Background Glucose intolerance and hyperinsulinemia are emerging risk factors in patients affected by Acute intermittent porphyria (AIP), a metabolic rare disorder caused by the haploinsufficiency of PBGD activity, the third enzyme of heme biosynthesis. Previously, we found that lipoic acid (α-LA), an insulin-mimetic, improved glycolysis and ATP production in PBGD-silenced hepatocytes. Here, we investigated whether nutritional interventions may correct carbohydrate metabolic dysfunctions in a murine model of AIP.

Methods Firstly, we assessed the short (2 weeks) and long-term (3 months) α-LA efficacy on glucidic and energy balance in the liver and insulin-sensitive tissues. Secondly, we explored new dietary options, previously tested in metabolic disorders, on the same targets by evaluating the effects of live organisms (Bacillus coagulans, BC-30^TM), postbiotics (heat-treated Bifidobacterium animalis subsp. lactis CECT8145, BPL1^® HT) and a lipoteichoic acid (LTA: metabolite derived from B. animalis strain) orally administered for 3 months. Compositional and functional changes in fecal microbiota before and after supplementation were assessed using shotgun metagenomic sequencing.

Results After 2 weeks, α-LA normalized GTT, insulin levels and reduced the aberrant hepatic insulin signaling activation in fasted AIP mice. Glycogenolysis/gluconeogenesis and Glut2, which mediates glucose-dependent transport into the blood, were upregulated in AIP+α-LA group, sustaining that α-LA ameliorates glucose handling. Glut3/4 transporters were higher in brain, muscle and white adipose tissue (WAT) of AIP+α-LA mice. At 3 months, PET/CT scan revealed enhanced glucose uptake in the liver, brain, muscle and WAT of AIP+α-LA mice. The administration of BC-30, BPL1^® HT, and LTA increased glucose uptake in skeletal muscle, resulting in improved glucose tolerance, insulin sensitivity, and muscular energy utilization. Additionally, LTA, BC-30 and α-LA improved lean/fat ratios and increased muscle mass by stimulating fat disposal in both brown (BAT) and WAT tissues. Lipid breakdown can be facilitated by muscle contractions during exercise and heat dissipation by BAT. Analysis of fecal microbiota revealed that metabolic improvements observed with the diets may be related to changes in intestinal flora. AIP mice plus BC-30 showed an enrichment in species involved in glucose control (i.e. Odoribacter laneus) and reduced Lachnospiraceae abundance, regulating carbohydrate digestion. LTA treatment lowered harmful gram-negative bacteria like E. coli, and α-LA and LTA enhanced those with protective activities against hyperglycemia (Clostridium cocleatum and Alistipes communis), potentially explaining the improvement in glucose tolerance.

Conclusions Oral insulin sensitizers (α-LA) or intervention with LTA, life BC-30 or BPL1^® HT restored hyperinsulinemia and improved carbohydrate metabolism in AIP mice.