António E. Abreu

Butyrate, a short-chain fatty acid (SCFA) produced by gut microbiota, plays crucial roles in maintaining intestinal homeostasis and modulating the gut-brain axis. Dysbiosis and SCFA imbalances are increasingly recognized as contributors to disease pathogenesis. A decrease in butyrate-producing bacteria leads to reduced butyrate levels, which have been linked to increased intestinal permeability, systemic inflammation, and neuroinflammation. Emerging evidence highlights a potential therapeutic role for butyrate in Parkinson’s Disease (PD). This review examines butyrate’s origins, functions, and mechanisms in the gut, its impact on the gut-brain axis, and its relevance in both “brain-first” and “gut-first” PD models. We also explore the effects of butyrate supplementation in animal models and human clinical studies, highlighting its promise as a therapeutic agent for PD. The understanding of butyrate as a versatile metabolite may pave the way for innovative strategies to prevent or manage PD, stressing the need for integrated approaches targeting both the nervous and gastrointestinal systems.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder with an unknown cause. Recent research has highlighted the importance of the gut in neuronal and immune maturation through the exchange of nutrients and cellular signals. This has led to the “gut-first PD” hypothesis, which aims to explain many of the sporadic cases and their prodromal intestinal symptoms, such as constipation and intestinal α-synuclein (aSyn) aggregation. The link between mitochondrial dysfunction and aSyn deposition is central to PD pathophysiology, since they can also trigger pro-inflammatory signals associated with aSyn deposition, potentially contributing to the onset of PD. As mitochondria are derived from ancestral alpha-proteobacteria, other bacteria may specifically target this organelle. We sought to use Nocardia cyriacigeorgica, a bacterium previously associated with parkinsonism, and dextran sulfate sodium (DSS) as pro-inflammatory modulators to gain further insight into the onset of PD. This study indicates that aSyn aggregation plus mitochondrial dysfunction without intestinal barrier leakage are not sufficient to trigger gut-first PD.