Interrelations between microbiota, metabolism and low-grade inflammation with obesity and gestational diabetes mellitus: Means to intervene during pregnancy

ABSTRACT Pregnant women with overweight and obesity may exhibit altered circulating lowgrade inflammatory and metabolic profile and gut and vaginal microbiota which may contribute to the development of gestational diabetes mellitus (GDM). These are further exaggerated in obesity. In this thesis, the aim was to investigate the interaction of low-grade inflammation, metabolism and gut and vaginal microbiota in pregnant women with obesity and overweight and whether these are related to the onset of GDM. Further, the effect of dietary intervention with fish oil and/or probiotics on these factors were studied. The study involved pregnant women with overweight and obesity (n = 99–434) in early and late pregnancy. Blood, faecal and vaginal samples were analysed for low-grade inflammatory and metabolic markers (metabolites, phosphorylated insulin-like growth factor binding-protein 1 (phIGFBP-1), IGFBP-1, active matrix metalloproteinase 8 (aMMP-8) and fatty acids) and gut and vaginal microbiota and vaginal aMMP-8, respectively. The women were randomised into four intervention groups (fish oil+placebo, probiotics+placebo, fish oil+probiotics, placebo+placebo) from early pregnancy onwards. The fish oil capsules contained 2.4 g of n-3 longchain polyunsaturated fatty acids (n-3 LC-PUFAs): 1.9 g docosahexaenoic acid, 0.22 g eicopentaenoic acid, and the remaining amount other n-3 fatty acids and probiotics Lacticaseibacillus rhamnosus HN001 and Bifidobacterium animalis ssp. lactis 420, each with 1010 colony-forming units per capsule. In early pregnancy, the pregnant women with obesity had higher level of lowgrade inflammatory markers and distinct metabolic profile and gut microbiota as compared to the women with overweight. Low serum phIGFBP-1, IGFBP-1 and high serum n-3 LC-PUFAs in early pregnancy were related to the onset of GDM. Some vaginal bacterial genera and species were related to GDM. The fish oil and/or probiotics intervention did not influence low-grade inflammation, serum phIGFBP-1, IGFBP-1 or serum/vaginal aMMP-8 but it reduced the relative abundance of some bacterial genera and species, namely fish oil reduced Ureaplasma urealyticum, probiotics Ureaplasma, U. urealyticum and Prevotella disiens, fish oil+probiotics Dialister invisus and P. timonensis, in vagina and increased serum n-3 LC-PUFAs. In conclusion, obesity alters inflammatory and metabolic profile and gut microbiota in pregnant women. Serum phIGFBP-1, IGFBP-1 and serum n-3 LCPUFAs as well as vaginal microbiota in early pregnancy were related to the onset of GDM. The fish oil and/or probiotics resulted lower relative abundance of potential pathobionts in vagina. KEYWORDS: overweight, obesity, pregnancy, low-grade inflammation, metabolism, gut microbiota, vaginal microbiota, fatty acidsTIIVISTELMÄ Ylipaino ja lihavuus voivat nostaa veren matala-asteisen tulehduksen merkkiaineita ja johtaa aineenvaihdunnan epätasapainoon ja muuttaa mikrobistoa. Raskauden aikana nämä muutokset voivat aiheuttaa raskausdiabetesta. Tässä väitöskirjassa oli tavoitteena tutkia matala-asteisen tulehduksen, aineenvaihdunnan ja mikrobiston yhteyksiä keskenään sekä niiden yhteyttä raskausdiabeteksen puhkeamiseen ylipainoisilla sekä lihavilla raskaana olevilla naisilla. Lisäksi, tavoitteena oli tutkia kalaöljyn ja/tai probioottien vaikutusta näihin kolmeen eri tekijään. Tutkimukseen osallistui ylipainoisia ja lihavia raskaana olevia naisia (n = 99–434) alku- ja loppuraskaudessa. Verinäytteistä analysoitiin matala-asteisen tulehduksen ja aineenvaihdunnan (aineenvaihdunnallinen profiili ja fosforyloitu insuliinin kaltaista kasvutekijää sitova proteiini 1 (phIGFBP-1), IGFBP-1 ja aktiivinen matriksin metalloproteinaasi 8 (aMMP-8) sekä rasvahappoja) merkkiaineita ja uloste- ja emätinnäytteistä mikrobiston koostumus. Tutkittavat satunnaistettiin neljään interventioryhmään (kalaöljy+lume, probiootit+lume, kalaöljy+probiootit, lume+lume) alkuraskaudessa. Kalaöjykapselit sisälsivät 2.4 g n‑3 pitkäketjuisia monityydyttyneitä rasvahappoja (n-3 LC-PUFA) (1.9 g dokosaheksaeenihappoa ja 0.22 g eikosapentaeenihappoa) ja probioottikapselit Lacticaseibacillus rhamnosus HN001 ja Bifidobacterium animalis ssp. lactis 420 ‑kantojen bakteereja (1010 pesäkkeen muodostavaa yksikköä/kanta). Matala-asteinen tulehduksen ja monien rasva-aineenvaihdunnan merkkiaineiden tasot veressä sekä suoliston Prevotellacaea-bakteerin suhteellinen osuus olivat korkeammat lihavilla verrattuna ylipainoisiin naisiin alkuraskaudessa. Loppuraskaudessa raskausdiabetekseen sairastuneiden naisten veren phIGFBP-1- ja IGFBP-1-tasot sekä emättimen eräiden bakteerien osuudet olivat matalammat ja veren n-3 LC-PUFA-tasot korkeammat alkuraskaudessa verrattuna naisiin, jotka eivät sairastuneet raskausdiabetekseen. Interventio vähensi emättimen Ureaplasma‑, Prevotella- ja Dialister-suvun bakteereja ja nosti n-3 LC-PUFA-tasoja veressä. Lihavuus voi muuttaa matala-asteista tulehdusta ja aineenvaihduntaa sekä mikrobistoa. Matalat phGFBP-1 ja IGFBP-1-tasot sekä muuttuneet n-3 LC-PUFAtasot olivat yhteydessä raskausdiabetekseen. Kalaöljy ja/tai probiootit laskivat mahdollisesti haitallisten bakteerien määrää emättimessä. AVAINSANAT: ylipaino, lihavuus, raskaus, matala-asteinen tulehdus, aineenvaihdunta, suoliston mikrobisto, emättimen mikrobisto, rasvahapo

Early pregnancy serum IGFBP-1 relates to lipid profile in overweight and obese women

Correction: Volume: 6 Issue: 10 Article Number: e05248 DOI: 10.1016/j.heliyon.2020.e05248Lower level of insulin-like growth factor-binding protein (IGFBP-1) has been observed in insulin resistance, while higher level of matrix metalloproteinase-8 (MMP-8) has been linked to obesity. The aim here was to study in overweight and obese women, typically manifesting with insulin resistance, whether IGFBP-1 and MMP-8 are related to and reflect systemic low-grade inflammation, metabolism and diet. Fasting serum from overweight and obese pregnant women (n = 100) in early pregnancy were analysed for IGFBP-1, phosphorylated IGFBP-1 (phIGFBP-1) and MMP-8. High-sensitivity CRP and GlycA were used as markers for low grade inflammation. GlycA and lipids were quantified using NMR. IGFBP-1 associated negatively with GlycA, evidenced by higher concentrations in the lowest quartile (median 1.53 (IQR 1.45-1.72)) compared to the highest (1.46 (1.39-1.55)) (P = 0.03). Several lipid metabolites, particularly HDL-cholesterol, correlated inversely with phIGFBP-1 (FDRPeer reviewe

The Impacts of Fish Oil and/or Probiotic Intervention on Low-Grade Inflammation, IGFBP-1 and MMP-8 in Pregnancy: A Randomized, Placebo-Controlled, Double-Blind Clinical Trial

Background: We investigated the impact of fish oil and/or probiotics on serum and vaginal inflammatory and metabolic proteins and their relation to the onset of gestational diabetes mellitus (GDM). Methods: Overweight/obese pregnant women received fish oil + placebo, probiotics + placebo, fish oil + probiotics or placebo + placebo from early pregnancy until six months postpartum (fish oil: 1.9 g docosahexaenoic acid and 0.22 g eicosapentaenoic acid; probiotics: Lactobacillus rhamnosus HN001 and Bifidobacterium animalis ssp. lactis 420, 1010 colony-forming units each). Serum high sensitivity C-reactive protein (hsCRP) and serum/vaginal (s/v) phosphorylated insulin-like growth factor binding-protein-1 (phIGFBP-1), IGFBP-1 and matrix metalloproteinase 8 (MMP-8) were analyzed. GDM was diagnosed according to 2 h 75 g OGTT. Results: The intervention had no impact on the change in proteins during pregnancy. Nevertheless, s-MMP-8 decreased and s-IGFBP-1 increased more in obese than in overweight women in the fish oil + probiotics group, while a decrease in s-MMP-8 was seen in obese women and an increase was seen in overweight women in the probiotics + placebo group. The late pregnancy s-phIGFBP-1 was higher in women who developed GDM in fish oil + probiotics-group compared to fish oil + placebo-group. The concentrations of s-phIGFBP-1 (635.9 ± 315.3 ng/mL vs. 753.2 ± 335.1 ng/mL, p = 0.005) and s-IGFBP-1 (3.78 ± 0.72 ng/mL vs. 3.96 ± 0.69 ng/mL, p = 0.042) were lower in early pregnancy in women who developed GDM than in women remaining healthy. Conclusions: The intervention per se had no impact on the proteins, but obesity and GDM may modify the effect. IGFBPs may affect the development of GDM

Overweight and obesity status in pregnant women are related to intestinal microbiota and serum metabolic and inflammatory profiles

Background: Overweight and obesity may predispose women to clinical complications during their pregnancy. We hypothesize that a higher degree of overweight status is related to a range of aberrations in biomarkers already in early pregnancy. Our objective was to investigate whether intestinal microbiota, serum metabolic and inflammatory profiles differ in relation to the degree of overweight status in pregnant women.Methods: This study investigated 52 overweight and 47 obese pregnant women in early pregnancy. Fecal samples were analyzed for intestinal microbiota composition by 16S ribosomal RNA gene sequencing and Qiime pipeline. Circulating serum metabolites, including lipids, amino acids and GlycA, a marker of low-grade inflammation, were analyzed by NMR metabolomics and hsCRP was quantified by immunoassay. Serum zonulin levels were analyzed to depict intestinal permeability by Zonulin ELISA kit and LPS activity for endotoxemia by Limulus amebocyte lysate assay. The analyses were adjusted for multiple comparisons using Benjamini-Hochberg procedure for false discovery rate controlling.Results: The relative abundance of bacterial family Prevotellaceae (adjusted P = 0.19) and markers of low-grade inflammation, hsCRP (P = 0.0015) and GlycA (P Conclusions: The detected alterations in intestinal microbiota and metabolic and inflammatory profiles related to obesity status may offer new alternative tools to supplement standard clinical measures to predict the risk for metabolic alterations during the early phase of pregnancy.</div

Interactions of dietary fat with the gut microbiota: evaluation of mechanisms and metabolic consequences

The current scientific literature proposes that both the amount and type of dietary fat modulate homeostasis of the gut microbiota; disturbances in homeostasis may have metabolic consequences with potentially serious clinical manifestations. The evidence for interactions between dietary fat and gut microbiota has been mostly derived from animal studies, but there is now also evidence emerging from human studies. We will review the current literature on how dietary fat influences the gut microbiota, particularly focusing on the type of fat. Mechanisms detailing how this crosstalk may impact on host metabolism and health will also be discussed. Some studies have reported somewhat controversial findings and therefore we will evaluate critically which possible aspects should be considered when interpreting current and planning further studies to explore the diet-microbiota crosstalk and its metabolic and clinical implications for the host.</p

Distinct Metabolomic Profile Because of Gestational Diabetes and its Treatment Mode in Women with Overweight and Obesity

ObjectiveWhether the presence of gestational diabetes (GDM) and its treatment mode influence the serum metabolic profile in women with overweight or obesity was studied.MethodsThe serum metabolic profiles of 352 women with overweight or obesity participating in a mother‐infant clinical study were analyzed with a targeted NMR approach (at 35.1 median gestational weeks). GDM was diagnosed with a 2‐hour 75‐g oral glucose tolerance test.ResultsThe metabolomic profile of the women with GDM (n = 100) deviated from that of women without GDM (n = 252). Differences were seen in 70 lipid variables, particularly higher concentrations of very low‐density lipoprotein particles and serum triglycerides were related to GDM. Furthermore, levels of branched‐chain amino acids and glycoprotein acetylation, a marker of low‐grade inflammation, were higher in women with GDM. Compared with women with GDM treated with diet only, the women treated with medication (n = 19) had higher concentrations of severalizes of VLDL particles and their components, leucine, and isoleucine, as well as glycoprotein acetylation.ConclusionsA clearly distinct metabolic profile was detected in GDM, which deviated even more if the patient was receiving medical treatment. This suggests a need for more intense follow‐up and therapy for women with GDM during pregnancy and postpartum to reduce their long‐term adverse health risks.</p

Early pregnancy serum IGFBP-1 relates to lipid profile in overweight and obese women

Lower level of insulin-like growth factor-binding protein (IGFBP-1) has been observed in insulin resistance, while higher level of matrix metalloproteinase-8 (MMP-8) has been linked to obesity. The aim here was to study in overweight and obese women, typically manifesting with insulin resistance, whether IGFBP-1 and MMP-8 are related to and reflect systemic low-grade inflammation, metabolism and diet. Fasting serum from overweight and obese pregnant women (n = 100) in early pregnancy were analysed for IGFBP-1, phosphorylated IGFBP-1 (phIGFBP-1) and MMP-8. High-sensitivity CRP and GlycA were used as markers for low grade inflammation. GlycA and lipids were quantified using NMR. IGFBP-1 associated negatively with GlycA, evidenced by higher concentrations in the lowest quartile (median 1.53 (IQR 1.45-1.72)) compared to the highest (1.46 (1.39-1.55)) (P = 0.03). Several lipid metabolites, particularly HDL-cholesterol, correlated inversely with phIGFBP-1 (FDR<0.1). Nutritional status and diet contributed to the levels of IGFBP-1, demonstrated as an inverse correlation with maternal weight (Spearman r = -0.205, P = 0.04) and dietary intake of vitamin A (r = -0.253, P = 0.014) and a direct correlation with dietary intake of polyunsaturated fatty acids (Spearman r = 0.222, P = 0.03). MMP-8 correlated inversely with pyridoxine (r = -0.321, P = 0.002) and potassium (r = -0.220, P = 0.033). Maternal serum IGFBP-1 may contribute to maternal lipid metabolism in overweight and obese women during early pregnancy. These findings may be of importance in identification of metabolic disturbances preceding the adverse metabolic outcomes in pregnancy

GlycA, a novel marker for low grade inflammation, reflects gut microbiome diversity and is more accurate than high sensitive CRP in reflecting metabolomic profile

Introduction Gut microbiota is, along with adipose tissue, recognized as a source for many metabolic and inflammatory disturbances that may contribute to the individual's state of health. Objectives We investigated in cross-sectional setting the feasibility of utilizing GlycA, a novel low grade inflammatory marker, and traditional low grade inflammatory marker, high sensitivity CRP (hsCRP), in reflecting serum metabolomics status and gut microbiome diversity. Methods Fasting serum samples of overweight/obese pregnant women (n = 335, gestational weeks: mean 13.8) were analysed for hsCRP by immunoassay, GlycA and metabolomics status by NMR metabolomics and faecal samples for gut microbiome diversity by metagenomics. The benefits of GlycA as a metabolic marker were investigated against hsCRP. Results The GlycA concentration correlated with more of the metabolomics markers (144 out of 157), than hsCRP (55 out of 157) (FDR Conclusion GlycA is a superior marker than hsCRP in assessing the metabolomic profile and gut microbiome diversity. It is proposed that GlycA may act as a novel marker that reflects both the gut microbiome and adipose tissue originated metabolic aberrations; this proposal will need to be verified with regard to clinical outcomes.</div