The human microbiome. Shantelle Claassen-Weitz Division of Medical Microbiology Department of Pathology.

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1 The human microbiome Shantelle Claassen-Weitz Division of Medical Microbiology Department of Pathology

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3 Source: Hamzelou, J. (2012) New Sientist, 14 April 2012, 6-7 Initial acquisition of GIT microbiota This baby had visitors already!!! Satokari et al. (2009) Lett Appl Microbiol. 48(1):8-12; Jiménez et al. (2008) Res Microbiol. 159(3):187-93; Gosalbes et al. (2012) Clin Exp Allergy. 43(2): ; Jiménez E et al. (2005). Curr Microbiol. 51(4):270-4; DiGiulio DB. (2012) Semin Fetal Neonatal Med. 17(1):2-11. Arrieta et al. (2014) Front Immunol. 5(September):1-18;

4 Initial acquisition of GIT microbiota Transplacental transfer of maternal systemic microbiota 3 2 Maternal GIT microbiota uptake via dendritic cells 1 Ascending maternal vaginal microbiota Source: Claassen et al. Satokari et al. (2009) Lett Appl Microbiol. 48(1):8-12; Jiménez et al. (2008) Res Microbiol. 159(3):187-93; Gosalbes et al. (2012) Clin Exp Allergy. 43(2): ; Jiménez E et al. (2005). Curr Microbiol. 51(4):270-4; DiGiulio DB. (2012) Semin Fetal Neonatal Med. 17(1):2-11

5 Initial acquisition of GIT microbiota Satokari et al. (2009) Lett Appl Microbiol. 48(1):8-12; Jiménez et al. (2008) Res Microbiol. 159(3):187-93; Gosalbes et al. (2012) Clin Exp Allergy. 43(2): ; Jiménez E et al. (2005). Curr Microbiol. 51(4):270-4; DiGiulio DB. (2012) Semin Fetal Neonatal Med. 17(1):2-11

6 Initial acquisition of GIT microbiota Probiotics during pregnancy Placebo during pregnancy Satokari et al. (2009) Lett Appl Microbiol. 48(1):8-12; Jiménez et al. (2008) Res Microbiol. 159(3):187-93; Gosalbes et al. (2012) Clin Exp Allergy. 43(2): ; Jiménez E et al. (2005). Curr Microbiol. 51(4):270-4; DiGiulio DB. (2012) Semin Fetal Neonatal Med. 17(1):2-11

7 Why is this early GIT colonization even important? Meconium is less diverse in infants who will develop late-onset sepsis. Madan et al. (2011) Arch Dis Child Fetal Neonatal Ed. 97:F456 F462. Source:

8 Why is this early GIT colonization even important? Meconium microbiota was associated with respiratory problems in infants. Gosalbes et al. (2013) Clin Exp Allergy. 43: Depositphoto.com/Shershellka

9 Why is this early GIT colonization even important? High prevalence of β-lactam and tetracycline resistance in meconium has been identified, implying that the GIT resistance reservoir starts to accumulate even before birth. Gosalbes et al. (2016) J Dev Orig Health Dis. 7(1):

10 Why is this early GIT colonization even important? Gestational duration Prenatal antibiotic treatment Maternal prenatal stress Maternal diabetes status Source: Claassen et al. Zijlmans et al. (2015) Psychoneuroendocrinology. 53: ; Gonzalez-Perez et al. (2016) J. Immunol. 196(9): ; Munyaka et al. (2014) Front. Pediatr.

11 Why is this early GIT colonization even important? Dominguez-Bello et al. (2010). PNAS.107(26): , Nagpal et al. (2016). Front. Microbiol.

12 Why is this early GIT colonization even important? Decker et al. (2011). Gut Microbes. 2:91-98, Marcobal et al. (2010). J Agric Food Chem. 58: ; Renz-Polster et al. (2005) Clin Exp Allergy. 35:

13 Why is this early GIT colonization even important?

14 Why is this early GIT colonization even important?

15 Why is this early GIT colonization even important?

16 Why is this early GIT colonization even important?

17 Why is this early GIT colonization even important? Some things to consider: Group B Strep (GBS): Mothers in the US are routinely tested for this bacteria, and about 1/3 of them have it. GBS lives in the vagina without causing any problems, but it doesn t play nicely with babies. It s a major cause of neonatal bloodstream infections and meningitis. Mothers who have been found to carry this bacteria are treated with antibiotics during labor an intervention that has reduced the rate of neonatal sepsis and saved a lot of babies lives. Chlamydia and gonorrhea: These are two sexually transmitted bacteria that we do routinely screen for during pregnancy. Chlamydia can cause pneumonia, but the big concern here is an eye infection that can cause permanent blindness (it s the reason for using erythromycin ointment after birth). Human Immunodeficiency Virus (HIV): This is a complicated topic, and the risk for transmitting HIV from a mother to a baby depends on the mother s viral load and what medications she is on. Sometimes, a cesarean delivery is performed to decrease the risk of infecting the baby. Just like the potential benefits, the potential risks are somewhat unknown as well. We don t know how many babies who got seeded would develop infections from these organisms, how many of those infected babies would die or suffer significant harm, or what other potential complications there might be. Without more studies, we re left to piece together little bits of evidence and use our best judgment.

18 Why is this early GIT colonization even important? Source: Claassen et al.

19 Why is this early GIT colonization even important? Thompson et al. (2015). Frontiers in Cellular and Infection Microbiology. Vol 5 Article 3 1

20 Why is this early GIT colonization even important? Microbiota signatures clustered predominantly by individual and were less dependent on feeding type or sampling time. Although microbiota signatures were less dependent on feeding type, they did find differences in microbiota composition clustering based on feeding type. Profiles sampled during the first 21 days were distinct from each other as well as later points (which clustered more closely). The latter finding implies that the most dynamic developmental changes in gut microbiota composition take place during the first 3 weeks of the three months time frame that was analysed. Timmerman et al. (2017) Scientific Reports. 7: 8327 DOI: /s

21 Why is this early GIT colonization even important?

22 Why is this early GIT colonization even important? Beneficial factors in breast milk Human milk contains proteins, fats, and carbohydrates, as well as immunoglobulins and endocannabinoids. The oligosaccharides in human milk (HMOs) have a clear probiotic effect by selectively stimulating the development of a Bifidobacterium-rich microbiota Compared with breastfed infants, formula-fed infants still have distinct features of their microbiotas, such as the overrepresentation of C. difficile. Breast milk contains numerous factors that modulate and promote the development of the immune system in infancy, including immunoglobulins such as IgA and IgG, antimicrobial compounds such as lysozyme and lactoferrin, immune regulatory cytokines such as TGF-β and interleukin 10 (IL-10), and lymphocytes that express gut homing markers. These substances in breast milk select bacteria that colonize the GI tract. For example, immune regulatory cytokines such as IL-10 and TGF-β in breast milk facilitate tolerance of the host immune system to intestinal bacteria and promote infant IL-10 production. Recent studies have shown that breast milk is not sterile. It contains as many as 600 different bacterial species and cfu/ml of bacteria cells. Genera of bacteria isolated from breast milk include mostly lactic acid bacteria such as Lactobacillus, Leuconostoc, Streptococcus, Enterococcus, Lactococcus, and Weissella, as well as some beneficial Bifidobacterium species. Fatty acids (FA) in breast milk are also associated with host health and development of the immune system. Some cohort studies have shown that the ratio of polyunsaturated FA is related to an infant's risk of atopic Tanaka & Nakayama. (2017) Allergology International. 66 (4)

23 Why is this early GIT colonization even important? Source: Claassen et al.

24 Why is this early GIT colonization even important? A large shift in the gut microbial community from Bifidobacterium-dominant to Bacteroidetes- and Firmicutes-dominant accompanies the introduction of solid foods, including indigestible carbohydrates. At approximately three years of age, bacterial composition and diversity is most like those of adults. These microbiotas remain fairly stable throughout adulthood in the absence of perturbations such as long-term dietary changes, disease-associated dysbiosis, or the use of antibiotics. Recent metagenomics studies have offered in-depth insights into the functions of infant gut microbiotas. The infant gut rapidly acquires a functional gene pool dominated by carbohydrate metabolism genes, which is broadly similar to that of an adult. However, the functional repertoires of the infant microbiotas shift dramatically during the first year of life, as the earliest microbiotas are enriched in bacteria with genes that facilitate lactate utilization, whereas solid foods enrich microbiotas with bacteria with genes that code for the utilization of a lager variety of carbohydrates, vitamin biosynthesis, and xenobiotic degradation. Tanaka & Nakayama. (2017) Allergology International. 66 (4)

25 Why is this early colonization even important? The introduction of solid foods had a marginal impact on the microbiome of exclusive breast fed (EBF) infants (24 enzymes overrepresented in EBF+solid (EBF+S) infants). In contrast, over 200 bacterial gene categories were overrepresented in non-ebf+s compared to non-ebf infants. The identified differences between EBF and non-ebf infants suggest that breast milk may provide the gut microbiome with a greater plasticity (despite having a lower phylogenetic diversity) that eases the transition into solid foods. Thompson et al. (2015). Frontiers in Cellular and Infection Microbiology. Vol 5 Article 3 1

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27 What happens after infancy to our GIT microbiota? Unlike early life profiles, an individual s large intestinal gut microbiota appears to be stable for a significant period of time upon reaching its stable climax community Faith et al. (2013) Science. 341(6141): ; Wopereis et al. (2014). Pediatr Allergy Immunol, 25:

28 What happens after infancy to our GIT microbiota? Group Age Segmentation (Mean ± SD) 1 Preweaning (0.3 ± 0.1) 2 Weaning (0.8 ± 0.4) 3 Weaned-3 years old (2.4 ± 0.6) years old (6.1 ± 1.9) years old (14.1 ± 3.6) years old (25.9 ± 2.7) years old (33.9 ± 2.3) years old (43.8 ± 3.1) years old (53.3 ± 2.6) years old (63 ± 2.7) years old (76.8 ± 2.1) years old (83.3 ± 2.4) years old (94.2 ± 2.7) 100 Over 100 years old (101.3 ± 1.8) Odamaki et al. (2016). BMC Microbiology 16:90

29 What about microbiota of other body sites? Although the gut microbiota expresses over 3.3 million bacterial genes, while the human genome expresses only 20 thousand genes. It is definitely not the only body site colonized by bacteria:

30 What about microbiota of other body sites? Placental microbiome The first profile of microbes in healthy term pregnancies identified a unique microbiome niche in normal placenta, composed of non-pathogenic commensal microbiota Placentas from normal deliveries and preterm deliveries contained different populations of microbial species. Aagaard et al. (2014) Sci. Transl. Med. 6:237ra265. doi: /scitranslmed

31 What about microbiota of other body sites? Vaginal microbiota Vaginal microbiota is different for women of different ethnic groups. Ravel et al. (2011) Proc. Natl. Acad. Sci. U.S.A. 108(Suppl. 1), doi: /pnas

32 What about microbiota of other body sites? Vaginal microbiota Women with BV had heterogeneous vaginal bacterial communities that were usually not dominated by a single taxon. In the absence of BV, vaginal bacterial communities were dominated by either Lactobacillus crispatus or Lactobacillus iners. Srinivasan et al. (2012) PLOS One. 7(6): e37818

33 What about microbiota of other body sites? Skin microbiota The skin microbiota differs across different skin sites, for example: (A) sebaceous, (B) moist, and (C) dry Grice et al. (2009) Science 324 (5931): DOI: /science

34 What about microbiota of other body sites? Breast milk microbiota A) Changes in breast milk profiles have been observed until 6months following delivery. Differences were also observed between normal weight and obese mothers. B) Mode of delivery influenced maternal breast milk microbiota profiles. A) Genus-level B) Genus-level Colostrum 1month 6months Vaginal Non-elective C-section Elective C-section Cabrera-Rubio et al. (2012) Am J Clin Nutr. 96:

35 What about microbiota of other body sites? Breast milk microbiota A) Changes in breast milk profiles have been observed until 6months following delivery. Differences were also observed between normal weight and obese mothers. B) Mode of delivery influenced maternal breast milk microbiota profiles. A) Genus-level B) Genus-level Colostrum 1month 6months Vaginal Non-elective C-section Elective C-section Cabrera-Rubio et al. (2012) Am J Clin Nutr. 96:

36 What about microbiota of other body sites? Respiratory microbiota Dicksonet al. (2014) Lancet Respir Med. 2(3): ; Dickson and Huffnagle (2015) PLoS Pathog. 11(7): e

37 What about microbiota of other body sites? Vascular microbiota

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