Obesogenic diet and gut microbiome synergistically enhance anti-PD-1 efficacy via Lactobacillus johnsonii and aromatic amino acid metabolites (nature.com)

• Obesogenic diets (4/6) associated with ICI response; only 2/6 non-obesogenic diets responded. Response independent of metabolic dysfunction.
• Diet switch from Psyllium to High Fat within 48h sensitized tumours to anti-PD-1, with rapid Lactobacillus enrichment and improved T cell function.
• L. johnsonii monocolonization with High Fat diet led to complete responses; combination required for synergy. Human FMT from high-BMI donors enhanced ICI efficacy.
• Serum metabolomics identified aromatic amino acid metabolites (e.g., indole-3-lactic acid) enriched in responders, with ILA boosting T cell activity.
• High Fat diet remodeled non-responder FMT microbiota to restore ICI sensitivity, demonstrating diet overrides donor status.

"A Nature study using 12 mouse diet models shows that obesity-associated immune checkpoint inhibitor (ICI) response depends on diet–gut axis interaction, not metabolic dysfunction. Obesogenic diets promote a gut microbial ecosystem (enriched in Lactobacillus johnsonii) that restores ICI sensitivity after diet switch or fecal microbiota transplantation (FMT) from non-responder donors. Monocolonization with L. johnsonii plus an obesogenic diet synergistically induces tumour regression through aromatic amino acid metabolites (e.g., indole-3-lactic acid). Human-to-mouse FMT from high-BMI donors enhanced ICI efficacy. The findings suggest immunomodulatory synergy between diet and microbiome could improve ICI outcomes."