Movement disorders: Parkinson's disease, bacterial butyrate is associated with epigenetic changes, or is associated with depressive symptoms

Parkinson's disease (PD) is a neurodegenerative disease typically characterized by dyskinesia
caused by the death of dopaminergic neurons located next to the substantia nigra.
A hallmark of PD is the aggregation of misfolded α-synuclein proteins in the central and peripheral nervous systems to form aggregates or Lewy bodies
.
The aggregation of α-synuclein found in the enteric nervous system, combined with early gastrointestinal (GI) symptoms of PD (such as constipation), leads to the hypothesis that the pathogenesis of PD may originate in the digestive tract or at least outside the
central nervous system (CNS).

Figure 1: Paper cover image

Furthermore, it has been hypothesized that α-synuclein aggregates can be transported from the enteric nervous system to the central nervous system
via the vagus nerve in a prion-like manner.
Patients who have undergone vagus resection have a reduced risk of PD, which supports this hypothesis
.

In addition, the finding that intertwined the digestive system with Parkinson's disease was that mice that overexpressed α-synuclein needed the presence of an intestinal microbiota to develop movement disorders
.
These same mice showed more movement impairment
after receiving fecal transplants from PD patients than those who received a transplant from a healthy donor.
In addition, multiple studies have shown that the composition and function of the gut microbiome of PD patients is significantly different
from that of healthy controls.

Recent meta-analyses have shown that reduced abundance of short-chain fatty acids (SCFAs)-producing bacteria is one of
the most consistent findings of PD microbiome composition across studies.
Short-chain fatty acids are saturated fatty acids
produced by the fermentation of dietary fiber by certain colonic bacteria.
Deficiencies of SCFAs have been linked to a variety of diseases, such as autoimmune diseases, cancer, metabolic syndrome, and neurological disorders
.
The concentrations of SCFAs acetate, propionate, and butyrate in stool samples from PD patients were significantly reduced
compared to healthy controls.
In addition to its central role as the primary energy source for colon cells, butyrate has been recognized as an important bacterial metabolite in particular, as it is a potent endogenous histone deacetylase (HDAC) inhibitor that indirectly affects DNA methylation, enabling it to episthetically alter gene expression
in multiple cell types.
Butyrate is also a ligand for some free fatty acid receptors and is essential
for inflammation regulation and secretion of peptide hormones.
Some studies have shown that butyrate can reduce the inflammatory properties
of innate and adaptive immune cells by inhibiting the release of reactive oxygen species and the production of inflammatory cytokines, as well as inducing activated immune cell apoptosis mechanisms.
In addition to its immunomodulatory properties, multiple in vivo studies have shown that butyrate affects the central nervous system
by reducing the permeability of the blood-brain barrier, reducing microglial activation, and alleviating anxiety and depression (both common PD prodromal symptoms).
Butyrate also showed its effect on in vitro astrocyte gene expression and neuroprotective effects
on mouse models of PD.
Some studies have also shown harmful effects
of SCFAs.
However, the possible effects of alterations in butyrate levels observed in PD patients on epigenomic status as well as clinical symptoms remain to be elucidated
.

To test whether butyrate affects epigenetic markers in the blood and brain of PD patients, and whether this correlates with the severity of symptoms, Aoji Xie of Parkinson's Disease Center in Michigan, performed DNA methylation analysis of whole blood samples and neuronal tissue from PD patients and controls in both cohorts and linked these findings to gut microbiome and metabolite data in feces, as well as clinical symptoms
.

Figure 2: Graph of paper results

They collected stool, whole blood samples and clinical data
from 55 PD patients and 55 controls.
We performed DNA methylation analysis on whole blood samples and analyzed the results in relation
to short-chain fatty acid concentrations and microbiota composition in feces.
In another cohort, prefrontal cortical neurons
were isolated from the control group and PD brain.
We determined genome-wide DNA methylation by targeted bisulfite sequencing
.

They found that lower fecal butyrate and reduced amounts of Roseburia, Romboutsia, and Prevotella genera were associated
with depressive symptoms in PD patients.

Genes containing butyrate-associated methylation sites include PD risk genes and significantly overlap with epigenetically altered sites in PD blood leukocytes (mainly neutrophils) and brain neurons, relative to the control group
.

In addition, butyrate-associated methylated DNA regions in PD overlap
with altered regions in gastrointestinal (GI), autoimmune, and psychiatric disorders.

The significance of the study is that it found that the decline in butyrate levels produced by bacteria was associated with epigenetic changes in white blood cells and neurons in PD patients, as well as the severity of their depressive symptoms.

PD shares butyrate-dependent epigenetic changes with certain digestive and psychiatric disorders, which may be related
to their epidemiological relationship.

Xie A, Ensink E, Li P, et al.
Bacterial Butyrate in Parkinson's Disease Is Linked to Epigenetic Changes and Depressive Symptoms.
_Movement Disorders_.
Published online June 20, 2022:mds.
29128.
doi:[10.
1002/mds.
29128](https://doi.
org/10.
1002/mds.
29128)