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Microbiota development,

does it start at birth, or before?

The first time a child is exposed to bacteria is when it passes through the birth canal. This is important not only for the development of its microbiota but also for its health later in life. Children delivered by Caesarean section not only start life with a different microbiota, but are also more likely to develop conditions like asthma and diabetes. In a study published in Nature Medicine recently, researchers called this commonly accepted theory into question by pointing out they had been unable to find any difference between the microbiota of the two birth methods. Does this mean textbooks will need to be rewritten? Not quite yet, say microbiologists.

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Vaginal delivery 

In a normal delivery, a child comes into direct contact with the bacteria in the birth canal, which colonize the skin, mouth, gut and upper respiratory tract. These are followed by bacteria from the child’s environment and carers. The composition of the microbiota will adapt to the conditions of the specific areas of the body. In the gut, the transition from milk to solid food will kick off a second major shift. From the age of about three, the composition of the gut microbiota will have stabilized and be comparable to that in adults. In healthy individuals, the gut microbiota will remain stable up to the age of about 75 [1]. 

 

 

Caesarean

Children born through Caesarean section are known to be at a greater risk of developing immune and autoimmune diseases and metabolic conditions including allergies, eczema, asthma, diabetes and obesity. Initially, their gut microbiota differs markedly from that in vaginally delivered children and contains more bacteria from the hospital and the skin of nursing staff. In addition, the proliferation of a number of bacterial species essential to the development of the immune system, including Bifidobacterium and Bacteroides, is seen to lag [1]. ‘After a number of months, the differences between the birth methods are no longer as distinct. 

 

 

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Global changes in microbiota composition during life.

Image: Sittrop Grafisch Realisatiebureau, Nijmegen

However, there has still been a difference in the initial priming of the immune system, and it may not be possible to rectify the effects of that’, says Guus Roeselers, Senior Group Leader Gut Microbiology at Danone Nutricia Research. The reason is that in the first 1,000 days of life, the immune system develops relatively quickly and is ‘trained’ by the bacteria present in the gut. ‘That initial dialogue between gut bacteria and the immune system determines one’s health later in life’, says Willem de Vos, Microbiology Professor at Wageningen University & Research.

 

 

Seeding of probiotics

To reduce the impact of a Caesarean delivery on gut colonization, the idea was developed to swab these babies with a vaginal smear from the mother, a procedure known as vaginal seeding.[2] Although researchers did see a partial recovery of the microbiota as a result of this practice, obstetricians and gynaecologists in the Netherlands and many other countries still advise against it [3], mainly because there is no evidence of its long-term effects and because there is a risk of transferring pathogens. Breast-feeding [4] and, if at all possible, avoiding the use of antibiotics [5] is still recommended for the development of the microbiota, as the use of antibiotics in early life also increases the risk of metabolic and immunological diseases. ‘The proper development of the microbiota can be disrupted in many different ways, sometimes in several ways at once’, says Roeselers. ‘Premature babies born through Caesarean section are given antibiotics because they are so vulnerable, and in the worst case will not be fed breast milk. That amounts to a quadruple coincidence of factors that negatively impact the microbiota.’

 

Administering probiotics [6] or synbiotics [7], a combination of pre- and probiotics, would be a safe alternative in those cases. An exploratory study conducted in Singapore and Thailand showed that children born through Caesarean section benefited from the addition of oligosaccharides and Bifidobacterium breve to their formula in the first weeks.7 Their gut was immediately colonized by bifido bacteria that synthesized acetate and promoted an acid environment. The same effects are seen in vaginally delivered children and are indicative of sound gut health. 

 

 

Controversy

Against that background, the article [8] in Nature Medicine by an American research group came as a complete surprise.  They reported being unable to see any difference between the initial microbiota found in children delivered through different birth methods. The authors speculate that this is because the first colonization of the gut already takes place in the womb, since that would be in line with earlier studies that found bacteria (based on DNA analysis) are present in the placenta and amniotic fluid.[9],[10]  

‘This piece caused quite a stir among microbiologists and doctors’, says Roeselers. ‘Not a lecture goes by without at least one of the attendees quoting it.’ However, like many other microbiologists, Roeselers is not convinced by the study or the interpretation of the results. This is mainly due to the large number of studies in which different study groups independently showed that the birth method definitely does make a difference. ‘The fact that we see such major differences is the main reason why prenatal colonization is highly improbable.’ 

 
 
A recent American reearch did not see any difference between the initial microbiota found in children delivered through different birth methods.

 

 

Antibiotics use

Another contributing factor, Roeseler knows from experience, is that it is standard practice for many doctors in the USA to give women about to give birth a course of antibiotics to prevent the transmission of pathogens, regardless of birth method. ‘Most doctors still regard bacteria as a risk rather than as important contributors to a child’s development. The antibiotics also reach the child through the mother. The idea is that the antibiotics will protect both the mother and the child. However, it also causes a change in the microbiota, which has an effect so strong that it even overshadows the differences due to birth methods. That would offer an explanation for the results of the American study’, says Roeselers. ‘In many European countries, the mother is not given antibiotics until after the birth, and we do see differences over here’, Willem de Vos adds. Like Roeselers, he is not convinced by the Americans’ conclusions. 

 

 

Scrutiny

Canadian and American scientists recently presented a review of all literature supporting the two hypotheses.[11] However, they, too, concluded there is no hard evidence for the hypothesis of colonization by bacteria starting in the womb. Not only did the review reveal cases where placental and amniotic samples had been examined using unsuitable techniques or without proper contamination risk controls, the reviewed literature did not yield any evidence either that the bacterial DNA found originated from live microorganisms.[9]. 

 

According to Roeselers, the presence of bacterial DNA in amniotic fluid is, in itself, not unlikely. Bacterial DNA is also found in blood. ‘However, that is not the same as significant numbers of live bacteria. When we look at the human anatomy, we see that it is replete with barriers intended to keep bacteria out. If a bacterium does manage to break through one of these barriers, our immune system will immediately kick in’, Roeselers continues. 

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Opposing concepts by which human microbiota is acquired early in life. 

A: In the sterile womb paradigm, the placenta, amniotic fluid, and fetal gut remain sterile during a healthy pregnancy, and the early microbiome is acquired during and after birth.

B: The “in utero colonization hypothesis” proposes that some microbial members of the infants’ gut microbiome are acquired before birth, probably via contact with a placental microbiome, which has been suggested to originate from the mother’s gut or oral microbiome.

Source: Microbiome. Reference 11.

 

 

Too soon

According to Willem de Vos, it would be far too soon to revise the commonly accepted hypothesis. ‘We have to keep both feet firmly on the ground. Research into the early development of the microbiota in infants is very difficult because effective controls are almost impossible. What’s more, the number of studies is still too small to be able to conduct proper comparative research. But it will happen, it’s only just starting to taking off.’ 

 

 

References

1.       Guus Roeselers & Jan Knol, Ontwikkeling van het darmmicrobioom vanaf het vroege leven. Sarah Lebeer, Vaginale bacteriën en het penismicrobioom, in Ons microbioom. December 2016, Biowetenschappen en Maatschappij. www.biomaatschappij.nl/wordpress/wp-content/uploads/2017/09/Ons-microbioom.pdf

2.       Dominguez-Bello MG, De Jesus-Laboy KM, Shen N, Cox LM, Amir A, Gonzalez A, Bokulich NA, Song SJ, Hoashi M, Rivera-Vinas JI, Mendez K, Knight R, Clemente JC. Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer. Nat Med 2016;22:250–3.

3.       Editorials “Vaginal seeding” of infants born by caesarean section, BMJ 2016;352:i227, doi: https://doi.org/10.1136/bmj.i227

4.       Korpela K, A Salonen, A Virta, R Kekkonen & WM de Vos (2016) Association of early antibiotic use and protective effects of breast-feeding – role of intestinal microbiota. JAMA Pediatrics 170(8):750-7. DOI: 10.1001/jamapediatrics.2016.0585

5.       Korpela K, A Salonen, LJ Virta, RA Kekkonen, K Forslund, P Bork & WM de Vos (2016) Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children. Nature Commun. 7:10410.

6.         Korpela K, Salonen A, Virta LJ, Kumpu M, Kekkonen RA, de Vos WM (2016) Lactobacillus rhamnosus GG Intake Modifies Preschool Children's Intestinal Microbiota, Alleviates Penicillin-Associated Changes, and Reduces Antibiotic Use. PLoS One. 11(4):e0154012.

7.         Chua MC, Ben-Amor K, Lay C, Neo AGE, Chiang WC, Rao R, Chew C, Chaithongwongwatthana S, Khemapech N, Knol J, Chongsrisawat V, Effect of Synbiotic on the Gut Microbiota of Cesarean Delivered Infants: A Randomized, Double-blind, Multicenter Study, J Pediatr Gastroenterol Nutr. 2017; 65: 102–106.

8.        Chu DM, Ma J, Prince AL, Antony KM, Seferovic MD, Aagaard KM. Maturation of the infant microbiome community structure and function across multiple body sites and in relation to mode of delivery. Nat Med. 2017 Mar;23(3):314-326. doi: 10.1038/nm.4272. Epub 2017 Jan 23.

9.        Aagaard, K. et al. The placenta harbors a unique microbiome. Sci. Transl. Med. 6, 237ra65 (2014).

10.    Collado, M.C., Rautava, S., Aakko, J., Isolauri, E. & Salminen, S. Human gut colonization may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid. Sci. Rep. 6, 23129 (2016).

11.    Perez-Muñoz ME, Arrieta MC, E. Ramer-Tait AE and Walter J, A critical assessment of the “sterile womb” and “in utero colonization” hypotheses: implications for research on the pioneer infant microbiome, Microbiome, 2017, 5:48, https://doi.org/10.1186/s40168-017-0268-4

 

 

 

 

 

Antibiotic use linked to behavioural changes

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