Intermittent fasting alleviates obesity-associated impairments in bone fracture healing: Exploring the role of gut microbiome

Abstract

Intermittent Fasting (IF) is a dietary strategy with metabolic benefits that can reverse certain obesity-related pathologies. This study aimed to investigate whether IF can mitigate delayed bone fracture healing associated with obesity. Using cohorts of mice on high-fat or control diets, we applied either an ad libitum feeding or an alternate-day fasting regimen to animals from both diet groups. We assessed bone healing outcomes by evaluating callus mineralization and adipocyte accumulation within the callus through micro computed tomography (micro-CT), histology, and immunohistochemical analyses. Since IF is known to modulate gut microbiome composition, often associated with improvement in various metabolic and inflammatory processes, particularly in high-fat-fed mice, we also explored the microbial community changes in IF mice through 16S rRNA sequencing of cecal samples. Metabolically, IF led to reduced body weight and improved glucose tolerance in obese mice. Regarding fracture healing outcomes, reduced/delayed mineralization and adipocyte accumulation in fracture callus tissue in the high-fat-fed cohort were significantly attenuated when the high-fat-fed mice were subjected to alternate-day fasting. These benefits of IF were not observed in lean mice fed a control diet. Furthermore, IF significantly altered the gut microbiota of mice on a high-fat diet, including an increased abundance of short-chain fatty acid producing bacteria, known for their positive effect on bone density, and a reduction in various pro-inflammatory taxa. While the mechanistic role remains unknown, these findings suggest that the improved fracture healing observed in obese mice following IF may be associated with alterations in gut microbiome composition and function.