Enhancing Mechanistic Research on Precision Probiotic Therapies (R61/R33 Clinical Trial Optional) | PAR 25 211

Opportunity Information: Apply for PAR 25 211

The NIH funding opportunity titled "Enhancing Mechanistic Research on Precision Probiotic Therapies (R61/R33 Clinical Trial Optional)" (PAR-25-211) is designed to push probiotic research beyond one-size-fits-all approaches by figuring out why the same probiotic can help some people but do little (or something different) in others. The central idea is precision probiotics: identifying measurable, person-specific biological and contextual factors that predict who will respond, and then using that knowledge to improve clinical outcomes. This NOFO is aimed at highly innovative, mechanistic work that explains probiotic response variability in humans and develops strategies to overcome barriers created by human heterogeneity.

The program uses a milestone-driven, two-stage "Phased Innovation Award" structure (R61/R33). The first stage (R61) supports up to two years of exploratory work focused on discovering and defining "unique host biological patterns" associated with differing probiotic effects. These patterns can include features such as an individual's baseline (native) microbiome, immune function, sex or gender-related biology, diet, age, genetic background, lifestyle factors, and health history. The R61 phase is intentionally suited for observational studies or secondary analyses of existing datasets, with the goal of identifying the signals, profiles, or combinations of factors that correlate with probiotic response heterogeneity and that can be used to classify subgroups (for example, likely responders vs non-responders).

The second stage (R33) supports follow-on research that tests whether the patterns identified in the R61 phase actually help improve or predict probiotic responsiveness when examined in rigorous mechanistic studies. This can be done in relevant animal models or in human subjects, and the NOFO notes that clinical trials are optional. In practice, the R33 phase is meant to move from correlation to more causal and mechanistic understanding: evaluating whether the candidate predictors from the R61 phase can reliably detect, explain, or enable improvements in probiotic response under well-controlled experimental designs. Across both phases combined, the total project period may not exceed five years.

A key feature of this NOFO is that the transition from R61 to R33 is not automatic. It is administratively reviewed and depends on clearly defined transition milestones that applicants must propose up front in the R61 application. That means applicants are expected to lay out concrete, measurable go/no-go criteria for what constitutes success in the discovery phase (for example, validated predictive signatures, reproducible subgroup definitions, thresholds of performance, feasibility metrics, or mechanistic hypotheses sufficiently supported to justify the next phase). Only if those milestones are met will NIH allow the award to move into the R33 stage.

This NOFO also notes there is a companion R33-only opportunity for teams that are ready to proceed directly to the second-phase type of work without needing the exploratory R61 stage (listed as PAR-AT-24-XXX (TEMP-25413) in the provided text). That option is relevant for groups that already have strong preliminary evidence for predictive patterns or mechanistic leads and want to focus immediately on testing them in rigorous mechanistic studies.

Eligibility is broad and includes many U.S.-based organization types: state, county, and local governments; special districts; independent school districts; public and private institutions of higher education; federally recognized tribal governments; tribal organizations (including those other than federally recognized tribal governments); public housing authorities; nonprofits (both 501(c)(3) and non-501(c)(3)); for-profit organizations (other than small businesses); and small businesses. The NOFO explicitly highlights additional eligible applicant categories such as HBCUs, Hispanic-serving institutions, Tribal Colleges and Universities, Alaska Native and Native Hawaiian Serving Institutions, and AANAPISI institutions, as well as faith-based and community-based organizations and eligible federal agencies. Foreign organizations (non-U.S. entities) are not eligible to apply, and non-domestic components of U.S. organizations are not eligible to apply; however, "foreign components" as defined by NIH policy are allowed, which generally means certain discrete collaborations or activities conducted outside the U.S. may be permissible under NIH rules even when the applicant organization is U.S.-based.

Administratively, this is a discretionary NIH grant program under a health-focused activity category, and it is associated with multiple CFDA numbers (93.121, 93.213, 93.313, 93.393, 93.866), reflecting that multiple NIH institutes or programs may be involved. The original closing date listed is June 2, 2027. The award ceiling and expected number of awards are not specified in the provided source text, which typically means applicants need to consult the full NOFO and any institute-specific guidance for budget expectations, paylines, and program priorities.

Overall, the opportunity is geared toward teams that can combine microbiome science, immunology, genetics, nutrition, clinical research, and computational or biostatistical approaches to (1) discover robust, person-level predictors of probiotic response using observational or existing data resources, and then (2) test and mechanistically validate those predictors in carefully designed experimental studies. The practical endpoint NIH is pushing toward is not just better probiotic products in general, but clearer, evidence-based ways to match probiotic interventions to the right people (or to adjust conditions so more people respond), reducing the inconsistency that has limited probiotics from achieving more reliable clinical impact.

• 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 2024-10-31.
• 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.

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