Egija Zaura Professor in Oral Microbial Ecology Department of Preventive Dentistry Academic Centre for Dentistry Amsterdam (ACTA)

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1 Egija Zaura Professor in Oral Microbial Ecology Department of Preventive Dentistry Academic Centre for Dentistry Amsterdam (ACTA) Women & their Microbes, June 2, 2017, Amsterdam

2 Joined Faculty of Dentistry of two universities of Amsterdam: 950 students 300 patients per day patients in total 950 employees 150 PhD students Gustav Mahlerlaan 3004, Amsterdam, the Netherlands

3 What is a healthy oral microbiome? Niche specificity of the oral microbiome Stability of the oral microbiome Male-female differences at the level of oral ecosystem Mobile oral microbiome

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5 Images from the internet

6 Bacteria (Microbiome > Bacteriome): o o ~ 1000 species identified Thousands of phylotypes predicted Fungi (Mycobiome): More than 100 species found in saliva of healthy adults (Ghannoum et al 2010) Protozoa (e.g. Entamoeba gingivalis, Trichomonas tenax) Viruses (Virome): Eukaryotic viruses Prokaryotic viruses (bacteriophages) Archaea (Methanobrevibacter smithii & M. oralis)

7 Front tooth Buccal Interproximal Molar tooth Lingual Upper jaw & saliva sample Zaura et al. (2009). Defining the healthy "core microbiome" of oral microbial communities

8 Fusobacteria TM7 Bacteroidetes Proteobacteria Actinobacteria Firmicutes Front tooth Molar tooth Palate Cheek Tongue Saliva Average Buccal Lingual Interproximal Buccal Lingual Interproximal Individual S1 Zaura et al. (2009). Defining the healthy "core microbiome" of oral microbial communities 8

9 PC2 (11.9% variance) PC2 (10.2% variance) PC2 (7.9% variance) Posterior tongue Interproximal plaque Anterior tongue Subgingival plaque Saliva Supragingival plaque Saliva PC1 (28.6% variance) Interproximal plaque Posterior tongue Anterior tongue Subgingival plaque PC1 (18.3% variance) TIFN Oral Health Project PC1 (14.6% variance)

10 Prevent non-oral microbial colonization Teach our immune system to recognize a friend from a foe Contribute to gastrointestinal & cardiovascular health

11 Nitric Oxide Salivary glands Nitrate Blood Oral bacteria Intestines Nitrite Stomach Nitric Oxide Hezel & Weitzberg,

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13 Microbial community stability over time Zhou et al (2013) Genome Biol

14 Zaura et al (2015) mbio 14

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16 E. Zaura et al (2017) ISME J; Andrei Prodan et al (2015) Eur J Oral Sci

17 Males: N=149 Females: N=118 Andrei Prodan et al (2015) Eur J Oral Sci 17

18 ph Buffered ph Andrei Prodan et al (2015) Eur J Oral Sci 18

19 To describe the boundaries of and the heterogeneity within the healthy oral ecosystem To decipher the relations between salivary bacterial composition (microbiome), salivary metabolites (metabolome) and the hostrelated biochemical salivary parameters and diet Zaura et al (2017) ISME J

20 268 systemically and orally healthy individuals, y Overnight fasting 24-h since the last oral hygiene procedure Unstimulated saliva between 9-10 a.m., 2x5 min Biochemical analyses (Prodan et al 2015) Microbiome 16S rrna gene amplicon sequencing (MiSeq Illumina) Metabolome assessment (Metabolon, Durham, NC, USA) Dietary assessment validated FFQ Statistical analyses: Spectral Clustering, PCA, LEfSe, CoNet, SAM, Elastic Net, Spearman Correlation, Procrustes analysis, Mantel test Zaura et al (2017) ISME J

21 Dietary items, based on food frequency questionnaire: Item Females Males P value (N=118) (N=137) Energy (kj/day) 9,897±2,747 14,296±4,572 <0.001 Total protein (g/day) 83.5± ±41 <0.001 Total fat (g/day) 88.7± ±50.9 <0.001 Linoleic acid (g/day) 14.7± ±10.5 <0.001 Alpha linoleic acid (g/day) 1.8± ±1.4 <0.001 Elcosapentaenoic acid (g/day) 0.12± ±0.16 NS Docosahexaenoic acid (g/day) 0.17± ±0.24 NS Total carbohydrates (g/day) 267.1± ±134.9 <0.001 Mono- & dissacharides (g/day) 114.7± ±63 <0.001 Polysaccharides (g/day) 152.5± ±88 <0.001 Fibres (g/day) 23± ±11.4 <0.001 Alcohol (g/day) 15.1± ± Calcium (mg/day) 954± ±435.9 <0.001 Vitamin B1 (mg/day) 1.14± ±0.63 <0.001 Vitamin B2 (mg/day) 1.63± ±0.77 <0.001 Vitamin B6 (mg/day) 2.14± ±1.03 <0.001 Vitamin B12 (µg/day) 5.98± ±3.9 <0.001 Vitamin D (µg/day) 3.02± ±2.7 <0.001 Vitamin C (mg/day) 94.8± ±60.2 <0.001 Folic acid equivalents (µg/day) 282.6± ±128.6 <0.001 Total organic acids (g/day) 1.74± ±1.14 <0.001 Zaura et al (2017) ISME J 21

22 Black male Aqua - female PERMANOVA: NS 22

23 65 OTUs differentiated between males and females (LEfSe - biomarker selection tool)23

24 F M P < PERMANOVA: F=10.98 P= metabolites overrepresented in females: Glycerol, caffeine and 3-hydroxyindolin-2-one 202 metabolites overrepresented in males Zaura et al (2017) ISME J 24

25 het-westerkwartier.nl 25

26 Homeostasis Health Caries Stable (healthy) microbiome Periodontitis Frequent sugar intake / episodes with low ph / Hyposalivation Inflammation Immune suppression Ecologic disturbances Adapted from Marsh et al.,

27 John Lukacs (2010) Clin Oral Invest: Sex differences in dental caries experience. 27

28 Haytac et al (2013) Periodontology

29 Synovial fluid Atherosclerotic plaques Placenta, Amniotic fluid Colorectal carcinoma Pancreatic cancer Respiratory tract 29

30 Hajishengallis (2015) Nature Reviews in Immunology 30

31 HMP project: 250 healthy individuals Placenta biopsies from over 300 healthy pregnancies Placenta harbors microbiome similar to the oral cavity Aagaard et al (2014) Sci Transl Med

32 Illustration (from animation) Science/AAAS

33 Gingival swelling and bleeding due to estradiol > pregnancy gingivitis (Niederman 2013) Opening the vascular bed > oral bacteria from the mother in blood Zaura et al (2014) Front Microbiol

34 Oral mucosa of mother Placenta Fetal lymphoid tissue APCs APCs Tregs Recognizing a friend from a foe Zaura et al (2014) Front Microbiol

35 Fetal immune system is trained for a post-natal commensal recognition of the oral bacteria of mother Microbiome of the mother is essential for establishment of a healthy microbiome-host crosstalk in her child It will open possibilities for personalized pre-conceptional and prenatal interventions

36 Healthy oral microbiome: Prevents non-oral microbial colonization Teaches our immune system to recognize a friend from a foe Contributes to gastrointestinal and cardiovascular health Is niche-specific, stable and can withstand stress Female oral physiology (salivary composition, ph) differs from that of males These gender-specific physiological host factors shape the oral microbiome and metabolome in a gender-specific way Males more prone to periodontal disease Females more prone to dental caries Dis-balanced oral microbiome and oral inflammation is related to health problems elsewhere in the body ( mobile oral MB ), including adverse pregnancy outcomes The role of Placental microbiome at health needs to be investigated

37 Academic Center for Dentistry Amsterdam Dept. of Preventive Dentistry: dr. Bernd Brandt, prof. Wim Crielaard Dept. of Oral Biochemistry: dr. Andrei Prodan Dept. of Periodontology: Prof. B. Loos & clinical staff TNO Earth, Environmental and Life Sciences Prof. dr. Bart Keijser Wageningen University Top Institute of Food and Nutrition (TIFN) Philips Wrigley GlaxoSmithKline Cargill

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