Exploring the impact of collagen-I genetic variants on intestinal structure and gut microbiota in mouse models of osteogenesis imperfecta

Osteogenesis imperfecta (OI), an inherited connective tissue disorder, primarily results from genetic variants that alter collagen-I. Collagen-I also plays a crucial role in intestinal structure and function. A recent large cohort reported an increased risk of gastrointestinal diseases in OI patients, including peptic ulcer disease, inflammatory bowel disease, and constipation. However, the extent of intestinal phenotypic alterations and gut microbiota shifts in OI remains uncertain. Using OI mouse models, Col1a1Jrt/+ and Oim-/-, we explored the effects of collagen-I genetic variants on intestinal morphology, function, and microbiota. Regular chow-fed female and male OI mice and respective wildtype littermates (WT) were studied at 4, 8, and 12 weeks of age. OI mice were significantly smaller than WT. They exhibited reduced intestinal expression and quantity of collagen-I; additionally, expression of collagen-III and elastin was reduced in male Oim-/- mice. Structurally, shorter crypts were observed in OI small intestine, suggesting potential structural atrophy secondary to disrupted intestinal collagen content. OI mice maintained gut integrity and demonstrated a greater gut length to body mass ratio, suggesting a morphological adaptive strategy for greater energy demands in OI. Microbiome profiling revealed generally similar microbial composition in OI mice and WT; however, reduced levels of Lactobacillus were consistently observed in female Col1a1Jrt/+ and Oim-/- mice. In keeping, we observed reduced cecal short-chain fatty acid concentrations in female Col1a1Jrt/+ and Oim-/- mice. This study unveils a previously unexplored sex-dependent intestinal phenotype in OI mice, highlighting gut health as a critical consideration in OI management.