The science is confirming the powerful connection between our gut microbiome and overall health at a mind-blowing rate. It is not surprising, since all disease starts in the gut. Probiotics have taken the center stage of the wellness and medical world which exploded the variety of probiotics we see marketed. Not all probiotics created equally – as all supplements. Probiotics can either be highly effective on our health or completely useless based on the strains of bacteria it contains.

What is gut microbiome and why it matters?

The gut microbiome is a microbial community impacting the brain, immune system, metabolism and gut motility. All of these systems are interconnected through the gut microbiome. A healthy gut microbiome has protective effects on the infant through all stages of life. The more pathogenic bacteria you have in your gut, the more endotoxin will be present triggering inflammation. Setting up a strong microbial foundation of a newborn’s gut is crucial to build a resilient immune system and thereby decrease the risk for immune disease in later life.

Gut microbiome from infancy to weaning

The microbiome is passed from mother to newborns, at first, through delivery. We are actually born without a gut microbiome, and we have to assemble one at every generation. The delivery mode determines the acquisition and the structure of the initial microbiome across multiple body habitats in newborns. If infants are born by caesarean section, the normal transfer of mums’ gut microbiome happens through fecal oral route into infants. Early life microbiome is very distinct from ‘after weaning’ period.

The first 6 months is described as a milk-oriented microbiota due to breastfeeding. It starts colonizing Bifidobacterium longum and dominate through this first 6 months. Bifidobacterium is transferred from mother to baby through vaginal delivery. Medical practices like cesarean delivery bypass this route by which Bifidobacterium can be transferred and then colonized in the infant’s gut. These species are essential for their early immune system development. The breastfed infant is nearly a monoculture of Bifidobacterium. Bifidobacterium infantis and breastmilk (oligosaccharide) interact in the infant gut. Whereas the formula-fed infant has a more diverse microbiome which may increase the risk of acquiring pathogenic species.  

At weaning between 6 and 12 months, other bacteria increase in abundance and the diversity of gut microbiome improves. This is when we achieve a more adult-like gut microbiome.

HMOs in breastmilk as single food

Breastmilk is an amazing and complex fluid. Human milk has a huge impact of the infant’s microbiome. For millions of years, breastmilk has been the single source of food that provides nourishment and protection for the infants in their first 6 months of life. It is composed of vitamins, minerals, fat, protein and carbohydrates. The third most abundant component of human milk is HMOs (human milk oligosaccharides), which are indigestible for human infants. It takes a lot of energy for the mum to construct these large milk oligosaccharides and then these will end up as infants stool in the diaper. Then what are they for? In the research paper of Dr David Mills, it was found that the genome sequence of Bifidobacterium longum subspecies Infantis reveals adaptations for milk utilization within the infant microbiome. B. infantis has unique adaptation to consume these human milk oligosaccharides so B. infantis has 700 genes unique that are not found in its most closely related B. longum. These 700 genes contain all enzymes and pathways needed to consume HMOs are found in key B infantis strains. B. infantis and longum are very closely related but separated by about 5 million years of evolution so that B. infantis was always associated with human milk oligosaccharides. But humans have changed almost everything including our lifestyle and eating habits (milk powders, society, daily habits, geology of the planet). In particular the gut microbiome has not escaped those changes. The major factor in determining which microbe will thrive and grow in the gut is solely determined by the source of carbohydrate available. For instance, infant formula does not have the same abundance and complexity of HMOs – contains only one or two HMOs in a tiny dose – as breastmilk does.  This seems to negatively impact beneficial bacteria such as Bifidobacterium infantis.

Gut dysbiosis and consequences

The infant gut microbiome communities are distinct from adulthood, but how we get those communities is very important. The early or milk-oriented microbiome is shaped dramatically by delivery mode (vaginal or caesarean), by the food (breastmilk or formula), and by antibiotics introduced in early life. Ideal state of gut microbiome has been derailed in the last 100 years making a mark on our health. If we have a dysbiosis in gut microbiome from early life (it does not do what it needs to do), then the development in metabolism and immune programming will be derailed as well.

The consequences of gut dysbiosis manifest in lot of different ways.

• Infants with colic have specific signatures associated with dysbiosis. Microbial alteration in the first few weeks of life can increase the prevalence of colic in infants.
• Infants exposed to antibiotics can increase their risk of being overweight in their early life.
• Infants with gut dysbiosis are predisposed to necrotizing enterocolitis and miss development of immune system – this can affect the acute responses to vaccines and infections.
• Bacteria from dysbiosis harbor a lot of antibiotic resistance genes compared to non-dysbiosis host.
• A study shows that infants with gut dysbiosis during the first 100 days of life are at increased risk of developing childhood asthma.

Historical changes in gut microbiota

A study made on the intestinal flora of infants in 1913 (by W.R. Logan) showed that the gut microbiota of infants 100 years ago is very distinct from kids of today. Shortly after birth, the infant has microbiota made up of skin bacteria, and then he is breastfed, it becomes less diverse and contains more Bifidobacterium. Bifidobacterium is very typical to infants as we already know. It is still true among breastfed babies for some countries like Bangladesh, Gambia, Malawi and Kenya. However, USA and Europe have much lower average abundance of Bifidobacterium – and higher abundance of other species.

When we look at Bangladesh and other countries, we find a strong associations between healthy development in wait for age and gut microbiome. The absence of Bifidobacterium in early life is associated with poor growth and poor health outcomes.

Changes in infant fecal biochemistry

Similar to microbiome diversity in infants, there are striking changes in fecal biochemistry of babies, specifically pH. Over the last 100 years, the fecal pH of breastfed babies has increased from pH 5.0 – 6.5. We can actually link the fecal pH in the gut microbiome to the population of Bifidobacterium in the stool – a lower pH shows higher levels of Bifidobacterium (as in the history). This dramatically changes over time in response to increased rate of caesarean birth, antibiotic use, formula feeding.

Pathogens from hospital room

If we look at the hospitalized infant microbiome, things get even more ugly. These infants are commonly colonized by room microbiome such as antibiotic resistant pathogens and are at increased risk for serious infection and death.  They have much less Bifidobacterium and more of these dysbiotic taxa like Klebsiella, E.coli, Pseudomonas.

What can we do about it?

Infants as they grow they continuously acquire microbiome species from their community in the first few years of life. This is the opposite of adult’s gut microbiome, since they have a stable microbiome community due to lack of space and food for new species. Now, it makes complete sense of introducing probiotics as early as possible – new species have more space, enough food to grow and less competition. Specific probiotics can provide one more source of exposure to new beneficial microbes in infants. As I already said, not all probiotics created equally – the strains of bacteria matters immensely!

Changing the infant gut microbiome by supplementing B. infantis EVC001 (18 billion CFU/day) has been proven to be very effective. Babies were given this specific strain of Bifidobacterium infantis for 21 days, starting 7 days after birth. It resulted in an average of 10-million-fold increase in the level of B. infantis in babies’ stool. Moreover, this level has persisted for several months after stopping the probiotics.

• Delivery more changes the chance of being colonized by Bifidobacterium. Vaginally delivered infants had 40% increase in the level of Bifidobacterium, but in caesarean delivered infants 25% of increase was observed. Supplementation with EVC001 invariably increases infantis abundance relative to unsupplemented infants. Colonization during the supplementation and beyond supplementation period has been increased (even when we stopped feeding B. infantis).
• These infantis can ferment HMOs in breastmilk and produce acetate and lactate – these substances has shown to inhibit growth of enteropathogens. These acidic products could lower the pH of the stool from pH 6 to pH 5.15 – gram negative bacteria cannot thrive at low pH.
• High levels of gram-negative bacteria like coli (endotoxin or lipopolysaccharide) are symptoms of gut dysbiosis. The presence of B. infantis in adequate amount showed protective effect on baby such as lower level of fecal endotoxin load by 4-fold and lower level of gut pathogens (fewer antibiotic resistant gene). Endotoxin drives inflammation which plays role in the onset of enterocolitis and different autoimmune diseases.
• Regarding the changes to the metabolites, the pH and the composition of gut microbiome, infants that were breastfed and supplemented with infantis had normal stool, meaning halved number of stools per day, improved stool quality, reduced watery stools.

Not all probiotics are the same and their effectiveness can differ as well. It has to be the right strain with the adaption genes to consume human milk oligosaccharides (HMOs). To be effective, it needs the right food which is oligosaccharide. Minor species differences can mean major genotypic or phenotypic differences – ex. B. infantis vs B. longum.

In conclusion, the gut health of an infant is key to a healthy adult life. Gut health influences the onset of obesity, diabetes, eczema, allergies, infections. Our lifestyle has changed over the past decades, so does our microbiome. Antibiotic use, caesarean birth, formula feeding directly affect the infants gut microbiome and cause dysbiosis which will have an overall negative health impact later. In this case, supplementing B. infantis (the right strain) in breastmilk would diminish these health risks and help support the infant’s early development.

References

Nguyen, H. Holdbrooks, P. Mishra et al. February 16, 2021, Impact of Probiotic B. infantis EVC001 Feeding in Premature Infants on the Gut Microbiome, Nosocomially Acquired Antibiotic Resistance, and Enteric Inflammation. Frontiers in Pediatrics.

Jennifer T. Smilowitz and Diana Hazard Taft, June 1, 2020, The infant gut microbiome and probiotics at work.

Duar, Rebbeca M., David Kyle, and Giorgio Casaburi. “Colonization Resistance in the Infant Gut: The Role of B. infantis in Reducing pH and Preventing Pathogen Growth.” High-throughput 9.2 (2020): 7.

Rhoads, J. Marc, et al. “Infant colic represents gut inflammation and dysbiosis.” The Journal of pediatrics 203 (2018): 55-61.

Henrick BM, Hutton AA, Palumbo MC, Casaburi G, Mitchell RD, Underwood MA, Smilowitz JT, Frese SA. (2018). Elevated fecal pH indicates a profound change in the breastfed infant gut microbiome due to reduction of Bifidobacterium over the past century. mSphere 3:e00041-18.

Smilowitz, J. T., C. B. Lebrilla, D. A. Mills, J. B. German and S. L. Freeman. 2014. Breast milk oligosaccharides: Structure function relationships in the neonate. Annual Review of Nutrition 34:143-69.

Fukuda, Shinji, et al. “Bifidobacteria can protect from enteropathogenic infection through production of acetate.” Nature 469.7331 (2011): 543.

Bethany MH, Stephanie C, Giorgio C, et al. Colonization by B. infantis EVC001 modulates enteric inflammation in exclusively breastfed infants. Pediatric Research 86, pages 749–757 (2019).