Bifidobacterium longum and prebiotic interventions restore early-life high-fat/high-sugar diet-induced alterations in feeding behavior in adult mice.

Cuesta-Marti C, Ponce-España E, Uhlig F, Stoltenborg I, Wasiewska LA, Kareem L, Hedayatpour D, Olavarría-Ramírez L, Rosell-Cardona C, Bastiaanssen TFS, Tofani GSS, Valderrama B, Vlckova K, Dickson SL, Lavelle A, Stanton C, Ross RP, Cryan JF, Dinan TG, Clarke G, O'Mahony SM, Schellekens H

Nat Commun 17 (1) - [2026-02-24; online 2026-02-24]

An unhealthy diet disrupts feeding behavior and the gut microbiota, but whether early-life dietary effects persist, or can be restored later in life, remains unclear. We investigated whether microbiota-targeted interventions (FOS + GOS or Bifidobacterium longum APC1472) could restore early-life high-fat/high-sugar (HFHS) diet-induced feeding alterations in adult female and male mice. HFHS exposure exclusively in early-life induced persistent, sex-specific feeding alterations in adult mice, despite normalized body weight. Early-life HFHS diet reduced hypothalamic cells expressing feeding-related markers (POMC, GHSR, PNOC, NOD2) in adult mice. Females were more vulnerable, with reduced LEPR+ cells and disrupted arginine/tryptophan metabolism, while males showed impaired peptidoglycan sensing and steroid metabolism. We show that microbiota interventions restore these effects via distinct mechanisms. FOS + GOS induced extensive microbiome compositional shifts and sex-specific restoration of gut-brain pathways, while B. longum APC1472 induced greater behavioral restoration with minimal microbiome compositional changes. These findings highlight sex-specific vulnerabilities and mechanism-dependent therapeutic potential of microbiota-based interventions after exposure to early-life unhealthy diets.

Integrated Microscopy Technologies Gothenburg [Service]

PubMed 41735265

DOI 10.1038/s41467-026-68968-2

Crossref 10.1038/s41467-026-68968-2

pmc: PMC12932662
pii: 10.1038/s41467-026-68968-2