Dysbiosis in Preeclampsia and Treatment With Short Chain Fatty Acids

HomeCirculation ResearchVol. 131, No. 6Dysbiosis in Preeclampsia and Treatment With Short Chain Fatty Acids Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBDysbiosis in Preeclampsia and Treatment With Short Chain Fatty Acids Charles R. Mackay and Francine Z. Marques Charles R. MackayCharles R. Mackay Correspondence to: Charles R. Mackay, PhD, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. Email E-mail Address: [email protected] School of Pharmaceutical Sciences, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China (C.R.M.). Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia (C.R.M.). and Francine Z. MarquesFrancine Z. Marques https://orcid.org/0000-0003-4920-9991 Hypertension Research Laboratory, School of Biological Sciences, Monash University, Clayton, VIC, Australia (F.Z.M.). Heart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, Australia (F.Z.M.). Originally published1 Sep 2022https://doi.org/10.1161/CIRCRESAHA.122.321701Circulation Research. 2022;131:507–509This article is a commentary on the followingGut Dysbiosis Promotes Preeclampsia by Regulating Macrophages and TrophoblastsHypertension in pregnancy, termed preeclampsia, may occur after ~20 weeks. Symptoms include proteinuria, and liver and kidney dysfunction. Preeclampsia is a serious condition that may lead to maternal and perinatal morbidity. In this edition of Circulation Research, Jin et al1 show, first, that that preeclamptic women have gut dysbiosis (disruption to the microbiota leading to altered immune and metabolic pathways). They did this by analyzing the makeup of the gut microbiota using 16S rRNA sequencing of faecal samples, a common way to assess gut microbiota composition. The α and β diversity and Firmicutes/Bacteroidetes (F/B) ratio of the gut microbiome in preeclamptic women were significantly changed, compared with nonpreeclampsia women.1 In preeclampsia, various immune cells and cytokines have been implicated.2 While it is currently fashionable to pin all human diseases on the gut microbiota, this is too simplistic. The microbiome is shaped by many factors, particularly diet and antibiotic use (both extreme in Western countries, and increasing elsewhere).3 Gut dysbiosis is common in Western countries and may be caused by insufficient intake of dietary fiber, or antibiotic use.4 But a consequence of dysbiosis is reduced and, sometimes, eliminated presence of certain bacteria that digest fiber. Many commensal gut bacteria produce short chain fatty acids (SCFAs) such as acetate, others such as Clostridium species produce butyrate, and others propionate.4 Dysbiosis was the hint to the authors that maybe SCFA production was affected because dysbiosis associates with low SCFA levels in gut or blood. SCFAs generally inhibit immune and inflammatory pathways, for instance, through Nfkb inhibition.5 SCFAs are the main products of the gut microbiome. Authors found that indeed the abundance of many intestinal SCFA-producing bacteria were significantly reduced in preeclampsia patients.1 This was combined with reduced levels of propionate and butyrate in the patients' faeces, serum, and even placenta.1 They next explored the potential immune mechanisms involved. T regulatory (Treg) cells are a subset of CD4+ T cells with anti-inflammatory and BP-lowering properties.6 Importantly, the numbers of Tregs,7 as well as epigenetic changes in Treg activating genes, is modulated by SCFAs.8 The percentages of Treg in peripheral blood CD4+ cells of preeclamptic women were significantly lower, and Th17 cells higher.1 Moreover, the serum level of lipopolysaccharide (LPS) was considerably increased in preeclampsia, suggesting that gut epithelial integrity may be compromised in preeclamptic women.1 All tell-tale signs of not enough SCFAs in the system, as high fiber or high SCFAs increase gut integrity, and decrease inflammatory cytokines.9 This study adds to previous findings that had implicated a role for dysbiosis and SCFAs in preeclampsia.10,11Article, see p 492The gut microbiota of preeclampsia patients, when transferred to rats using fecal microbiota transplantation, significantly elevated serum LPS levels, suggesting that the transferred microbiota led to dysfunction of the gut epithelial barrier.1 A hypothesis may be that the transferred bacteria were not producing enough SCFAs. Next, the authors treated preeclamptic rats with Akkermansia muciniphila (a propionate producing bacteria), or sodium propionate or sodium butyrate in the drinking water.1 These treatments significantly increased propionate and butyrate levels in the faeces, serum, and/or placenta, decreased BP, and improved spiral artery remodeling. A. muciniphila, propionate or butyrate significantly increased M2 macrophage proportions and decreased M1 macrophages.1 M1 macrophages are pro-inflammatory, while M2 macrophages are anti-inflammatory. Each produce different cytokines depending on their pro- or anti-inflammatory roles. These phenotypes are the extremes, and there are intermediates.SCFAs bind metabolite-sensing G-protein coupled receptors (GPCRs), but they also inhibit HDACs (histone deacetylases)12; thus, one is never quite sure the precise mechanism by which SCFAs may be inhibiting inflammation or promoting gut integrity. The authors found that treatment with the GPCR GPR43 siRNA significantly attenuated the effects of propionate in inhibiting M1 polarization and promoting M2 polarization.1 In all of our studies, we have generally found a role for GPR43 in protection from disease,8,9,13 making this a fascinating receptor. However, the relative roles of GPCRs and HDACs in this setting still need to be determined. The authors also found that propionate activated AKT signaling through another GPCR, GPR41, and promoted trophoblast invasion.1 Activated AKT mediates several pathways, including those relevant for cell survival, growth, proliferation, migration, and angiogenesis. Some of these processes must be protective against preeclampsia.There are reasons to think that hypertension in pregnancy involves similar pathways as essential hypertension. Hypertension (at least in mice) also involves deficient GPR43 signaling, and insufficient SCFA stimulation. Globally, 1 in 3 adults have high blood pressure, and over half are on medication to reduce blood pressure.14 Hypertension is a scourge of modern living. Dysbiosis is also common in Western countries, partly due to insufficient consumption of dietary fiber.15 Fiber is the fuel for the gut microbiome, shapes its composition and may protect against dysbiosis.4 SCFAs such as acetate, propionate, and butyrate are breakdown products of fiber. SCFAs are very important modulators of many physiological and molecular processes, including inflammation and metabolism.5 Hypertension has many features of an inflammatory disease, including a pathogenic role for inflammatory cytokines such as IL-17.16 A straightforward paradigm is that insufficient fiber=reduced levels of SCFAs=disruption of immune and metabolic processes, which leads to disease. Insufficient fiber intake and associated dysbiosis seems important for hypertension and cardiovascular disease, as it does for preeclampsia.17 Dysbiosis (through insufficient fiber intake, or antibiotic use) may be the basis of many Western diseases such as fatty liver, diabetes, Alzheimer's disease, and hypertension and cardiovascular disease.What are the implications of the current study? Should pregnant women consciously eat more fiber, or probiotics, and avoid antibiotics to protect against dysbiosis, and prevent preeclampsia? Probiotics are usually bacteria that are excellent producers of SCFAs. A high intake of probiotics has already been reported to lower the risk of preeclampsia.18 However, lots of women with dysbiosis do not get preeclampsia, so there must be other pregnancy-associated triggers that contributes to the condition. Regardless, we may have a new opening to prevent or treat this condition by preventing dysbiosis.Article InformationSources of FundingF.Z. Marques is supported by a Senior Medical Research Fellowship from the Sylvia and Charles Viertel Charitable Foundation Fellowship, and by National Heart Foundation Future Leader Fellowships (101185, 105663).Disclosures C.R. Mackay is the founder of a company, Shandong Shanwei ImmunoTech Ltd., specializing in fiber supplements.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 508.Correspondence to: Charles R. Mackay, PhD, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. Email charles.mackay@monash.eduReferences1. Jin J, Gao L, Zou X, Zhang Y, Zheng Z, Zhang X, Li J, Tian Z, Wang X, Gu J, et al. Gut dysbiosis promotes preeclampsia by regulating macrophages and trophoblasts.Circ Res. 2022; 131:492–506. doi: 10.1161/CIRCRESAHA.122.320771LinkGoogle Scholar2. Ali SM, Khalil RA. Genetic, immune and vasoactive factors in the vascular dysfunction associated with hypertension in pregnancy.Expert Opin Ther Targets. 2015; 19:1495–1515. doi: 10.1517/14728222.2015.1067684CrossrefMedlineGoogle Scholar3. Martino C, Dilmore AH, Burcham ZM, Metcalf JL, Jeste D, Knight R. Microbiota succession throughout life from the cradle to the grave.Nat Rev Microbiol. 2022; 29:1–4. doi: 10.1038/s41579-022-00768-zCrossrefGoogle Scholar4. Xu C, Marques FZ. How dietary fibre, acting via the gut microbiome, lowers blood pressure.Current Hypertension Reports. 2022:Accepted 28/06/2022.CrossrefGoogle Scholar5. Tan J, McKenzie C, Potamitis M, Thorburn AN, Mackay CR, Macia L. The role of short-chain fatty acids in health and disease.Adv Immunol. 2014; 121:91–119. doi: 10.1016/B978-0-12-800100-4.00003-9CrossrefMedlineGoogle Scholar6. Barhoumi T, Kasal DA, Li MW, Shbat L, Laurant P, Neves MF, Paradis P, Schiffrin EL. T regulatory lymphocytes prevent angiotensin II-induced hypertension and vascular injury.Hypertension. 2011; 57:469–476. doi: 10.1161/HYPERTENSIONAHA.110.162941LinkGoogle Scholar7. Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly-Y M, Glickman JN, Garrett WS. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.Science. 2013; 341:569–573. doi: 10.1126/science.1241165CrossrefMedlineGoogle Scholar8. Kaye DM, Shihata WA, Jama HA, Tsyganov K, Ziemann M, Kiriazis H, Horlock D, Vijay A, Giam B, Vinh A, et al. Deficiency of prebiotic fiber and insufficient signaling through gut metabolite-sensing receptors leads to cardiovascular disease.Circulation. 2020; 141:1393–1403. doi: 10.1161/CIRCULATIONAHA.119.043081LinkGoogle Scholar9. Macia L, Tan J, Vieira AT, Leach K, Stanley D, Luong S, Maruya M, Ian McKenzie C, Hijikata A, Wong C, et al. Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome.Nat Commun. 2015; 6:6734. doi: 10.1038/ncomms7734CrossrefMedlineGoogle Scholar10. Chang Y, Chen Y, Zhou Q, Wang C, Chen L, Di W, Zhang Y. Short-chain fatty acids accompanying changes in the gut microbiome contribute to the development of hypertension in patients with preeclampsia.Clin Sci (Lond). 2020; 134:289–302. doi: 10.1042/CS20191253CrossrefMedlineGoogle Scholar11. Yong W, Zhao Y, Jiang X, Li P. Sodium butyrate alleviates pre-eclampsia in pregnant rats by improving the gut microbiota and short-chain fatty acid metabolites production.J Appl Microbiol. 2022; 132:1370–1383. doi: 10.1111/jam.15279CrossrefMedlineGoogle Scholar12. Tan JK, McKenzie C, Mariño E, Macia L, Mackay CR. Metabolite-sensing G protein-coupled receptors-facilitators of diet-related immune regulation.Annu Rev Immunol. 2017; 35:371–402. doi: 10.1146/annurev-immunol-051116-052235CrossrefMedlineGoogle Scholar13. Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, Schilter HC, Rolph MS, Mackay F, Artis D, et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43.Nature. 2009; 461:1282–1286. doi: 10.1038/nature08530CrossrefMedlineGoogle Scholar14. Beaney T, Schutte AE, Stergiou GS, Borghi C, Burger D, Charchar F, Cro S, Diaz A, Damasceno A, Espeche W, et al; MMM Investigators*. May measurement month 2019: the global blood pressure screening campaign of the international society of hypertension.Hypertension. 2020; 76:333–341. doi: 10.1161/HYPERTENSIONAHA.120.14874LinkGoogle Scholar15. Collaborators GBDD. 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Intake of probiotic food and risk of preeclampsia in primiparous women: the norwegian mother and child cohort study.Am J Epidemiol. 2011; 174:807–815. doi: 10.1093/aje/kwr168CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. 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Circulation Research. 2022;131:492-506 September 2, 2022Vol 131, Issue 6 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.122.321701PMID: 36048918 Originally publishedSeptember 1, 2022 KeywordsEditorialsdietdietary fiberdysbiosishypertensionpre-eclampsiaPDF download Advertisement