Pro- and anti-inflammatory effects of short chain fatty acids on immune and endothelial cells

Li, Meng; Esch, Betty C.A.M. van; Wagenaar, Gerry T. M.; Garssen, Johan; Folkerts, Gert; Henricks, Paul A.J.

doi:10.1016/j.ejphar.2018.05.003

Cited by 428 publications

(357 citation statements)

References 106 publications

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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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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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“…Histone post-translational modifications are fundamental regulators of gene expression and are tightly controlled by histone deacetylases (HDACs). It is reported that SCFAs modulate immune and inflammatory responses via activation of their receptors free fatty acid receptors type 2 and3 (FFAR2 and FFAR3) and G protein-coupled receptor 109A (GPR109A) to inhibit HDACs [16][17][18]. In this study, we determined if SCFAs (acetate, propionate and butyrate) were anti-inflammatory in a fetal cell line, in fetal organoids and in fetal mouse intestine after an inflammatory stimulus with IL-1β.…”

Section: Introductionmentioning

confidence: 96%

Short chain fatty acids produced by colonizing intestinal commensal bacterial interaction with expressed breast milk are anti-inflammatory in human immature enterocytes

et al. 2020

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Necrotizing enterocolitis (NEC) is a devastating intestinal emergency that affects ten percent of very low birth weight premature babies and costs society in both expense and heartache. It is probably caused by an inappropriate interaction of colonizing bacteria with an immature intestine. A possible preventative measure is to feed prematures their mother's expressed breast milk in conjunction with a probiotic. This synbiotic prevention reduces the severity and incidence of this condition. This study was designed to determine the mechanism of the synbiotic effect in human and mouse fetal intestine. Breast milk interacting with a NEC preventative probiotic such as Bifidobacterium infantis can produce increased levels of short chain fatty acids (acetate, propionate and butyrate) (SCFAs). SCFAs are known to be anti-inflammatory in mature enterocytes and immunocytes. Very little is known about their role in immature intestine. When exposed to a human fetal cell line, fetal intestinal organoids and fetal mouse intestine, these SCFAs were anti-inflammatory. Their mechanism of antiinflammation differed from those reported for mature cells by involving the G-protein coupled receptor (GPR 109A) and inhibiting histone deacetylase 4 and 5. These bacterial metabolites may help explain the synbiotic anti-inflammatory effect of breast milk and probiotics given to premature infants at risk for NEC.

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“…Although fecal samples from monkeys treated with MPTP did not reveal changes in the SCFA metabolite concentrations as seen in PD (Unger et al, 2016), there was a notable difference in the basal concentrations of all SCFA metabolites between sexes. Interestingly, females had remarkably increased levels of certain SCFAs with known anti-inflammatory properties (Li et al, 2018). SCFA have been associated with intestinal barrier function and endotoxin translocation to the circulation, however no correlations were found between these measures in this study (Maciejewska et al, 2018).…”

Section: Mptp and Sex-specific Responses In Gastrointestinal Measuresmentioning

confidence: 53%

Sexually dimorphic responses to MPTP found in microglia, inflammation and gut microbiota in a progressive monkey model of Parkinson’s disease

Joers

Masilamoni

Kempf

et al. 2020

Preprint

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Inflammation has been linked to the development of nonmotor symptoms in Parkinson's disease (PD), which greatly impact patients' quality of life and can often precede motor symptoms. Suitable animal models are critical for our understanding of the mechanisms underlying disease and the associated prodromal disturbances. The neurotoxin 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey model is commonly seen as a "gold standard" model that closely mimics the clinical motor symptoms and the nigrostriatal dopaminergic loss of PD, however MPTP toxicity extends to other nondopaminergic regions. Yet, there are limited reports monitoring the MPTP-induced progressive central and peripheral inflammation as well as other nonmotor symptoms such as gastrointestinal function and microbiota. The main objective of this study is to gain a broader understanding of central and peripheral inflammatory dysfunction triggered by exposure to a neurotoxicant known to degenerate nigral dopaminergic neurons in order to understand the potential role of inflammation in prodromal/pre-motor features of PD-like degeneration in a progressive non-human primate model of the disease. We measured inflammatory proteins in plasma and CSF and performed [ 18 F]FEPPA PET scans to evaluate translocator proteins (TSPO) or microglial activation in a small cohort of rhesus monkeys (n=5) given weekly low doses of MPTP (0.2-0.8 mg/kg, im). Additionally, monkeys were evaluated for working memory and executive function using various behavior tasks and for gastrointestinal hyperpermeability and microbiota composition. Monkeys were also treated with novel TNF inhibitor XPro1595 (10mg/kg, n=3) or vehicle (n=2) every three days starting 11 weeks after the initiation of MPTP to determine whether nonmotor symptoms are tied to TNF signaling and whether XPro1595 would alter inflammation and microglial behavior in a progressive model of PD. Our analyses revealed sex-dependent sensitivity to MPTP that resulted in early microglial activation by PET, acute plasma IL-6 and CSF TNF, and earlier parkinsonism as measured by motor deficits in males compared to female monkeys. Sex differences were also identified in microbiota and their metabolites and targeted short chain fatty acids at both basal levels and in response to MPTP. Both sexes displayed cognitive impairment prior to a significant motor phenotype. Importantly, XPro1595 shifted peripheral and central inflammation, and significantly reduced CD68-immunoreactivity in the colon. As such, our findings revealed a sexually dimorphic inflammatory response to chronic MPTP treatment and suggest that males may have higher vulnerability than females to inflammation-induced degeneration. If these findings reflect potential differences in humans, these sex differences have significant implications for therapeutic development of inflammatory targets in the clinic.

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Pro- and anti-inflammatory effects of short chain fatty acids on immune and endothelial cells

Cited by 428 publications

References 106 publications

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

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

Short chain fatty acids produced by colonizing intestinal commensal bacterial interaction with expressed breast milk are anti-inflammatory in human immature enterocytes

Sexually dimorphic responses to MPTP found in microglia, inflammation and gut microbiota in a progressive monkey model of Parkinson’s disease

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