the gap in knowledge regarding their efficacy, the best probiotic/prebiotic (pro/prebiotic) formulations, dosage and the fact that many products using the term pro/prebiotic do not meet the requisite criteria. Rigorous and reproducible studies are needed to demonstrate the mechanistic basis for pro/prebiotic consumption/administration, strain-specific health benefits and host characteristics (genetic, metabolic and biochemical, health status, gender, age) of subjects who could benefit from such interventions. The specific conditions in which these interventions could be recommended, their underlying molecular mechanisms of action, their interactions with the host, and doses needed for measurable effective responses are not clearly understood. The Probiotics definition as originally framed by World Health Organization (WHO) and Food and Agriculture Organization of the United Nations (FAO) and is broadly accepted and as ” live microorganisms which, when administered in adequate amounts confer a health benefit on the host. Prebiotics are “non-viable food components that confer a health benefit on the host associated with modulation of the microbiota”. By definition, prebiotics are neither hydrolyzed nor absorbed in the upper part of the gastro-intestinal tract, constitute a selective substrate for one or a limited number of beneficial bacteria and are able to alter the colonic microbiota in favor of a healthier composition. While widespread beneficial effects across taxonomic groups have been reported, rare adverse events, negative results, failure to meet specifications for well-defined pro/prebiotic preparations and available data for long-term safety have impeded definitively concluding clear health claims for strain-specific pro/prebiotic effects. The lines of research require cautionary guidance and well-controlled settings to include studies of any short term or long term risks, in vulnerable populations e.g., preterm neonates and other immunocompromised individuals.

Diet and Gut Microbiota: Many environmental exposures, including the diet and the use of antibiotics, alter microbial communities and human microbial coevolution. For example, since the diet serves as a modulator of the gut microbiota, initial gut microflora would partially depend on whether the infant is breast-fed or bottle-fed. Despite the progress made, current knowledge of the molecular interface between pro/prebiotic factors and host interactions with resident microbes is limited. Research is needed to better understand the effect of administering pro/prebiotic, singly or in combination, and the actions of their microbial metabolites on the host in the context of complex interactions with food, dietary patterns, antibiotics and other prescribed medications, health status, gender, age, etc. Research is also needed to understand whether supplementation with pro/prebiotics would have implications in restoring ecologic balance/resilience of perturbed microbiota, gut barrier reinforcement, production of specific metabolites, enzyme activity, and immunologic and competitive function against bacterial, fungal and viral infections, including a possible adjuvant role against emerging infections. In addition, integrating omics technologies to validly and reproducibly measure the functional interplay of pre/probiotic interventions on composition and functional effects in gut microbiota and host physiology is also critical for designing effective therapeutic and preventive manipulations of the gastro-intestinal microbiota.

Quorom Sensing and Modulation by Probiotics: Well-characterized probiotic strains (e.g., lactobacillus; bifidobacterium) secrete a variety of signaling molecules that can modify inter-bacterial signaling (quorum sensing) and suppress the expression of virulence genes in some pathogens. Probiotic strains can produce several classes of low molecular weight (LMW) bioactive molecules including: bacteriocins and other antimicrobial agents, short chain fatty acids, biosurfactants, vitamins, antioxidants, nucleic acids, etc. The presence of LMW microbial metabolites and signal molecules in human physiologic fluids could have particular physiological and/or diagnostic value that could be used to design products with specific beneficial 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 the rational basis for mechanistic studies of specific pre/probiotic combinations for nutritional and medical purposes targeted to specific functions in the human host. A growing body of recent evidence suggests that regular intake of probiotics suppresses H. Pylori infection in humans, maintaining lower levels of this pathogen in the stomach but the mechanism is poorly understood.

Specific Objectives and Scope of this FOA

This FOA encourages translational and clinical studies using a variety of pro/prebiotic carriers (foods, dietary supplements, etc.) to generate measurable functional evidence for the safety and effectiveness use of pro/prebiotics in maintaining health and/or prevent and treat diseases. If food is used, information should be readily available regarding the food matrix or relevant dietary and microbial composition of it.

Selection of probiotic strains will follow the FAO/WHO recommendations that probiotic microorganisms should not harbor transmissible drug resistance genes encoding resistance to clinically used drugs. Screening and selection criteria for probiotics(s) prebiotics should be focused on probiotic strains with demonstrated quality for a number of parameters in animals and fit for human consumption. Phase I and II a/b studies will require further proof of concept and testing assessments for a number of parameters, including antibiotic resistance assays, screening for virulence factors, resistance to host defense mechanisms and induction of hemolysis.

To ensure valid and reproducible results, appropriate animal models or human subjects enrolled in these studies must be characterized in terms of metabolic, biochemical, microbial, and health or disease status. The FOA will also support studies to develop new or to refine known biomarkers of health and disease with respect to the pro/prebiotics interventions. The impact of pro/prebiotic interventions must be measured and objectively documented for health and/or disease. Where needed, it is mandatory that the applicant (s) proposing clinical studies should provide sufficient details of plans and appropriately documented evidence of pre-IND (Investigational New Drug) status or other relevant regulatory correspondence at the time of application. Prior to any funded award being implemented in humans, investigators would be responsible for obtaining the approval for an IND from the United States Food and Drug Administration (FDA).

Probiotics, as defined, should be able to survive the passage through the digestive system and proliferate in the gut. Importantly, rigorous genomic and molecular identification and taxonomic profiling using omics based technologies of the species and the strain is crucial. The ability to remain viable at the target site and to be effective should be demonstrated for the strain used (including colony formation units, strain identification and characterization, transient adhesion or interaction with the intestinal epithelium and colonization of the colon, if pertinent). This shows the importance of the food matrix, including the amount of food that must be ingested in order to obtain the health benefit and proof for stability and viability of the strain in the food, until the consumption time. Food and supplements may be transporters of their own microbiomes as ingested and this aspect has to receive appropriate attention, due to microbe-microbe interactions. Understanding the functional niche, evolutionary and ecologic interplay among gut microflora and host physiology including its genetics is critical for designing therapeutic/preventive manipulations of the gastrointestinal microbiota

Common NIH research areas of interest may include, but are not limited to and are not in any priority order, the following:

  1. Identification of the underlying mechanisms of action of pro/prebiotic formulation(s) to prevent and/or treat human diseases including conditions caused by emerging pathogens, such as bacteria, fungi and viruses.
  2. Studies of pro/prebiotics interventions on: microbial composition, co-metabolism, microbial-host interactions, and microbiome resilience, as it affects local and systemic metabolism, gene expression and signaling pathways.
  3. Interactions of pro/prebiotic formulations with diet, dietary supplements and/or dietary components, which produce microbial metabolites with measurable effects in risk reduction and disease prevention.
  4. Development of predictive models to understand variability in response to pro/prebiotic interventions, as influenced by variables such as: nutritional status, dietary patterns, health status, age, gender, race, or other factors.
  5. Characterization of probiotic strain activities on glycans and identification of glycan-mediated signaling pathways in health and disease, including further clarification of the effect of probiotics on mucin degradation and its consequences.
  6. Examination of the effects of drug abuse (narcotics/opiates) on the efficacy of pre/probiotics and intestinal microbiome/microflora in populations with co-occurring infections including HIV, HCV and others; study how manipulation of the microbiome would alter the human virome and pathogenesis of complications of drug use such as HIV, HCV-related disease, and interactions with pro/prebiotics.
  7. Studies of probiotics pharmacokinetics/pharmacodynamics in healthy and immunocompromised subjects.
  8. Development and validation of diagnostic tests and biomarkers to evaluate early response to pro/prebiotics interventions.
  9. Analysis of pro/prebiotic effect on resident biofilm-growing pathogens.
  10. Analysis of interaction between pro/prebiotics with medications including antibiotics and other chemotherapeutic agents as it relates to bioavailability, treatment outcome, efficacy and adverse events.
  11. Metabolomic profiling in samples from individuals/populations undergoing pro/prebiotic intervention to identify individuals/populations susceptible to the intervention.
  12. Microbial comparison of oral cavity and gut of individuals undergoing pro/prebiotic intervention.
Areas of Interest to the National Cancer Institute (NCI)

NCI plans to support rigorous translational and clinical studies to promote cancer prevention and treatment and to understand the molecular processes (including how pro/prebiotics compete with pathogens, increase the production of protective metabolites and reduce the production of pro-carcinogens, etc.) with the aim to determine how a person’s risk of developing cancer or cancer treatment outcomes can be modified by pro/prebiotics.

Several probiotics appear to have cancer protective characteristics but there are still many unanswered questions regarding the dose and timing of probiotics and the pro/prebiotics formulations which should be used for optimal result and a consideration of the types and stages of cancer or carcinogenesis for obtaining the optimal result. The pro/prebiotic consumption has local effect in the gastrointestinal tract lumen, and/or distant effect, involving immunological messengers, hormonal intermediates, and microbial metabolites.

Because food plays a critical role in maintaining and/or changing the gut microbiota, diet and nutrition should be considered in conjunction with pro/prebiotic interventions along with the subject’s stage of life and health condition, the dose and strain of probiotics, concurrent diseases and the medications taken for them, etc.

The Division of Cancer Prevention (DCP) at the NCI encourages research to understand, but not limited to:

  • The role of diet, bioactive food components and vaccines in modulating the metabolic output or diversity of the microbiota and how these interactions specifically alter cancer risk and progression.
  • Evaluating new or known specific biomarkers, gene expression and/or molecular targets influenced by pro/prebiotic interventions in the context of cancer risk and prevention.
  • Studies to generate and characterize biochemical and genetic profiles of subjects likely to benefit from prebiotic and/or probiotic interventions, and the ones placed at risk by these of interventions.
  • Analysis of the effect of probiotics, like bifidus, on the mucin production, degradation and configuration as it relates to colorectal cancer prevention and progression.

The Division of Cancer Treatment and Diagnosis (DCTD) at the NCI encourages mechanistic and translational researches focusing on:

  • The modulating effect of pro/prebiotics on outcomes of conventional cancer care, immunotherapy, and investigational drug/treatment immunotherapy, such as overall survivor, quality of life, metastasis and recurrence.
  • The adverse effect and interaction of pro/prebiotics on standard cancer treatment.
  • The development of pre/probiotic-based microbiota cancer therapies.
  • Modulation effect of natural products interventions (e.g. medicinal natural product, diet, nutrient, bioactive food component) on pre/prebiotics for cancer treatment outcome.
  • Computation modeling and experimental approaches including biomarker discovery associated this field of study.
  • Interrelationship of circadian rhythm/clock and pre/probiotics on treatment outcome.

The Division of Cancer Control and Population Studies (DCCPS) at NCI encourages studies to understand:

  • Assessment of multiple interactions among pro/prebiotics and commensal microbiome with host genetics in the context of nutritional status, demographics and other factors that may contribute to the variability in response as it relates to cancer prevention and progression.
  •  Co-occurrence among microbes reflected in shared response to the environment as opposed to competitive interactions

The Center to Reduce Cancer Health Disparities (CRCHD) at NCI encourages research focused on the interplay of race/ethnicity with pro/prebiotics combinations, and the underlying biological factors that may contribute to cancer health disparities in response to these interventions.

Areas of Interest to the National Center for Complementary and Integrative Health (NCCIH)

NCCIH actively supports research to examine mechanisms of action for probiotics/prebiotics and microbiome as high research priorities. Particularly interested outcomes include prevention and symptom management of inflammatory and pain conditions, mild to moderate anxiety, depression, and sleep conditions, and behavioral research to promote healthier lifestyles [e.g., healthy eating, physical exercise]. NCCIH will accept applications focusing on probiotic (with or without prebiotic) studies, their interactions with other natural products, or the effects of mind-body modalities on microbes.

Research approaches supported include mechanistic in vitro models and pre-clinical animal studies, as well as mechanistic clinical trials where applicable addressing the following problems:

  • Probiotic [with or without prebiotic] studies that can produce a meaningful change in measurable biological signatures (e.g., mechanism of action) in the genotype/phenotype of interest.
  • Probiotic [with or without prebiotic] studies that demonstrate mechanistic effects on essential functions [immunoregulatory; anti-inflammatory; signaling pathways; energy metabolism] that enhance health and justify selection of the modality proposed to be used in the study.
  • Probiotic [with or without prebiotic] studies utilizing multi-omic and cell-based technologies and ensure rigor and reproducibility, validation or optimization strategies on essential functions [e.g., dose-dependent or cumulative effects] that impact biological signatures and minimize the risk of toxicity and adverse events.
  • Probiotic [with or without prebiotic] studies that distinguish microbiome-genomic from host genomic expression, and their individual yield of metabolites, interactions, and impacts on human health [e.g., gut-brain; gut-hepatic; gut-bone axis].
  • Probiotic [with or without prebiotic] studies focused on distinguishing impacts of microbially produced and dietary-metabolites, including their impacts on essential functions across the life span [e.g., developmental biology; senescence].
  • Probiotic [with or without prebiotic] studies of lifestyle and behavior role on energy metabolism and health impacts.

Deadline:  standard dates and standard AIDS dates apply


Filed Under: Funding Opportunities