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Complex Interactions Involving Nutritional Interventions

Introduction and Explanation of Need

Nutritional interventions have millennia of history as therapeutic agents. They commonly include the phytochemicals found in fruits and vegetables, fermented foods containing probiotic cultures, other natural products, and traditional medicine practices that rely heavily on plants. In all cases, the interventions are delivered as complex mixtures and are thought to act across multiple biological systems. Despite this, there is relatively little research on the use of complex mixtures for their health-promoting effects or on the study of how natural products impact multiple biological systems. In part, this is due to the difficulty in systematically studying the complexity of multicomponent and multisystem interactions. Despite the advances in all areas of medicine, scientists still struggle to rigorously study complex multisystem interactions.

Given the difficulty of assessing complex interactions with current approaches, innovative strategies are needed to further elucidate how nutritional interventions, whether in the form of botanicals, probiotics, or dietary constituents, may have health benefits. The potential benefits of these complex interactions could manifest themselves in multiple ways. This includes multiple components of a dietary intervention acting on a single biological system (e.g., nervous or digestive), a single component acting on multiple systems (e.g., omega-3 fatty acids), or multiple components acting on multiple systems (e.g., traditional herbal medicine, probiotics). It also includes the possibility that these complex interactions produce more than additive (i.e., synergistic) effects. Cocktail approaches are used increasingly in modern medicine, as evidenced by current approaches in chemotherapy and antiretroviral and antimicrobial regimens. While the principle of complex interactions and synergy is mentioned often to justify research on natural products, rigorous efforts to quantify these multicomponent and multisystem activities in nutritional interventions is lacking. Classic pharmaceutical development seeks to identify a single active compound that acts at a single target site. This has been a very successful endeavor, as evidenced by the high percentage of pharmaceuticals derived from natural products, but it might not readily apply to the study of multisystem and multicomponent interactions involving nutritional interventions. Thus, a deeper understanding of the systems-level interactions of natural products with human biology, including the microbiome, is needed to answer fundamental questions regarding their health-promoting effects.

What Does Success Look Like?

  • NCCIH supports a robust portfolio of research focused on the study of nutritional interventions, including individual plants/probiotics as well as multibotanical and multistrain formulas, and their potentially synergistic interactions with single or multiple biological systems.
  • Enhanced multisystem research approaches that tie together various cellular, gut microbial, and genetic contributors to health restoration and disease prevention.
  • Substantial development or application of cutting-edge multidisciplinary approaches, including bioinformatic and data sciences, to uncover contributions from multiple constituents that may produce subtle changes individually yet yield outsized benefits across multiple biological systems in combination.
  • Translation of innovative mechanistic studies from in vitro and animal models into human efficacy and effectiveness studies with a strong focus on multisystem outcomes.



  • Use phenotypic models (e.g., cellular, invertebrate, rodent) to study the potential of multiple components in botanical mixtures to act through multiple mechanisms and produce better outcomes than individual constituents.
  • Explore innovative multisystem mechanistic interactions (e.g., between the digestive system and the brain or between immune and musculoskeletal or myofascial systems) of botanicals.
  • Investigate the theoretical framework underlying the roles of individual components in multibotanical formulae, including how they contribute to activity, bioavailability, and/or toxicity.

Dietary Phytochemicals

  • Investigate phytochemicals abundant in fruits and vegetables and how their diverse individual activities interact in combination and across multiple systems.
  • Develop and test a unifying hypothesis to explain the broad activity of polyphenols.


  • Explore spatial and temporal dynamics of biological activities of probiotics in the gastrointestinal tract.
  • Investigate novel mechanisms underlying multisystem effects (e.g., interlinking the gastrointestinal tract, immune system, and brain) of probiotics.
  • Conduct systematic and mechanistic studies of how the gut microbiome influences interactive effects of probiotics with other dietary interventions.
  • Explore discrete combinations of plants and/or plant constituents with probiotic strains to ascertain how their combined activities differ from either individually.

Methods Development

  • Develop and validate computational models to predict the presence of synergistic components in complex dietary interventions.
  • Develop and test advanced prognostic and diagnostic systems with a combination of biosensors and artificial intelligence to monitor and predict host physiological status improved by probiotics and complex dietary interventions.
  • Compare and validate various traditional diagnostic and prognostic medical systems in contrast to analogous contemporary Western medical diagnostic and prognostic systems.
  • Develop and validate in vitro and/or in vivo models capable of simultaneously assessing multiple biological systems.
  • Develop and validate innovative systems biology models incorporating diverse phytochemical inputs and their interaction with multiple biological systems.

Low-Priority Topics

  • Studies on combinations of macronutrients (fats, carbohydrates, proteins) for their nutritional effects.
  • Studies on vitamins, minerals, or amino acids individually or in combination for their nutritional effects or to address nutritional deficiencies.
  • Broad epidemiological studies of correlations between dietary patterns and health outcomes.
  • Research in humans using dietary constituents individually or in combination for treatment or prevention of chronic disease conditions specifically within the mission of other NIH Institutes and Centers (e.g., cancer, diabetes, cardiovascular disease).
  • Studies on mechanisms already well established or known for a natural product or a category of natural products.