Relationships of gut microbiota, short-chain fatty acids, inflammation, and the gut barrier in Parkinson’s disease

Abstract

Background: Previous studies have reported that gut microbiota, permeability, short-chain fatty acids (SCFAs), and inflammation are altered in Parkinsons disease (PD), but how these factors are linked and contribute to disease processes and symptoms remains uncertain. Objectives: This study sought to compare and identify associations among these factors in PD patients and controls to elucidate their interrelations and links to clinical manifestations of PD. Methods: Stool and plasma samples and clinical data were collected from 55 PD patients and 56 controls. Levels of stool SCFAs and stool and plasma inflammatory and permeability markers were compared between patients and controls and related to one another and to the gut microbiota. Results: Calprotectin was increased and SCFAs decreased in stool in PD in a sex-dependent manner. Inflammatory markers in plasma and stool were neither intercorrelated nor strongly associated with SCFA levels. Age at PD onset was positively correlated with SCFAs and negatively correlated with CXCL8 and IL-1β in stool. Fecal zonulin correlated positively with fecal NGAL and negatively with PD motor and non-motor symptoms. Microbiota diversity and composition were linked to levels of stool SCFAs, inflammation, and zonulin. These relationships differed somewhat between patients and controls and by sex. Conclusions: Intestinal inflammatory responses and reductions in fecal SCFAs occur in PD, are related to the microbiota and to disease onset, and are not reflected in plasma inflammatory profiles. Some of these relationships are PD- and sex-dependent. Alterations in microbiota-host interactions and links between intestinal inflammation and reduced SCFA levels and earlier PD onset warrant further investigation.

New Avenues for Parkinson’s Disease Therapeutics: Disease-Modifying Strategies Based on the Gut Microbiota

“…Moreover, they serve as energy substrate for intestinal epithelial cells [ 182 ] and have also been shown to reinforce the integrity of the blood–brain barrier (BBB) in mice [ 183 ]. One study reported low levels of SCFAs and high levels of calprotectin in stool samples from PD patients [ 184 ], which was associated with disruption of the intestinal barrier integrity. However, a recent study found no significant correlations between abundance of SCFAs and immune or permeability-related factors in stool or plasma, raising doubts about the association between SCFAs production and inflammation [ 184 ].…”

“…One study reported low levels of SCFAs and high levels of calprotectin in stool samples from PD patients [ 184 ], which was associated with disruption of the intestinal barrier integrity. However, a recent study found no significant correlations between abundance of SCFAs and immune or permeability-related factors in stool or plasma, raising doubts about the association between SCFAs production and inflammation [ 184 ]. Additionally, another study showed in mice that, despite the overall protective function of SCFAs, they might have the potential to regulate autoimmune CNS inflammation both positively and negatively [ 185 ].…”

CNS-Draining Meningeal Lymphatic Vasculature: Roles, Conundrums and Future Challenges

“…It will also be essential to explore if the modulation of meningeal lymphatic function (decreasing or increasing its drainage capacity) affects the neuroimmune response and behavior performance in PD ( Joers et al, 2017 ; Butkovich et al, 2020 ). Additional experiments are also needed in order to understand if enhancing meningeal lymphatic drainage in PD might prove to be efficacious in alleviating not only brain α-synuclein pathology and neuroinflammation but also PD-related clinical symptoms, including motor deficits, sensory abnormalities, sleep disturbances, autonomic dysfunction, impaired gut motility, dysbiosis and fatigue ( Pfeiffer, 2016 ; Chapelet et al, 2019 ; Prigent et al, 2019 ; Butkovich et al, 2020 ; Aho et al, 2021 ).…”