Dietary Protein Modulation, Gut Microbiota, and Metabolic Control in Methylmalonic Acidemia: A Prospective Longitudinal Study.

Transition to an intact protein-enriched diet significantly reduced plasma leucine levels without affecting isoleucine or valine.

• Eight genetically confirmed MMA patients were studied in a prospective, longitudinal, single-center design.
• The intact protein-enriched phase consisted of 80% intact protein and 20% medical formula.
• Plasma leucine reduction reached statistical significance (p = 0.008).
• Isoleucine and valine levels were not significantly affected by the dietary change.

Transition to an intact protein-enriched diet reduced urinary methylmalonic acid, 3-hydroxypropionate, lactate, and pyruvate, indicating improved propionyl-CoA clearance.

• Four sequential dietary/treatment phases were analyzed: baseline mixed-protein diet (50% intact protein/50% medical formula), protein restriction, intact protein enrichment, and adjunctive metronidazole therapy.
• Urinary metabolites were measured as part of untargeted/tandem metabolomic profiles at each phase.
• Decreases in these urinary metabolites were interpreted as reflecting improved propionyl-CoA clearance.
• Plasma amino acids, urinary metabolites, stool microbiota, and metabolomic profiles were all analyzed at each phase.

Gut microbiota diversity progressively declined across dietary phases, accompanied by reductions in butyrate-producing genera.

• Stool microbiota was assessed by 16S rRNA long-read sequencing at each study phase.
• Butyrate-producing genera that decreased included Novisyntrophococcus, Lacrimispora, and Hespellia.
• Microbiota diversity declined progressively across the sequential study phases.
• The study used a prospective longitudinal design with eight MMA patients.

Adjunctive metronidazole therapy further lowered urinary methylmalonic acid and 3-hydroxypropionate with parallel decreases in fecal 3-indolelactic acid and phytosphingosine.

• Metronidazole was administered at 20 mg/kg/day for 10 days/month for 3 months.
• Urinary methylmalonic acid decreased with statistical significance (p = 0.017) following metronidazole therapy.
• Urinary 3-hydroxypropionate also decreased significantly (p = 0.028).
• Parallel decreases in fecal 3-indolelactic acid and phytosphingosine were observed, suggesting suppression of gut-derived propionate and tryptophan metabolism.

Metronidazole therapy induced dysbiosis with expansion of Trabulsiella (Proteobacteria) despite a decrease in systemic propiogenic burden.

• Antibiotic-induced dysbiosis was characterized by expansion of Trabulsiella, a member of the Proteobacteria phylum.
• Despite this dysbiosis, systemic propiogenic burden decreased during metronidazole treatment.
• Metronidazole was used as adjunctive therapy in the fourth sequential phase of the study.
• The dissociation between dysbiosis and reduced propiogenic burden suggests gut-targeted suppression of propionate-producing bacteria contributed to metabolic improvement.

Both dietary protein composition and intestinal microbiota influence metabolic stability and clinical outcomes in MMA, supporting microbiome-informed dietary strategies.

• The study was designed to evaluate effects of stepwise dietary modification and short-term metronidazole therapy on systemic and gut-derived metabolic profiles.
• MMA is caused by defective conversion of methylmalonyl-CoA to succinyl-CoA.
• Emerging evidence cited in the background suggests gut microbiota contribute to propiogenic substrate load in MMA.
• Findings were interpreted as supporting selective gut-targeted interventions to optimize metabolic control in organic acidemias.