Oral lipoteichoic and lipoic acids improve insulin resistance and body composition in porphyria mice on a high-carbohydrate diet.

Abstract

Acute intermittent porphyria (AIP) is a genetic metabolic disorder characterized by neurovisceral attacks. Although high-carbohydrate diets or intravenous glucose administration can help alleviate incipient attacks in patients, these interventions may also promote insulin resistance and increase metabolic risk. This study explored targeted dietary interventions to manage hyperinsulinemia and to enhance glucose uptake in insulin-sensitive organs under high-carbohydrate diet. Body composition and fecal microbiota profile were also investigated in a murine model of the disease. Wild-type and AIP mice (n = 6/group) were supplemented with tapioca maltodextrin in drinking water for 12 weeks, alongside heat-treated Bifidobacterium animalis subsp. lactis CECT-8145 (BPL1®HT), its by-product lipoteichoic acid (LTA), or the insulin-sensitizing agent α-lipoic acid (α-LA). Liver-targeted therapies, previously assessed in AIP mice, were also included in this study. AIP mice on a high-carbohydrate diet exhibited hyperinsulinemia and tissue-specific differences in glucose uptake compared to wild-type mice. Dysbiosis, marked by reduced fecal Dorea spp. and Adlercreutzia muris, alongside higher abundance of Escherichia coli, was also showed. Supplementation with α-LA and LTA revealed superior ability to improve glucose tolerance test and skeletal muscle glucose uptake, reduce hyperinsulinemia, and enhance body composition by increasing lean mass relative to fat, compared to gene therapy or liver-targeted insulin administration. Notably, LTA restored fecal microbiota profiles resembling those of wild-type mice. In conclusion, supplementation with LTA from BPL1®HT and α-LA may represent promising dietary interventions to manage glucose tolerance, improve insulin sensitivity in muscle and adipose tissues, and potentially ameliorate body composition in AIP patients under a high-carbohydrate diet.