GuT-Brain Axis modifications induced by fructose are prevented by Bacillus spores through modulation of secondary bile acids

In recent years, dietary habits have shifted towards an increased consumption of ultraprocessed rich in refined sugars, such as fructose and sucrose. This dietary shift has been linked to increased rates of metabolic dysfunction to different organs, including brain. A potential mechanism linking sugar dietary intake to brain dysfunction could be through modulation of the “microbiota-gut brain axis”. Therefore, the aim of this study was to analyse the consequences of a fructose-rich diet on the gut-brain axis and the potential therapeutic impact of Bacillus spores administration in counteracting brain alterations induced by this unhealthy diet. Following the results of a metabolomic analysis to identify specific diet-induced changes in bacteria-derived metabolites, we focused on secondary bile acids (BAs), which play a key role in regulation of inflammation and act as a communication bridge along the gut-brain axis. Interestingly, a significant reduction of the neuroprotective secondary bile acid deoxycholic (DCA) and of its specific receptor TGR5 was observed in brain of sugar fed rats in comparison to control rats, while these changes were prevented in sugar fed rats concomitantly treated with probiotic spores. In line, the probiotic-driven increase in TGR5 signaling pathway led to the decrease in fructose-induced pro-inflammatory pathway (reduced NFkB activation, TNF-a and IL-6) as well as to the increase in critical markers of synaptic function and plasticity (namely BDNF, pre- and post-synaptic proteins, glutamate receptors) in hippocampus and frontal cortex. This was paralleled by spore-associated increase in brain memory function as evaluated by novel object recognition test. Overall, these results highlight that a probiotic spore supplementation, as increasing secondary-BAs and activating TGR5 signaling pathways can be a promising strategy for ameliorating brain dysfunction and cognitive decline induced by unhealthy sugar-rich diet.