Butyrate and the Brain: Why Butyrate Deserves a Place in Parkinson’s Research

For decades, Parkinson’s disease (PD) has been viewed as a disorder of the brain. This perspective was shaped by the presence of misfolded alpha-synuclein aggregates throughout the brain, combined with the loss of dopamine-producing neurons. Collectively, these dysfunctions drive the devastating motor symptoms, speech difficulties, and cognitive decline that characterise PD.

However, recent research challenges this brain-centric view. Alpha-synuclein has been identified to appear in the enteric (gut) nervous system – otherwise termed as our ‘second brain’ – before its appearance in the brain. This discovery has fuelled the hypothesis that PD may actually begin in the gut, instead of the brain. 

The Gut-Brain Axis: Where Parkinson’s May Begin

Long before motor symptoms emerge, many individuals with PD experience gut disturbances such as constipation, inflammation, and reduced microbial diversity (i.e., less diversity within the bacterial populations residing in your gut). When the microbiome becomes unbalanced, it can drive local inflammation that spreads beyond the gut. Over time, this chronic inflammation can compromise the blood-brain-barrier, increase its permeability and allow inflammatory molecules to reach the brain. This, in turn, activates microglia (the brain’s immune cells), creating a neuroinflammatory environment.  

"In animal models, it appears that sodium butyrate supplementation tends to reduce alpha-synuclein aggregation, protects dopaminergic neurons, and improves motor functions"

This inflammatory loop between the gut and the brain increases oxidative stress and impairs neuronal resilience. Dopaminergic neurons are particularly vulnerable because they have high metabolic demands, generate oxidative by-products during dopamine metabolism, and possess low antioxidant defences. As a result, gut-driven neuroinflammation may selectively damage this neuronal population, leading to the hallmark motor symptoms seen in PD.

This raises an interesting question – could investigating alpha-synuclein pathology within the enteric nervous system reveal new diagnostic or therapeutic opportunities for patients with PD?  

Butyrate: A Small Molecule with a Big Impact  

As humans, we are incapable of digesting certain types of dietary fibre. Therefore, we rely on our gut microbiome to ferment this indigestible fibre into beneficial short-chain fatty acids (SCFAs), such as butyrate. Butyrate exerts many neuroprotective effects: it strengthens the intestinal barrier to prevent inflammation, crosses into the brain to promote gene expression linked to neuronal survival, regulates microglial activity, and supports mitochondrial energy metabolism.

When Butyrate is Lost: A Missing Link in Parkinson’s

To maintain optimal butyrate levels, the presence of butyrate-producing bacteria is fundamental. Key species include Faecalibacterium, Roseburia, and Eubacterium – all of which have been reported as reduced in people with PD. 

This depletion may leave patients deficient in butyrate, weakening the gut barrier integrity and increasing systemic inflammation that cascades into neuroinflammation and, ultimately, neuronal death. Supporting this, studies have shown that lower faecal butyrate levels in PD have been correlated with greater symptom severity. 

In animal models, while results are mixed, it appears that sodium butyrate supplementation tends to reduce alpha-synuclein aggregation, protects dopaminergic neurons, and improves motor functions. Human studies appear to echo these findings; however, controlled clinical trials confirming causality are still lacking.

Why This Matters for Women

Importantly, this hypothesis may be particularly relevant for women. PD manifests differently in women, who commonly show higher rates of anxiety, depression, and personality changes than their male counterparts. 

One contributing factor may be the decline of oestrogen after menopause. Oestrogen helps sustain butyrate-producing bacteria, which in turn support gut barrier integrity and reduce inflammation that could otherwise cascade into neuroinflammation. The loss of oestrogen may disrupt these bacteria, leading to local gut inflammation that can become chronic over time.  

"The loss of oestrogen may disrupt these [butyrate] bacteria, leading to local gut inflammation"

Restoring butyrate levels could therefore be especially beneficial for peri-and post-menopausal women, helping to mitigate hormone-related gut and brain vulnerabilities. It could also be used to help alleviate some of the emotional and cognitive symptoms in women already affected by PD.

Feed the Gut to Protect the Brain

So, how can we implement this information? One suggestion is dietary fibre enrichment, specifically with resistant starches (such as from reheated potatoes), as this is a particularly effective prebiotic for butyrate-producing bacteria. Rebalancing your microbiome supports long-term butyrate production, which in turn may protect against neuroinflammation. For individuals with pre-existing gut conditions, hormonal imbalances, or a family history of PD, direct butyrate supplementation may serve as a preventative measure.

While more research is undoubtedly required, the case for butyrate so far is strong. Further studies could uncover how hormones, gut health, and inflammation intersect to influence neurological disease. In doing so, we may find that supporting the gut is one of the most powerful ways to protect our brain.

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This article was written by Susannah Leese and edited by Julia Dabrowska, with graphics produced by Suzana Sultan. If you enjoyed this article, be the first to be notified about new posts by signing up to become a WiNUK member (top right of this page)! Interested in writing for WiNUK yourself? Contact us through the blog page and the editors will be in touch.