The short-chain fatty acids butyrate and propionate protect against inflammation-induced activation of mediators involved in active labor: implications for preterm birth

Abstract Spontaneous preterm birth is a global health issue affecting up to 20% of pregnancies and leaves a legacy of neurodevelopmental complications. Inflammation has been implicated in a significant proportion of preterm births, where pro-inflammatory insults trigger production of additional pro-inflammatory and pro-labor mediators. Thus, novel therapeutics that can target inflammation may be a novel avenue for preventing preterm birth and improving adverse fetal outcomes. Short-chain fatty acids (SCFAs), such as butyrate and propionate, are dietary metabolites produced by bacterial fermentation of fiber in the gut. SCFAs are known to possess anti-inflammatory properties and have been found to function through G-coupled-receptors and histone deacetylases. Therefore, this study aimed to investigate the effect of SCFAs on pro-inflammatory and pro-labor mediators in an in vitro model of preterm birth. Primary human cells isolated from myometrium and fetal membranes (decidua, amnion mesenchymal and amnion epithelial cells) were stimulated with the pro-inflammatory cytokines tumor necrosis factor alpha (TNF) or interleukin 1B (IL1B). The SCFAs butyrate and propionate suppressed inflammation-induced expression of pro-inflammatory cytokines and chemokines, adhesion molecules, the uterotonic prostaglandin PGF2alpha and enzymes involved in remodeling of myometrium and degradation of the fetal membranes. Notably, propionate and butyrate also suppressed inflammation-induced prostaglandin signaling and myometrial cell contraction. These effects appear to be mediated through suppression of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) activation. These results suggest that the SCFAs may be able to prevent myometrial contractions and rupture of membranes. Further in vivo studies are warranted to identify the efficacy of SCFAs as a novel anti-inflammatory therapeutic to prevent inflammation-induced spontaneous preterm birth.

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Differential effects of short-chain fatty acids on proliferation and production of pro- and anti-inflammatory cytokines by cultured lymphocytes

Life Sciences ◽

10.1016/s0024-3205(03)00490-9 ◽

2003 ◽

Vol 73 (13) ◽

pp. 1683-1690 ◽

Cited By ~ 165

Author(s):

Claudia R Cavaglieri ◽

Anita Nishiyama ◽

Luis Claudio Fernandes ◽

Rui Curi ◽

Elizabeth A Miles ◽

...

Keyword(s):

Fatty Acids ◽

Inflammatory Cytokines ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Differential Effects ◽

Anti Inflammatory ◽

Chain Fatty Acids

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Absorption of Codonopsis pilosula Saponins by Coexisting Polysaccharides Alleviates Gut Microbial Dysbiosis with Dextran Sulfate Sodium-Induced Colitis in Model Mice

BioMed Research International ◽

10.1155/2018/1781036 ◽

2018 ◽

Vol 2018 ◽

pp. 1-18 ◽

Cited By ~ 14

Author(s):

Yaping Jing ◽

Anping Li ◽

Zhirong Liu ◽

Pingrong Yang ◽

Junshu Wei ◽

...

Keyword(s):

Fatty Acids ◽

Gut Microbiota ◽

Inflammatory Cytokines ◽

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Codonopsis Pilosula ◽

Anti Inflammatory ◽

Chain Fatty Acids

Objectives. Inflammatory Bowel Disease (IBD) is an autoimmune disease, and the gut microbiota has become a new therapeutic target. Herbal medicine (HM) has shown good efficacy in the clinical treatment of IBD; however, the synergistic actions of the dominant chemicals in HM decoctions are unclear. Methods. In this study, we explored whether the complicated interconnections between HM and the gut microbiota could allow crosstalk between HM ingredients. Saponins and polysaccharides, i.e., the dominant chemicals in the Codonopsis pilosula Nannf (CPN) decoction, were investigated in a dextran sulfate sodium- (DSS-) induced mouse model. Bacterial 16S rRNA sequencing analyzed the change of gut microbiota structure and diversity. Gas chromatography (GC) determined the content of short-chain fatty acids (SCFAs) in feces. ELISA detected the expression of proinflammatory and anti-inflammatory cytokines associated with TH17/Treg balance. UPLC-QTOF-MS technology combined with PKsolver software analyzed the absorption of the highest exposure for monomeric compounds of CPN saponins in serum. The results indicated that CPN polysaccharides showed prebiotic-like effects in mice with DSS-induced colitis by simultaneously stimulating the growth of three important probiotics, i.e., Bifidobacterium spp., Lactobacillus spp., and Akkermansia spp., and inhibiting the growth of pathogenic bacteria, including Desulfovibrio spp., Alistipes spp., and Helicobacter spp. Moreover, CPN polysaccharides improved intestinal metabolism, enhanced the production of short-chain fatty acids, upregulated the expression of anti-inflammatory cytokines and downregulated the secretion of proinflammatory cytokines correlated with Th17/Treg balance, promoted the absorption of certain CPN saponins in the serum, and stimulated recovery of the holistic gut microbiota. Conclusion. CPN polysaccharides have the good prebiotic properties and shown good application prospects in the prevention and treatment of acute colitis. These findings provide insights into the specific bacteria responsible for active, inactive biotransformation of HM ingredients and those that are altered by HM administration.

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Short-Chain Fatty Acids and Lipopolysaccharide as Mediators Between Gut Dysbiosis and Amyloid Pathology in Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-200306 ◽

2020 ◽

Vol 78 (2) ◽

pp. 683-697 ◽

Cited By ~ 2

Author(s):

Moira Marizzoni ◽

Annamaria Cattaneo ◽

Peppino Mirabelli ◽

Cristina Festari ◽

Nicola Lopizzo ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Fatty Acids ◽

Endothelial Dysfunction ◽

Gut Microbiota ◽

Inflammatory Cytokines ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Amyloid Pathology ◽

Pro Inflammatory Cytokines ◽

Chain Fatty Acids

Background: Metagenomic data support an association between certain bacterial strains and Alzheimer’s disease (AD), but their functional dynamics remain elusive. Objective: To investigate the association between amyloid pathology, bacterial products such as lipopolysaccharide (LPS) and short chain fatty acids (SCFAs: acetate, valerate, butyrate), inflammatory mediators, and markers of endothelial dysfunction in AD. Methods: Eighty-nine older persons with cognitive performance from normal to dementia underwent florbetapir amyloid PET and blood collection. Brain amyloidosis was measured with standardized uptake value ratio versus cerebellum. Blood levels of LPS were measured by ELISA, SCFAs by mass spectrometry, cytokines by using real-time PCR, and biomarkers of endothelial dysfunction by flow cytometry. We investigated the association between the variables listed above with Spearman’s rank test. Results: Amyloid SUVR uptake was positively associated with blood LPS (rho≥0.32, p≤0.006), acetate and valerate (rho≥0.45, p < 0.001), pro-inflammatory cytokines (rho≥0.25, p≤0.012), and biomarkers of endothelial dysfunction (rho≥0.25, p≤0.042). In contrast, it was negatively correlated with butyrate (rho≤–0.42, p≤0.020) and the anti-inflammatory cytokine IL10 (rho≤–0.26, p≤0.009). Endothelial dysfunction was positively associated with pro-inflammatory cytokines, acetate and valerate (rho≥0.25, p≤0.045) and negatively with butyrate and IL10 levels (rho≤–0.25, p≤0.038). Conclusion: We report a novel association between gut microbiota-related products and systemic inflammation with brain amyloidosis via endothelial dysfunction, suggesting that SCFAs and LPS represent candidate pathophysiologic links between the gut microbiota and AD pathology.

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Colon microbiota fermentation of dietary prebiotics towards short-chain fatty acids and their roles as anti-inflammatory and antitumour agents: A review

Journal of Functional Foods ◽

10.1016/j.jff.2016.06.032 ◽

2016 ◽

Vol 25 ◽

pp. 511-522 ◽

Cited By ~ 98

Author(s):

Javier Fernández ◽

Saúl Redondo-Blanco ◽

Ignacio Gutiérrez-del-Río ◽

Elisa M. Miguélez ◽

Claudio J. Villar ◽

...

Keyword(s):

Fatty Acids ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Antitumour Agents ◽

Anti Inflammatory ◽

Chain Fatty Acids

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Do short chain fatty acids and phenolic metabolites of the gut have synergistic anti-inflammatory effects? – New insights from a TNF-α-induced Caco-2 cell model

Food Research International ◽

10.1016/j.foodres.2020.109833 ◽

2020 ◽

pp. 109833

Author(s):

Shilian Zheng ◽

Hua Zhang ◽

Ronghua Liu ◽

Chia-liang Huang ◽

Hongyan Li ◽

...

Keyword(s):

Fatty Acids ◽

Cell Model ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Phenolic Metabolites ◽

Tnf Α ◽

Anti Inflammatory ◽

Chain Fatty Acids

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Circulating Short-Chain Fatty Acids in Preterm Birth: A Pilot Case-Control Study

Reproductive Sciences ◽

10.1007/s43032-019-00126-0 ◽

2020 ◽

Vol 27 (5) ◽

pp. 1181-1186

Author(s):

Colette A. Nickodem ◽

Ramkumar Menon ◽

Thomas McDonald ◽

Brandie DePaoli Taylor

Keyword(s):

Fatty Acids ◽

Preterm Birth ◽

Case Control Study ◽

Short Chain Fatty Acids ◽

Case Control ◽

Short Chain ◽

Control Study ◽

Chain Fatty Acids

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Cyclomaltoheptaose mixed esters of anti-inflammatory drugs and short-chain fatty acids and study of their enzymatic hydrolysis in vitro

Carbohydrate Research ◽

10.1016/j.carres.2008.10.001 ◽

2009 ◽

Vol 344 (4) ◽

pp. 526-530 ◽

Cited By ~ 5

Author(s):

Feng Cao ◽

Yong Ren ◽

Weiyi Hua

Keyword(s):

Fatty Acids ◽

Enzymatic Hydrolysis ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Inflammatory Drugs ◽

Anti Inflammatory ◽

Chain Fatty Acids

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Short-chain fatty acids increase TNFα-induced inflammation in primary human lung mesenchymal cells through the activation of p38 MAPK

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00306.2018 ◽

2019 ◽

Vol 316 (1) ◽

pp. L157-L174 ◽

Cited By ~ 7

Author(s):

Sandra Rutting ◽

Dia Xenaki ◽

Monique Malouf ◽

Jay C. Horvat ◽

Lisa G. Wood ◽

...

Keyword(s):

Fatty Acids ◽

P38 Mapk ◽

Human Lung ◽

Short Chain Fatty Acids ◽

Mapk Signaling ◽

Mesenchymal Cells ◽

Short Chain ◽

Lung Fibroblasts ◽

Anti Inflammatory ◽

Chain Fatty Acids

Short-chain fatty acids (SCFAs), produced as by-products of dietary fiber metabolism by gut bacteria, have anti-inflammatory properties and could potentially be used for the treatment of inflammatory diseases, including asthma. The direct effects of SCFAs on inflammatory responses in primary human lung mesenchymal cells have not been assessed. We investigated whether SCFAs can protect against tumor necrosis factor (TNF)α-induced inflammation in primary human lung fibroblasts (HLFs) and airway smooth muscle (ASM) cells in vitro. HLFs and ASM cells were exposed to SCFAs, acetate (C2:0), propionate (C3:0), and butyrate (C4:0) (0.01–25 mM) with or without TNFα, and the release of proinflammatory cytokines, IL-6, and CXCL8 was measured using ELISA. We found that none of the SCFAs suppressed TNFα-induced cytokine release. On the contrary, challenge with supraphysiological concentrations (10–25 mM), as might be used therapeutically, of propionate or butyrate in combination with TNFα resulted in substantially greater IL-6 and CXCL8 release from HLFs and ASM cells than challenge with TNFα alone, demonstrating synergistic effects. In ASM cells, challenge with acetate also enhanced TNFα-induced IL-6, but not CXCL8 release. Synergistic upregulation of IL-6 and CXCL8 was mediated through the activation of free fatty acid receptor (FFAR)3, but not FFAR2. The signaling pathways involved were further examined using specific inhibitors and immunoblotting, and responses were found to be mediated through p38 MAPK signaling. This study demonstrates that proinflammatory, rather than anti-inflammatory effects of SCFAs are evident in lung mesenchymal cells.

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