Bidirectional regulatory potentials of short-chain fatty acids and their G-protein-coupled receptors in autoimmune neuroinflammation

Park, Jeong-Ho; Wang, Qin; Wu, Qi; Mao-Draayer, Yang; Kim, Chang H.

doi:10.1038/s41598-019-45311-y

Cited by 117 publications

(141 citation statements)

References 58 publications

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“…The Treg frequency directly correlated with fecal SCFA concentrations. Similar ndings were made in an US cohort: patients suffering from a secondary progressive MS (SPMS) showed SCFA blood concentrations which were 50-65% reduced in comparison to healthy controls (19).…”

Section: Introductionsupporting

confidence: 69%

Fecal markers in Multiple Sclerosis Sex makes the difference

Becker

Abuazab²,

Schwiertz³

et al. 2020

Preprint

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Background. Multiple Sclerosis (MS) is primarily considered as a neuro-inflammatory CNS disease. Yet, experimental data suggest a role for gut microbiota and microbial products like short chain fatty acids (SCFA) in the pathogenesis of MS. Very recently a high-ranked publication reported beneficial effects of propionate, a SCFA, in MS patients. Based on experimental and preliminary human data, we hypothesized that not only the gut microbiota but also microbial products and fecal inflammatory markers might be altered in MS.Methods. In a pilot study, we investigated fecal markers (short chain fatty acids, calprotectin) as well as clinical markers in patients with relapsing-remitting MS (RRMS) under different therapeutic regimes and compared the results to age-matched control subjects.Results. We observed a non-significant reduction in fecal SCFA in RRMS patients compared to control subjects. Fecal calprotectin concentrations did not differ significantly between MS patients and control subjects. We observed a significant reduction in fecal SCFA concentrations in women compared to men.Conclusions. We conclude that the observed sex-associated difference in fecal SCFA concentrations might be a contributing factor in the pathogenesis of MS, especially when taking into account the female predominance in MS. We suggest investigating the role of SCFA in MS in a longitudinal study (starting in drug-naïve patients) in larger cohorts of MS patients with defined therapeutic regimes. Such a study would allow to distinguish between drug effects and disease-immanent effects and might help to identify a potentially modifiable sex-associated contributing factor in MS.Trial registration. Registered by the local Ethics Committee (Reg.Nr. 81/18, Ethikkommission der Aerztekammer des Saarlandes, Saarbruecken, Germany).

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Section: Introductionsupporting

confidence: 69%

Fecal markers in Multiple Sclerosis Sex makes the difference

Becker

Abuazab²,

Schwiertz³

et al. 2020

Preprint

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“…It is proposed, that in normal and pathological conditions PPA and butyrate increase neuronal histone acetylation, but are metabolized mainly in glia (Nguyen et al, ). Glial effects may be related to the presence of free fatty acid receptors on brain macro‐ and microglia (Erny, Hrabe de Angelis, & Prinz, ; Park, Wang, Wu, Mao‐Draayer, & Kim, ). Our EM studies revealed that the rapid activation of glia has developed even after a single injection of a relatively low dose of PPA (Lobzhanidze et al, ).…”

Section: Discussionmentioning

confidence: 99%

Behavioural and brain ultrastructural changes following the systemic administration of propionic acid in adolescent male rats. Further development of a rodent model of autism

Lobzhanidze

Japaridze²,

Lordkipanidze

et al. 2020

Intl J of Devlp Neuroscience

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Short chain fatty acids, produced as gut microbiome metabolites but also present in the diet, exert broad effects in host physiology. Propionic acid (PPA), along with butyrate and acetate, plays a growing role in health, but also in neurological conditions. Increased PPA exposure in humans, animal models and cell lines elicit diverse behavioural and biochemical changes consistent with organic acidurias, mitochondrial disorders and autism spectrum disorders (ASD). ASD is considered a disorder of synaptic dysfunction and cell signalling, but also neuroinflammatory and neurometabolic components. We examined behaviour (Morris water and radial arm mazes) and the ultrastructure of the hippocampus and medial prefrontal cortex (electron microscopy) following a single intraperitoneal (i.p.) injection of PPA (175 mg/kg) in male adolescent rats. PPA treatment showed altered social and locomotor behaviour without changes in learning and memory. Both transient and enduring ultrastructural alterations in synapses, astro‐ and microglia were detected in the CA1 hippocampal area. Electron microscopic analysis showed the PPA treatment significantly decreased the total number of synaptic vesicles, presynaptic mitochondria and synapses with a symmetric active zone. Thus, brief systemic administration of this dietary and enteric short chain fatty acid produced behavioural and dynamic brain ultrastructural changes, providing further validation of the PPA model of ASD.

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“…While it is possible that SCFA levels may directly impact immunological pathways not assessed in this study, the lack of clear association between SCFA production and in ammation likely evinces the complexity of the relationship between these physiological processes. Both pro-and anti-in ammatory activities of SCFAs have been documented (44,45), and dietary supplementation of SCFAs produces variable effects on in ammation which appear to be strongly in uenced by the range of SCFA concentrations involved (46). Further investigation of the effects of SCFAs on immune responses in the gut, the blood, and the central nervous system in the context of PD pathology is needed.…”

Section: Discussionmentioning

confidence: 99%

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

Aho

Houser

Pereira

et al. 2020

Preprint

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Background: Previous studies have reported that gut microbiota, permeability, short-chain fatty acids (SCFAs), and inflammation are altered in Parkinson’s disease (PD), but how these factors are linked and contribute to disease processes and symptoms remains uncertain. 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. Certain relationships differed 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.

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Bidirectional regulatory potentials of short-chain fatty acids and their G-protein-coupled receptors in autoimmune neuroinflammation

Cited by 117 publications

References 58 publications

Fecal markers in Multiple Sclerosis Sex makes the difference

Fecal markers in Multiple Sclerosis Sex makes the difference

Behavioural and brain ultrastructural changes following the systemic administration of propionic acid in adolescent male rats. Further development of a rodent model of autism

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

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