Butyrate and related epigenetic changes link Parkinson’s disease to inflammatory bowel disease and depressive symptoms

Abstract

Background The gut microbiome and its metabolites can impact brain health and are altered in Parkinson's disease (PD) patients. It has been recently demonstrated that PD patients have reduced fecal levels of the potent epigenetic modulator butyrate and its bacterial producers. Here, we investigate whether the changes in the gut microbiome and associated metabolites are linked to PD symptoms and epigenetic markers in leucocytes and neurons. Methods Stool, whole blood samples, and clinical data were collected from 55 PD patients and 55 controls. We performed DNA methylation analysis on whole blood samples and analyzed the results in relation to fecal short-chain fatty acid concentrations and microbiota composition. In another cohort, prefrontal cortex neurons were isolated from control and PD brains. We identified the genome-wide DNA methylation by targeted bisulfite sequencing. Results We show that lower fecal butyrate and reduced Roseburia, Romboutsia, and Prevotella counts are linked to depressive symptoms in PD patients. Genes containing butyrate-associated methylation sites include PD risk genes and significantly overlap with sites epigenetically altered in PD blood leucocytes, predominantly neutrophils, and in brain neurons, relative to controls. Moreover, butyrate-associated methylated-DNA (mDNA) regions in PD overlap with those altered in gastrointestinal, autoimmune, and psychiatric diseases.

Gut microbiome alterations in fecal samples of treatment-naïve de novo Parkinson’s disease patients

“…26 Several studies have linked lower levels of SCFA-producing taxa with gut inflammation, epigenetic changes, and depressive symptoms in PD. [27][28][29][30] In concordance, decreased levels of the SCFA-producing genera Butyricoccus, Colidextribacter and the families Butyricoccaceae and Veillonellaceae were found in the current study. On the other hand, the SCFA-producing family Rikenellaceae was increased in PD.…”

Microbiota and nutrition as risk and resiliency factors following prenatal alcohol exposure

“…Butyrate can inhibit histone deacetylase, thereby promoting histone acetylation and subsequent chromatin relaxation and gene expression (reviewed in Stilling et al, 2016). A recent clinical study found that reduced amounts of fecal butyrate, and butyrate-producing bacteria, were associated with increased depression symptoms in individuals with Parkinson's disease (Xie et al, 2022). This study also identified leukocyte genes whose methylation correlated with fecal butyrate levels in patients.…”

“…To connect these butyrate-associated changes in peripheral methylation to changes within the brain, the researchers compared the identified leukocyte genes to previous work that identified genes with altered methylation in prefrontal cortical neurons (Li et al, 2020). They found significant overlap and correlated likelihood of methylation in Parkinson's disease patients for the leukocyte and neuronal genes, suggesting the potential for decreased butyrate levels to contribute to neurological changes through effects on brain DNA methylation (Xie et al, 2022). Choline is a dietary source of one-carbon units for DNA methylation.…”

Gut-directed therapy in Parkinson’s disease

“…Faecalibacterium can maintain gut barrier function by producing the SCFA butyrate and secreting anti-inflammatory mediators (Lenoir et al, 2020). Lower levels of butyrate have been associated to postural instability, gait abnormalities, Movement Disorder Society-Sponsored Revised Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III motor scores, and depression in PD patients (Li et al, 2017;Xie et al, 2022). Surprisingly, Lactobacillus, Bifidobacterium, and Akkermansia levels are greater in PD patients (Nishiwaki et al, 2020), despite these bacteria are widely recognized as "beneficial", and often included in probiotic preparations (Tan et al, 2020).…”