Nishant Mehta Ph.D. candidate

As adults, we have fully matured microbiomes that are constantly interacting with the food we ingest. This conglomeration of hundreds of different bacterial strains work together in synergy to digest food and release byproducts that contribute to our well-being. As humans, we have evolved the capacity to generate new life through an intricate combination of genes from the mother and father. However, these genes only encode for human life, not bacterial life. Nothing in our DNA directly translates to bacterial proteins or furthers the reproduction of bacterial life. How then, do trillions of bacteria end up colonizing our gut? How does the commensal relationship between microbes and human cells first arise?

For decades, most of the scientific community agreed that the intrauterine development of the fetus takes place in a sterile environment, free from microbes[2]. Recent evidence, due in part to the advent of advanced sequencing technology, is challenging this belief. Vestiges of microbes have been found in the fetal amniotic fluid, fetal membranes, and placenta [3]. In fact, DNA of the common gut bacterial strains Lactobillus and Bifidobacterium were found in all biopsies of the placenta from C-section births (which circumvent classic exposure to the mother’s native microbes)[4]. This evidence suggests that the gut microbiome is undergoing development even before birth. It is hypothesized that the mother can pass gut microbes on to the developing fetus. A randomized patient trial showed evidence that the consumption of probiotics during pregnancy changes the immune signature of cells in the fetal gut and amniotic fluid [5]. This finding suggests fetal interaction with maternal microbes in the uterus. However, most of the new evidence suggesting microbial colonization in the fetus must be taken with a grain of salt. High-throughput sequencing experiments performed on small samples such as fetal biopsies are prone to contamination that can drastically skew results. Even if there is some microbial interaction in utero, the consensus is that the vast majority of gut microbial colonization happens during and immediately following birth.

As a newborn travels through and exits the birth canal, exposure to the vaginal, fecal, and skin microbiota of the mother takes place. First, bacterial species such as Escherichia coli, Staphylococcus, and Streptococcus colonize the infant gut. These initial species create a local environment devoid of oxygen that allows strictly anaerobic species such as Bacteroides and Bifidobacterium to colonize the gut in the first few days of life [6]. In addition to direct exposure to maternal and environmental microbiota during birth, microbes are also directly transferred to newborns through breast milk. As discussed in a previous blog post titled ‘Probiotics and Breast Milk’, human breast milk is a direct source of microbes such as Staphylococcus, Bifidobacterium, and Lactobillus strains, among many others. Breast milk also contains human milk oligosaccharides (HMOs), which are prebiotics, or molecules that promote the growth of microbial communities[7]. The infant microbiome is dynamic — it changes from an environment that facilitates breast milk utilization to one dominated by anaerobic organisms that can help digest solid foods. By 1 year of age, the gut microbiome starts to converge on a profile that resembles a fully-formed adult gut[8]. This rapid colonization and convergence of microbes emphasizes the importance of exposures that take place during birth and in the first year of life.

Unfortunately, the natural development of the neonatal microbiome can be disrupted through three common human interventions: C-section delivery, early antibiotic use, and formula feeding. Babies that are born through C-section harbor no vaginal microbes initially and are instead first colonized by skin bacteria (e.g. Corynebacterium, Propionibacterium)[9]. This delays the colonization of healthy anaerobic species Bifidobacterium and Bacteroides and increases the levels of pathogenic C. diff bacteria in the gut[10]. Differences in bacterial composition of the gut due to mode of delivery are noticeable up to 7 years later[11]. Additionally, the use of antibiotics during labor delivery or directly after birth have been associated with lower abundance of healthy Lactobillus and Bifidobacterium strains and an overall lower diversity of gut bacteria[12]. Finally, introduction of formula early in the postnatal period has been shown to perturb the colonization of intestinal microbiota and can increase prevalence of C. diff while decreasing amounts of Bifidobacterium[13]. While the scientific community is still unsure how long-lasting these perturbations can be, we are sure that the immediate changes in microbial composition are quite significant.

If you were born through C-section, were exposed to antibiotics at a young age, or were formula-fed early on, does that mean you are doomed to have an imbalanced microbiome? Not necessarily! Although you may have to work a bit harder than those who were born and fed naturally, lifestyle choices as an adult can drastically alter your microbiome. New evidence shows that choosing a plant-based diet vs. an animal-based diet can markedly and reproducibly alter the human gut microbiome[14]. In mice, exercise has also been shown to drastically shift microbial populations[15]. We also know that probiotics are useful for a variety of conditions such as antibiotic-associated diarrhea, H. pylori and C. diff infections, and irritable bowel syndrome[16]. This evidence suggests that probiotics can significantly shift microbial populations. At Thryve, we aim to be at the forefront of this discovery. We want to better understand how humans can change their own microbiome through the administration of targeted probiotics. By gathering a wealth of microbial sequencing data, we are confident that patterns and correlations will be identified that can improve human health.

References:

[1] (image) “Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome,” The Microbe Discovery Project, 03-Jul- 2016

[2] M. W. Groer, A. A. Luciano, L. J. Dishaw, T. L. Ashmeade, E. Miller, and J. A. Gilbert, “Development of the preterm infant gut microbiome: a research priority,” Microbiome, vol. 2, p. 38, Oct. 2014.

[3] N. T. Mueller, E. Bakacs, J. Combellick, Z. Grigoryan, and M. G. Dominguez-Bello, “The infant microbiome development: mom matters,” Trends Mol. Med., vol. 21, no. 2, pp. 109–117, Feb. 2015.

[4] R. Satokari, T. Grönroos, K. Laitinen, S. Salminen, and E. Isolauri, “Bifidobacterium and Lactobacillus DNA in the human placenta,” Lett. Appl. Microbiol., vol. 48, no. 1, pp. 8–12, Jan. 2009.

[5] S. Rautava, M. C. Collado, S. Salminen, and E. Isolauri, “Probiotics Modulate Host-Microbe Interaction in the Placenta and Fetal Gut: A Randomized, Double-Blind, Placebo-Controlled Trial,” Neonatology, vol. 102, no. 3, pp. 178–184, Sep. 2012.

[6] I. G. Pantoja-Feliciano et al., “Biphasic assembly of the murine intestinal microbiota during early development,” ISME J., vol. 7, no. 6, pp. 1112–1115, Jun. 2013.

[7] “The First Prebiotics in Humans: Human Milk Oligosaccharides : Journal of Clinical Gastroenterology,” LWW. [Online]. Available: http://journals.lww.com/jcge/Fulltext/2004/07002/The_First_Prebiotics_in_Humans__Human_Milk. 8.aspx. [Accessed: 10-Mar-2017].

[8] C. Palmer, E. M. Bik, D. B. DiGiulio, D. A. Relman, and P. O. Brown, “Development of the Human Infant Intestinal Microbiota,” PLOS Biol., vol. 5, no. 7, p. e177, Jun. 2007.

[9] M. G. Dominguez-Bello et al., “Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns,” Proc. Natl. Acad. Sci., vol. 107, no. 26, pp. 11971–11975, Jun. 2010.

[10] J. Penders et al., “Gut microbiota composition and development of atopic manifestations in infancy: the KOALA Birth Cohort Study,” Gut, vol. 56, no. 5, pp. 661–667, May 2007.

[11] S. Salminen, G. R. Gibson, A. L. McCartney, and E. Isolauri, “Influence of mode of delivery on gut microbiota composition in seven year old children,” Gut, vol. 53, no. 9, pp. 1388–1389, Sep. 2004.

[12] F.Fouhyetal.,“High-ThroughputSequencingRevealstheIncomplete,Short-TermRecoveryof Infant Gut Microbiota following Parenteral Antibiotic Treatment with Ampicillin and Gentamicin,” Antimicrob. Agents Chemother., vol. 56, no. 11, pp. 5811–5820, Nov. 2012.

[13] J. Penders, C. Vink, C. Driessen, N. London, C. Thijs, and E. E. Stobberingh, “Quantification of Bifidobacterium spp., Escherichia coli and Clostridium difficile in faecal samples of breast-fed and formula-fed infants by real-time PCR,” FEMS Microbiol. Lett., vol. 243, no. 1, pp. 141–147, Feb. 2005.

[14] L. A. David et al., “Diet rapidly and reproducibly alters the human gut microbiome,” Nature, vol. 505, no. 7484, pp. 559–563, Jan. 2014.

[15] J. E. Lambert, J. P. Myslicki, M. R. Bomhof, D. D. Belke, J. Shearer, and R. A. Reimer, “Exercise training modifies gut microbiota in normal and diabetic mice,” Appl. Physiol. Nutr. Metab., vol. 40, no. 7, pp. 749–752, Feb. 2015.

[16] M. L. Ritchie and T. N. Romanuk, “A Meta-Analysis of Probiotic Efficacy for Gastrointestinal Diseases,” PLOS ONE, vol. 7, no. 4, p. e34938, Apr. 2012.