**Background:** Bronchial asthma (BA) is one of the most common allergic diseases in childhood, affecting over 300 million people worldwide. Gut microbiota and its metabolites, particularly short-chain fatty acids (SCFAs) like propionate, have been implicated in various diseases, but their role in pediatric BA was poorly understood. This study aimed to determine whether intestinal propionate during the lactation period influences the development of bronchial asthma.
**Methods:** In the mouse experiments, pregnant C57BL/6 mice were given drinking water containing 200 mM acetate, 200 mM propionate, 200 mM butyrate, or control plain water starting from embryonic day 14 or immediately after delivery. Offspring were weaned at day 21 and raised on plain water. At 6 weeks of age, offspring were sensitized and challenged with intratracheal administration of house dust mite (HDM) extract (1 μg for sensitization, 10 μg for challenge). Inflammatory cells in bronchoalveolar lavage fluid (BALF) and lung were evaluated 72 hours after the last challenge. GPR41 knockout (GPR41−/−) and GPR43 knockout (GPR43−/−) mice were used to identify the receptor mediating propionate effects. RNA sequencing was performed on small intestinal lamina propria (SILP) eosinophils from propionate-fed and control mice. For the human study, 269 pregnant women with a family history of allergic diseases were recruited (CHIBA Study). Fecal samples were collected at 1 week, 1 month, 1 year, and 5 years of age; breast milk samples at 1 week, 1 month, and 6 months. After exclusions, 204 participants were analyzed: 23 in the BA-onset group and 181 in the non-BA group. Fecal SCFAs were measured by gas chromatography-mass spectrometry.
**Key Results:** In mice, propionate-fed animals had significantly fewer eosinophils and CD4+ T cells in BALF and lung compared to control, acetate, and butyrate groups (p < 0.05 and p < 0.01 by one-way ANOVA and Tukey's test). HDM-induced Th2 cytokines IL-5 and IL-13 were significantly decreased in the propionate group. GPR41 deficiency completely eliminated the protective effect of propionate, while GPR43 deficiency did not. Using heterozygous breeding, the effect was shown to depend on GPR41 expression in offspring, not mothers. Gpr41 mRNA was strongly expressed in eosinophils from both SILP and lungs. RNA sequencing revealed 110 upregulated and 56 downregulated genes in eosinophils from propionate-fed mice, with toll-like receptor (TLR) signaling pathway as the top hit in Gene Ontology analysis. TLR2, TLR8, and TLR9 mRNA were significantly upregulated in SILP and lung eosinophils from propionate-treated wild-type mice but not in GPR41−/− mice. In the human cohort, fecal propionate at 1 month of age was lower in the BA group compared to the NBA group (statistically not significant for individual SCFAs), while no differences were observed at 1 week, 1 year, or 5 years. Breast milk SCFA concentrations did not differ between groups. Microbiome analysis suggested Bacteroides, Varibaculum, Bifidobacterium, and Parabacteroides as potential propionate-producing genera.
**Clinical Implications:** This study provides evidence that propionate during the lactation period can protect against subsequent allergic airway inflammation through a GPR41-dependent mechanism involving TLR upregulation on eosinophils. The finding that fecal propionate is decreased at 1 month of age in infants who later develop asthma suggests that early-life gut microbiota composition and propionate production may be a modifiable risk factor for childhood asthma. If confirmed in larger cohorts, interventions to increase intestinal propionate in early infancy—such as maternal diet modification, probiotic supplementation, or direct propionate administration—could represent novel preventive strategies for pediatric bronchial asthma. The study is limited by its relatively small human cohort size (n=204, 23 BA cases) and the Japanese-specific population, which may explain discrepancies with Western studies that found butyrate rather than propionate associations with asthma.