Synergistic effects of dietary interventions and probiotics on GUT-lung immune modulation: exploring combined fiber-rich diet, intermittent fasting, and probiotic strategies to alleviate lung inflamma

The National Institute of Allergy and Infectious Diseases awarded The Regents of the University of California, San Francisco $205,000 on September 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate synergistic effects of dietary interventions and probiotics on gut-lung immune modulation.

The project explores how fiber-rich diet combined with intermittent fasting and probiotic strategies can attenuate sterile lung injury. Research Aim 1 tests whether a two-week fiber-rich diet plus intermittent fasting additively reduces acute lung injury caused by ischemia-reperfusion-induced inflammation by enhancing short-chain fatty acid and tryptophan metabolite production. The study uses a mouse model with comprehensive analysis including gut microbiota profiling via 16S rRNA sequencing, metabolomics via gas chromatography-mass spectrometry of feces, blood, and lung tissue, and single-cell RNA sequencing of alveolar macrophages. Research Aim 2 investigates how propionate- and indole-3-propionate-producing probiotics, alone or in combination, affect lung ischemia-reperfusion injury over a three-week pretreatment period, with in vitro co-culture experiments first defining bacterial synergy in metabolite production before testing the most promising combination in vivo.

The award is a Project Grant with a period of performance from September 1, 2026, through August 31, 2028. Work is performed in San Francisco, California. The program supports research to establish, expand, and improve biomedical research in infectious diseases and related areas.

Abstract

Each year, 35 million americans struggle with chronic lung disease, and 200,000 suffer from acute lung injury, which carries a 40% mortality rate. The GUT-lung axis represents a promising therapeutic target because GUT microbiota and their metabolites profoundly influence lung immune responses. While dietary interventions such as a fiber-rich (FR) diet increase short- chain fatty acids (scfas) and intermittent fasting increases tryptophan metabolites (e.g., indole- 3-propionate, IPA), the potential synergy of combining these dietary strategies remains unclear. Probiotic strains capable of producing scfas or IPA are also promising, but optimal combinations and their effects on lung inflammation have not been fully elucidated. This R21 project aims to determine how the integration of an FR diet with intermittent fasting or the use of combined probiotics can attenuate sterile lung injury. Aim 1 will test whether a 2-week FR diet plus intermittent fasting additively reduces acute lung injury caused by ischemia- reperfusion (IR)-induced inflammation by enhancing scfa and IPA production. Mice will undergo lung IR after dietary treatment, and comprehensive analysis will include GUT microbiota profiling (16S rrna sequencing), metabolomics (gas chromatography-mass spectrometry of feces, blood, and lung tissue), and single-cell RNA sequencing of alveolar macrophages. Aim 2 will investigate how propionate- and IPA-producing probiotics, alone or in combination, affect lung IR injury over a 3-week pretreatment period. An in vitro CO-culture experiment will first define bacterial synergy in metabolite production before testing the most promising pair in vivo. Correlations between specific bacteria taxa, metabolite levels, and inflammatory markers will elucidate the mechanisms underlying GUT-lung crosstalk. By integrating state-of-the-art in vivo and in vitro approaches, the proposed research will elucidate how dietary and probiotic strategies enhance lung immunity. Findings will inform the development of novel, non-pharmacological interventions for the prevention and treatment of lung and potentially other inflammatory diseases, advancing health promotion, resilience, and disease prevention goals.