Enhancing Mechanistic Research on Precision Probiotic Therapies (R61/R33 Clinical Trial Optional) | PAR 24 238

Opportunity Information: Apply for PAR 24 238

The NIH funding opportunity PAR-24-238, titled "Enhancing Mechanistic Research on Precision Probiotic Therapies (R61/R33 Clinical Trial Optional)," is aimed at fixing a common problem in probiotic research and practice: people often respond very differently to the same probiotic, and those inconsistent results make it hard to reliably improve clinical outcomes. This NOFO is designed to push the field beyond one-size-fits-all probiotic studies by supporting highly innovative, mechanistic research that explains why responses vary across individuals and how to use that information to design more precise, more effective probiotic interventions. The emphasis is on identifying person-specific features that shape probiotic response, defining subgroups of likely responders, and developing strategies to overcome barriers created by human heterogeneity.

The award uses a milestone-driven, two-phase "phased innovation" structure called the R61/R33 mechanism. The first phase (R61) is an exploratory, early-stage period lasting up to two years. In this phase, projects are expected to use observational studies and/or secondary data analyses to discover and validate host biological patterns associated with differences in probiotic effects. The NOFO gives examples of the types of person-specific features that may matter, such as an individual’s baseline or native microbiome, immune system characteristics, sex or gender-related factors, diet, age, genetic background, lifestyle, and overall health history. The key output of the R61 period is not simply descriptive findings, but credible, well-defined patterns or signatures that can plausibly explain heterogeneity in clinical effects and can be carried forward into mechanistic testing.

The second phase (R33) supports the next step: rigorously designed mechanistic studies to test whether the patterns identified in R61 can actually be used to detect, explain, or improve probiotic responsiveness. This phase can involve relevant animal models or human subjects, and it is intended to move beyond correlation toward mechanism, including clarifying causal pathways and testing approaches that could improve outcomes in defined subgroups. Clinical trials are optional under this NOFO, meaning applicants can propose clinical trial activities when justified, but the program is not limited to clinical trials and is also open to mechanistic human or animal work that may not meet the definition of a clinical trial.

A central feature of this NOFO is that progression from the R61 phase to the R33 phase is not automatic. The transition is administratively reviewed and depends on successful completion of clearly stated transition milestones that applicants must specify in the R61 application. In practice, that means applicants need to lay out concrete, measurable go/no-go criteria for what counts as success in the discovery/identification phase and what evidence will justify moving into the mechanistic validation phase. Across both phases, the total project period cannot exceed five years, reinforcing the expectation that the work is focused, milestone-based, and oriented toward actionable advances rather than open-ended exploration.

The NOFO also notes a companion option for teams that are already positioned to begin the later-stage work and do not need the exploratory R61 period. In those cases, investigators may consider the companion R33-only announcement (listed as PAR-AT-24-XXX, TEMP-25413 in the text provided), which supports a single phased award without the initial exploratory component. This creates two entry points: one for projects that still need discovery work to define responder patterns, and another for projects ready to test and validate mechanistic hypotheses immediately.

Eligibility is broad and includes many types of U.S.-based organizations and government entities. Eligible applicants include state, county, and local governments; special district governments; independent school districts; public and private institutions of higher education; federally recognized Native American tribal governments; tribal organizations other than federally recognized tribal governments; public housing authorities/Indian housing authorities; nonprofits with or without 501(c)(3) status (excluding institutions of higher education when specified); for-profit organizations (other than small businesses); and small businesses. The NOFO explicitly highlights additional eligible applicant categories such as HBCUs, Hispanic-serving institutions, AANAPISIs, tribally controlled colleges and universities (TCCUs), Alaska Native and Native Hawaiian Serving Institutions, faith-based or community-based organizations, regional organizations, eligible federal agencies, and U.S. territories or possessions. At the same time, non-domestic (non-U.S.) entities are not eligible to apply, and non-domestic components of U.S. organizations are not eligible. However, foreign components, as defined by NIH policy, are allowed, which can enable certain international collaborations as part of an otherwise eligible U.S.-led application.

Administratively, the opportunity is an NIH discretionary grant program in the education and health activity category, with CFDA numbers listed as 93.121, 93.213, 93.313, 93.393, and 93.866. The opportunity was created on June 17, 2024, and the original closing date shown is June 2, 2027. The notice does not provide an award ceiling or expected number of awards in the provided text, so applicants would typically look to the full NOFO and NIH Institute/Center participation details to understand budget expectations, paylines, and programmatic priorities.

Overall, this NOFO is best understood as an effort to make probiotic therapy more predictable and clinically meaningful by building a precision framework: first discover which measurable host factors drive response differences, then test those factors mechanistically to show how they can be used to improve responsiveness and outcomes. The phased structure, milestone requirements, and focus on heterogeneity signal that NIH is prioritizing projects that can move from real-world variability to testable mechanisms and, ultimately, to practical strategies for matching probiotics to the people most likely to benefit.

• The National Institutes of Health in the education, health sector is offering a public funding opportunity titled "Enhancing Mechanistic Research on Precision Probiotic Therapies (R61/R33 Clinical Trial Optional)" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.121, 93.213, 93.313, 93.393, 93.866.
• This funding opportunity was created on 2024-06-17.
• Applicants must submit their applications by 2027-06-02.
• Eligible applicants include: State governments, County governments, City or township governments, Special district governments, Independent school districts, Public and State controlled institutions of higher education, Native American tribal governments (Federally recognized), Public housing authorities/Indian housing authorities, Native American tribal organizations (other than Federally recognized tribal governments), Nonprofits having a 501 (c) (3) status with the IRS, other than institutions of higher education, Nonprofits that do not have a 501 (c) (3) status with the IRS, other than institutions of higher education, Private institutions of higher education, For-profit organizations other than small businesses, Small businesses, Others.

Apply for PAR 24 238

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