Small intestine-residing probiotics suppress neurotoxic bile acid production via extracellular vesicle-mediated inhibition of Clostridium scindens.

Dysbiosis in gut microbiota and abnormalities in bile acids have been linked to neurodegenerative diseases. While many studies have focused on the relationship between colonic bacteria and Alzheimer's disease (AD), this study propose that alterations in the small intestine microbiota may play a more critical role. This is because the small intestine is pivotal in recycling bile acids through enterohepatic circulation. This study uses amyloid precursor protein knock-in (APPNL-G-F/NL-G-F) transgenic mice to investigate the association between intestinal microbiota and bile acid metabolism. The results showed that the accumulation of beta-amyloid (Aβ) leads to a significant decrease in Lactobacillus johnsonii and a notable increase in bacteria of the genus Clostridium in the small intestine, which are important microorganisms for producing toxic bile acids. Extracellular vesicles (EVs) involved in bacterial interactions and bacteria-host interactions are currently a focus of research. Treatment with L. johnsonii-derived EVs at concentrations of 1010 and 1012/mL) inhibited the growth of Clostridium scindens and suppressed the production of toxic secondary lithocholic acid (TLA) at non-cytotoxic concentrations (108/mL). Furthermore, the removal of small RNA from L. johnsonii-derived EVs resulted in the loss of their ability to suppress TLA production. These results suggest that the small intestine microbiota may play a more critical role than the colonic microbiota in AD. Deterioration of small intestine microbiota led to the metabolism disruption of certain secondary bile acids, which have been reported to exacerbate AD pathology. The EVs released by L. johnsonii, which is abundant in the small intestine, can suppress toxic TLA and have the potential to be developed into health-promoting probiotics.