Gut dysbiosis impairs intestinal renewal and lipid absorption in Scarb2 deficiency-associated neurodegeneration

The study details the connection between SCARB2 deficiency and gastrointestinal dysfunction, revealing that the loss of SCARB2 leads to alterations in bile acid metabolism and dysbiosis in the gut microbiome. This disruption affects the signaling pathway involving FXR, which normally regulates bile acid synthesis and intestinal lipid absorption. The hyperactive FXR in Scarb2-deficient mice leads to a decrease in epithelial cell turnover and lipid malabsorption, particularly impacting the absorption of vitamin E, which is crucial for maintaining neurological health. The researchers further explored the impact of these changes on the gut-liver axis and found alterations in the expression of genes related to bile acid synthesis.

Key findings from the study include:

1. SCARB2 Deficiency and Gut Dysbiosis: Scarb2 deficiency in mice is associated with gut dysbiosis and altered bile acid pools, leading to hyperactivation of FXR in the intestine, which impairs epithelium renewal and lipid absorption.
2. Vitamin E Deficiency and Neuromotor Impairment: Patients with SCARB2 mutations have severely reduced vitamin E levels and cannot absorb dietary vitamin E, correlating with neuromotor impairments and neuropathy.
3. Improvement with Vitamin E Supplementation: Supplementing vitamin E or inhibiting FXR signaling in Scarb2-deficient mice mitigates neuromotor impairments and neuropathy.
4. Impaired Intestinal Renewal: Hyperactive FXR reduces the rate of epithelium turnover and proliferation, as indicated by slower migration of EdU-labeled cells and fewer Ki67-positive cells in Scarb2^−/− mice.
5. Wnt Signaling Disruption: Reduced nuclear beta-catenin and a decrease in Sox9-positive cells suggest that Wnt signaling is impaired in Scarb2^−/− mice, affecting the intestinal crypt transcription factor regulated by this pathway.

This research reveals a novel mechanism by which SCARB2 deficiency impacts the gut microbiome and bile acid metabolism, leading to impaired lipid absorption and vitamin E deficiency. The findings highlight the importance of considering gastrointestinal health and nutritional status in the management of SCARB2-related neurodegenerative diseases. By targeting FXR signaling or addressing vitamin E deficiencies, it may be possible to improve the neurological outcomes in patients with SCARB2 mutations, providing potential therapeutic avenues for managing the associated neuromotor impairments. The work entitled “ Gut dysbiosis impairs intestinal renewal and lipid absorption in Scarb2 deficiency-associated neurodegeneration” was published on Protein & Cell (published on Apr.18, 2024).