Concept: Enhancing Mechanistic Research on Precision Probiotic Therapies

Project Concept Review

Council Date: May 12, 2023

Program Director: Hye-Sook Kim, Ph.D.  

Background

Naturally occurring microbial-based therapeutics include probiotics—living microorganisms, such as bacteria and yeast, with promising beneficial health effects. These effects may include alleviation of gastrointestinal symptoms, “strengthening” of the immune system, protection against infectious diseases, prevention of metabolic disorders, improvement of mental health, and promotion of early development and general well-being. A major challenge in probiotic research is differential responses to the same probiotic intervention among individuals, resulting in significant variability in clinical effects. Such variability may stem from high heterogeneity in humans in terms of diet, age range, genetic background, gender, health history, lifestyle, and gut microbiome composition and has hampered effective evaluation of clinical efficacies of probiotics and their integration as well as implementation into current health care systems. One potential solution to tackle this major challenge is to develop a precision probiotics intervention paradigm that has the capability to predict interindividual variations and tailor probiotic strains to individual-specific features. However, this approach requires fundamental understanding of real-life variability of probiotic responses at the individual level as well as development of innovative research tools and strategies to address the complexity of person-specific characteristics. 

In April 2022, the National Center for Complementary and Integrative Health (NCCIH) and the Office of Dietary Supplements (ODS) within the National Institutes of Health (NIH), in collaboration with other NIH Institutes, Centers, and Offices as well as the U.S. Department of Agriculture, convened a 2-day workshop, “Precision Probiotic Therapies—Challenges and Opportunities,” to identify gaps in our current understanding of the biology of the gut microbiota and of probiotics, and to discuss the associated research questions and methodological challenges.

During the workshop, several major issues emerged. First, it was recognized that the study designs of most probiotic clinical trials did not fully capture the complex patterns of the gut microbiome, host genetic variability, dietary differences, and environmental exposures of both the microbes and hosts, although all of these are critical considerations for probiotic responsiveness within individuals. Second, although many cross-sectional observational epidemiologic studies have examined these complex patterns, few of their insights have been effectively translated to robust mechanistic studies to test for causality or to rigorous mechanistic clinical trials. Third, understanding the intricate relationships among multiple complex systems, including the microbiome, host, and environment, requires advanced computational and artificial intelligence (AI) approaches. 

Purpose of Proposed Initiative

This proposed initiative aims to support highly innovative mechanistic research to develop precision probiotic interventions using a two-phase approach.

Objectives

The first phase of the proposed initiative will support observational clinical studies or secondary data analysis to identify: 1) unique patterns of microbial/probiotic host-environment interactions; 2) probiotic strains in healthy and clinical populations that may be important for intended probiotic health effects. 

The second phase will use the data gathered and strains identified in phase 1 to test for causality in rigorously designed mechanistic studies in relevant animal models or in human subjects. Studies that have already identified putative probiotic strains and/or unique patterns of interplay may be supported to pursue the second phase directly. These studies would focus on health conditions such as metabolic and mental disorders, gastrointestinal dysfunction, and pain. 

Examples of research topics of interest to this initiative include, but are not restricted to:

Phase 1 (observational clinical studies or secondary data analysis):

• Rigorous assessment of the microbiome and host biology for mapping person-specific factors.
• Development of computational analysis and AI tools for determining critical factors to identify patient subpopulations.

Phase 2:

• Identification of novel biomarkers in diagnosis and prognosis.
• Mechanistic studies in clinically relevant preclinical models or human populations to interrogate mechanisms of action of and resistant/interfering factors to probiotic interventions.
• Identification of new targets for intended probiotic effects.
• Discovery and development of novel probiotic strains. 
• Determination of dynamic mechanisms of probiotic interventions.