Probiotic Supplements and The Breastfeeding Infant – Why Not

Here are 4 and a bit reasons to pause the probiotic prescription pad.

There certainly are a plethora of probiotic products marketed for infants – but should we give these to the exclusively-breastfed infant? Here are 4 and a bit reasons to pause and reconsider prescribing probiotics directly to the exclusively- or predominantly-breastfed infant under 6 months.

 

Reason no 1. Breastmilk has it covered.

Breastmilk is the Ultimate Gardener of the Infants Gut Ecosystem

Each mother’s breastmilk contains 100 to 600 different living bacterial species (Hunt, Foster et al. 2011, Boix-Amorós, Collado et al. 2016). This data refers to the species-level richness, if we were to take it to the strain level data, we would find we would be talking about a much bigger number. Breastmilk is a source of primary colonisers including bifidobacteria and lactobacilli species, in addition to a range of butyrate-producing bacteria (Jost, Lacroix et al. 2014, Jost, Lacroix et al. 2015, Milani, Mancabelli et al. 2015, Murphy, Curley et al. 2017).

Alongside bacteria, breastmilk is a source of many prebiotic and prebiotic-like compounds including the human milk oligosaccharides (HMOs). HMOs selectively feed specific bifidobacteria species that play an important role in infant health by supporting healthy gut mucosal immune development along with other important functions (Bode 2015, Wickramasinghe, Pacheco et al. 2015, Arboleya, Stanton et al. 2016). Each mother has a unique set of up to 50 or more HMOs (Niñonuevo, Perkins et al. 2008, Bode 2015). (Note: This may be a conservative estimate of HMO diversity as characterisation of HMOs has been constrained by analytical techniques).  Surprisingly, breastmilk has a higher concentration of HMOs than it does protein (Bode 2012). This perhaps exemplifies how evolution has prioritised providing nourishment to the infant gut microbiome. Aside from HMOs there are many other prebiotic and prebiotic-like compounds in breastmilk (Liu and Newburg 2013, Lonnerdal 2013, Pacheco, Barile et al. 2015). Human milk also supplies an array of selective bacteriostatic compounds that are active against potential pathogens and pathobionts (Lonnerdal 2013, Hassiotou and Geddes 2015).

How does microbiota of the breastfed infant cope with rough and tumbles?

The gut microbiome of the breastfed infant has recently been described as resilient in comparison to that of the formula-fed infant (Carvalho-Ramos, Duarte et al. 2018).  Studies looking specifically at antibiotic exposure have found that the breastfed infant appears to have a great degree of microbiome resilience or bounce back capacity (Savino, Roana et al. 2011, Azad, Konya et al. 2015, Carvalho-Ramos, Duarte et al. 2018). Given that breastmilk is arguably the perfect synbiotic, it’s not surprising that researchers are finding breastfed infants display microbiome resilience.

Any early antibiotic exposure is of course vastly disruptive to the infant’s ecosystem. Breastmilk is the perfect synbiotic to reduce the disturbance. Breastmilk can be considered the ultimate gardener (and restorer) of the infant gut: seeding, feeding and weeding. Hence, in my opinion, for the most part there is no need for any additional help in this area. One important thing we can do is empower mothers with this knowledge and help them to access good breastfeeding help to support them in attaining their breastfeeding goals. Often a first step to this is linking them in with good peer support organisations like La Leche League and The Australian Breastfeeding Association.

But surely a probiotic supplement will be beneficial to any infant on antibiotics? Or will it? And that’s the question I want us to look at more closely.  In this context I assert that it’s important that we consider what that infant is already receiving from breastmilk when we are weighing this up. Furthermore, we need to carefully weigh the evidence for any probiotic treatment but particularly in a young infant – and consider both the potential for harm and benefit based on the evidence on the specific strain in question (more of this below).

 

Reason No 2.  Direct probiotic supplementation may confer some risks to the young infant.

Probiotic supplements contain excipients (and occasionally contaminants) and young infants have a leaky- and immune-naïve gut.

Of course, no probiotic supplement contains only bacteria. They all contain some form of excipients (ranging from simple oil suspensions to complex multi-ingredient powders). Some contain additional sweeteners. Further, post-market surveillance studies indicate that bacteria contamination occurs reasonably commonly, and occasionally with potential pathogens (Drago, Rodighiero et al. 2010, Patro, Ramachandran et al. 2016). Bacterial contamination can also occur in the home.

Why is the infant under 6 months particularly vulnerable to ill effects?

In a nutshell the answer is that their gut is immature and leaky, and they are less able to break down proteins and neutralise pathogens.

 

More detail on this here

The young infant has greater intestinal mucosal permeability and immature intestinal barrier function. The neonate gut is especially permeable (Le Huërou-Luron, Blat et al. 2010). Breastmilk components assist with the development of the barrier both directly (Turfkruyer and Verhasselt 2015) and via the promotion of a healthy microbiome (Mikami, Kimura et al. 2012, Goldsmith, O’Sullivan et al. 2015).  The young infant also has lower gastric acid output. The neonate has a fasting gastric pH of 6-7 contrasting markedly with the adult of pH range of 1-3.5 (Kaye 2011). The infant’s gastric pH gradually decreases each month and matches that of an adult by age 20 to 30 months (Kaye 2011). Furthermore, the infant secretes less gastric and pancreatic proteolytic enzymes and the enzymes have lower activity than that of adults (Blackburn 2007). The combination of reduced proteolytic action (through higher stomach pH, lower enzyme levels and activity) and increased gastrointestinal permeability results in infants absorbing a greater amounts of intact proteins. It also means they are more vulnerable to infection from microbial contaminants should there be any in the probiotic product either at the time of purchase or from contamination in the home.

Add to this that the infant is also immune-naïve, hence more vulnerable to infection. The immature gastrointestinal mucosa is arguably also likely to be more vulnerable to irritation and potential allergic sensitization when exposed to additional ingredients present in supplements.

Exposure to substances other than breastmilk (including food, cows milks, and formula) prior to developmental readiness appears to cause inflammation (Coovadia, Rollins et al.) and in some cases micro-bleeding  (Tawai 2012) – both of which dilute the actions of breastmilk (Coovadia, Rollins et al. , Kramer and Kakuma 2012, Quigley, Carson et al. 2016).

Reason No 3. They may not provide any benefit.

Evidence for efficacy in formula-fed infants cannot be generalised to breastfed infants.

When considering evidence for efficacy we need to take into consideration the population characteristics. Exclusively breastfed, partially-breastfed and exclusively formula-fed infants all have different health risks. Many studies assessing the safety and efficacy of probiotics in infants <6 months old have been conducted in formula-fed infants. This population is different to exclusively breastfed infants in numerous ways, including having greater risk of infectious disease (Quigley, Kelly et al. 2007, Duijts, Jaddoe et al. 2010, Quigley, Carson et al. 2016), and a disrupted microbiome (Dogra, Sakwinska et al. 2015, Madan, Hoen et al. 2016). Consequently, probiotics may be more likely to have a beneficial effects in formula-fed infants. Hence these effects cannot be generalized to breastfed infants.  Additionally, strain specificity always needs to be considered – evidence relating to one strain cannot be generalized to another strain.

One specific area of probiotic research is the application of probiotics in preterm infants with the intention of reducing the risk of necrotizing enterocolitis (NEC) – a devastating disease for the preterm infant. There appears to be some promising results suggesting that some specific probiotic strains may be able to assist with preventing NEC (Olsen, Greisen et al. 2016, Uberos, Aguilera-Rodríguez et al. 2017). Once again when looking at the evidence it is important to clarify if the evidence of benefit applies to infants being fed their own mothers’ milk, donor breastmilk, and/or formula.

There are some more recent studies assessing specific probiotic strains in breastfed infants. Before we consider prescribing these, I think it’s important that we look at what outcomes were measured and consider whether these are clinically meaningful and relevant to the infants we are working with.

Reason No 4. It may detract from breastfeeding.

When we prescribe probiotics to breastfed babies, what subtle messages are we giving parents? Are we missing an opportunity to empower and educate parents about what their infants are getting from breastfeeding? Are we potentially missing an opportunity to promote breastfeeding?

This is something I ponder.

Something I strive to do is really minimise how often I recommend anything other than a breast going into a young baby’s mouth. This is for all the reasons mentioned above but also because I don’t want parent’s headspace to be taken up with another thing they have to do to their infant.

 

Treating through the mother – an alternative we would like to promote

Treating through the mother is not a new idea. Certainly, from a more general perspective assuring the mothers physical, mental, and emotional wellbeing has far-reaching flow on effects to the infant’s health.

The entero-mammary pathway hypothesis would suggest that there is a potential for a mother’s intestinal microbial community to continue to interact with their infants’ gut via breastmilk. Animal data (Young, Hine et al. 2015, de Andrés, Jiménez et al. 2018)(reviewed by (Addis, Tanca et al. 2016) and preliminary human studies support this hypothesis (Whitten and Hawrelak 2018).

Based on this premise, nourishing the mothers gut microbiome via dietary modification and prebiotic supplementation may be a tangible way of exposing the infant and potentially seeding the infant with a greater array of beneficial microbes.

Additionally, supplementing mothers with some specific probiotic strains may result in breastmilk transfer of this strain. The following strains have preliminary clinical data suggesting potential for breastmilk transfer L.fermentum CECT5716, L. salivarius CECT5713, L. gasseri CECT5714, L. reuteri DSM 17938, L. salivarius PS2 (Whitten and Hawrelak 2018) and potentially L. rhamnosus GG (based on its appearance in the stool of infants who’s mothers were supplemented, although this may be explained via intra-partum transfer during vaginal birth rather than breastmilk transfer (Dotterud, Avershina et al. 2015, Simpson, Avershina et al. 2018, Whitten and Hawrelak 2018)).  Preliminary data does suggest that potential for transfer to breastmilk is a strain specific trait (Whitten and Hawrelak 2018).

Probiotic supplementation to the mother may also influence the immune messages that are transferred through the breastmilk such as increasing breastmilk cytokine TGF-β2 (Rautava, Kalliomäki et al. 2002) and immunoglobulin sIgA (Prescott 2008). These two components may promote mucosal integrity and support reduced tendency to allergic conditions, for example (Brenmoehl, Ohde et al. 2018).

So there you have it, four and a bit things to think about before you bring out your probiotic script pad for the breastfeeding infant.

Addis, M. F., A. Tanca, S. Uzzau, G. Oikonomou, R. C. Bicalho and P. Moroni (2016). “The bovine milk microbiota: insights and perspectives from -omics studies.” Molecular BioSystems 12(8): 2359-2372.

Arboleya, S., C. Stanton, C. A. Ryan, E. Dempsey and P. R. Ross (2016). “Bosom Buddies: The Symbiotic Relationship Between Infants and Bifidobacterium longum ssp. longum and ssp. infantis. Genetic and Probiotic Features.” Annual Review of Food Science and Technology 7(1): 1-21.

Azad, M. B., T. Konya, R. R. Persaud, D. S. Guttman, R. S. Chari, C. J. Field, M. R. Sears, P. J. Mandhane, S. E. Turvey, P. Subbarao, A. B. Becker, J. A. Scott, A. L. Kozyrskyj and C. S. I. the (2015). “Impact of maternal intrapartum antibiotics, method of birth and breastfeeding on gut microbiota during the first year of life: a prospective cohort study.” BJOG: An International Journal of Obstetrics & Gynaecology: n/a-n/a.

Blackburn (2007). Maternal, Fetal, & Neonatal Physiology: A Clinical Perspective. St Louis, Saunders Elsevier.

Bode, L. (2012). “Human milk oligosaccharides: Every baby needs a sugar mama.” Glycobiology 22(9): 1147-1162.

Bode, L. (2015). “The functional biology of human milk oligosaccharides.” Early Human Development 91(11): 619-622.

Boix-Amorós, A., M. C. Collado and A. Mira (2016). “Relationship between Milk Microbiota, Bacterial Load, Macronutrients, and Human Cells during Lactation.” Frontiers in Microbiology 7: 492.

Brenmoehl, J., D. Ohde, E. Wirthgen and A. Hoeflich (2018). “Cytokines in milk and the role of TGF-beta.” Best Practice & Research Clinical Endocrinology & Metabolism 32(1): 47-56.

Carvalho-Ramos, I. I., R. T. D. Duarte, K. G. Brandt, M. B. Martinez and C. R. Taddei (2018). “Breastfeeding increases microbial community resilience.” Jornal de Pediatria 94(3): 258-267.

Coovadia, H. M., N. C. Rollins, R. M. Bland, K. Little, A. Coutsoudis, M. L. Bennish and M.-L. Newell “Mother-to-child transmission of HIV-1 infection during exclusive breastfeeding in the first 6 months of life: an intervention cohort study.” The Lancet 369(9567): 1107-1116.

de Andrés, J., E. Jiménez, I. Chico-Calero, M. Fresno, L. Fernández and J. M. Rodríguez (2018). “Physiological Translocation of Lactic Acid Bacteria during Pregnancy Contributes to the Composition of the Milk Microbiota in Mice.” Nutrients 10(1): 14.

Dogra, S., O. Sakwinska, S.-E. Soh, C. Ngom-Bru, W. M. Brück, B. Berger, H. Brüssow, N. Karnani, Y. S. Lee, F. Yap, Y.-S. Chong, K. M. Godfrey and J. D. Holbrook (2015). “Rate of establishing the gut microbiota in infancy has consequences for future health.” Gut Microbes 6(5): 321-325.

Dotterud, C. K., E. Avershina, M. Sekelja, M. R. Simpson, K. Rudi, O. Storrø, R. Johnsen and T. Øien (2015). “Does maternal perinatal probiotic supplementation alter the intestinal microbiota of mother and child?” Journal of pediatric gastroenterology and nutrition 61(2): 200-207.

Drago, L., V. Rodighiero, T. Celeste, L. Rovetto and E. De Vecchi (2010). “Microbiological Evaluation of Commercial Probiotic Products Available in the USA in 2009.” Journal of Chemotherapy 22(6): 373-377.

Duijts, L., V. W. V. Jaddoe, A. Hofman and H. A. Moll (2010). “Prolonged and Exclusive Breastfeeding Reduces the Risk of Infectious Diseases in Infancy.” Pediatrics 126(1): e18-e25.

Goldsmith, F., A. O’Sullivan, J. T. Smilowitz and S. L. Freeman (2015). “Lactation and Intestinal Microbiota: How Early Diet Shapes the Infant Gut.” Journal of Mammary Gland Biology and Neoplasia 20(3): 149-158.

Hassiotou, F. and D. T. Geddes (2015). “Immune Cell–Mediated Protection of the Mammary Gland and the Infant during Breastfeeding.” Advances in Nutrition 6(3): 267-275.

Hunt, K. M., J. A. Foster, L. J. Forney, U. M. E. Schütte, D. L. Beck, Z. Abdo, L. K. Fox, J. E. Williams, M. K. McGuire and M. A. McGuire (2011). “Characterization of the Diversity and Temporal Stability of Bacterial Communities in Human Milk.” PLoS ONE 6(6): e21313.

Jost, T., C. Lacroix, C. Braegger and C. Chassard (2015). “Impact of human milk bacteria and oligosaccharides on neonatal gut microbiota establishment and gut health.” Nutrition Reviews 73(7): 426-437.

Jost, T., C. Lacroix, C. P. Braegger, F. Rochat and C. Chassard (2014). “Vertical mother-neonate transfer of maternal gut bacteria via breastfeeding.” Environ Microbiol 16(9): 2891-2904.

Kaye, J. (2011). “Review of paediatric gastrointestinal physiology data relevant to oral drug delivery.” International Journal of Clinical Pharmacy 33(1): 20-24.

Kramer, M. S. and R. Kakuma (2012). “Optimal duration of exclusive breastfeeding.” Cochrane Database Syst Rev 8: CD003517.

Le Huërou-Luron, I., S. Blat and G. Boudry (2010). “Breast- v. formula-feeding: impacts on the digestive tract and immediate and long-term health effects.” Nutrition Research Reviews 23(01): 23-36.

Liu, B. and D. S. Newburg (2013). “Human Milk Glycoproteins Protect Infants Against Human Pathogens.” Breastfeeding Medicine 8(4): 354-362.

Lonnerdal, B. (2013). “Bioactive proteins in breast milk.” J Paediatr Child Health 49 Suppl 1: 1-7.

Madan, J. C., A. G. Hoen, S. N. Lundgren, S. F. Farzan, K. L. Cottingham, H. G. Morrison, M. L. Sogin, H. Li, J. H. Moore and M. R. Karagas (2016). “Effects of Cesarean delivery and formula supplementation on the intestinal microbiome of six-week old infants.” JAMA pediatrics 170(3): 212-219.

Mikami, K., M. Kimura and H. Takahashi (2012). “Influence of Maternal Bifidobacteria on the Development of Gut Bifidobacteria in Infants.” Pharmaceuticals 5(6): 629-642.

Milani, C., L. Mancabelli, G. A. Lugli, S. Duranti, F. Turroni, C. Ferrario, M. Mangifesta, A. Viappiani, P. Ferretti, V. Gorfer, A. Tett, N. Segata, D. van Sinderen and M. Ventura (2015). “Exploring Vertical Transmission of Bifidobacteria from Mother to Child.” Applied and Environmental Microbiology 81(20): 7078-7087.

Murphy, K., D. Curley, T. F. O’Callaghan, C.-A. O’Shea, E. M. Dempsey, P. W. O’Toole, R. P. Ross, C. A. Ryan and C. Stanton (2017). “The Composition of Human Milk and Infant Faecal Microbiota Over the First Three Months of Life: A Pilot Study.” Scientific Reports 7: 40597.

Niñonuevo, M. R., P. D. Perkins, J. Francis, L. M. Lamotte, R. G. LoCascio, S. L. Freeman, D. A. Mills, J. B. German, R. Grimm and C. B. Lebrilla (2008). “Daily Variations in Oligosaccharides of Human Milk Determined by Microfluidic Chips and Mass Spectrometry.” Journal of Agricultural and Food Chemistry 56(2): 618-626.

Olsen, R., G. Greisen, M. Schrøder and J. Brok (2016). “Prophylactic Probiotics for Preterm Infants: A Systematic Review and Meta-Analysis of Observational Studies.” Neonatology 109(2): 105-112.

Pacheco, A. R., D. Barile, M. A. Underwood and D. A. Mills (2015). “The Impact of the Milk Glycobiome on the Neonate Gut Microbiota.” Annual review of animal biosciences 3: 419-445.

Patro, J. N., P. Ramachandran, T. Barnaba, M. K. Mammel, J. L. Lewis and C. A. Elkins (2016). “Culture-Independent Metagenomic Surveillance of Commercially Available Probiotics with High-Throughput Next-Generation Sequencing.” mSphere 1(2): e00057-00016.

Prescott, S. L., Wickens, K. , Westcott, L. , Jung, W. , Currie, H. , Black, P. N., Stanley, T. V., Mitchell, E. A., Fitzharris, P. , Siebers, R. , Wu, L. , Crane, J. (2008). “Supplementation with Lactobacillus rhamnosus or Bifidobacterium lactis probiotics in pregnancy increases cord blood interferon‐γ and breast milk transforming growth factor‐β and immunoglobin A detection.” Clinical & Experimental Allergy 38(10): 1606-1614.

Quigley, M. A., C. Carson, A. Sacker and Y. Kelly (2016). “Exclusive breastfeeding duration and infant infection.” European Journal of Clinical Nutrition 70(12): 1420-1427.

Quigley, M. A., Y. J. Kelly and A. Sacker (2007). “Breastfeeding and Hospitalization for Diarrheal and Respiratory Infection in the United Kingdom Millennium Cohort Study.” Pediatrics 119(4): e837-e842.

Rautava, S., M. Kalliomäki and E. Isolauri (2002). “Probiotics during pregnancy and breast-feeding might confer immunomodulatory protection against atopic disease in the infant.” Journal of Allergy and Clinical Immunology 109(1): 119-121.

Savino, F., J. Roana, N. Mandras, V. Tarasco, E. Locatelli and V. Tullio (2011). “Faecal microbiota in breast-fed infants after antibiotic therapy.” Acta Paediatrica 100(1): 75-78.

Simpson, M. R., E. Avershina, O. Storrø, R. Johnsen, K. Rudi and T. Øien (2018). “Breastfeeding-associated microbiota in human milk following supplementation with Lactobacillus rhamnosus GG, Lactobacillus acidophilus La-5, and Bifidobacterium animalis ssp. lactis Bb-12.” Journal of Dairy Science 101(2): 889-899.

Tawai (2012). “Iron and Exlusive Breastfeeding.” Breastfeeding Review: Professional Publication Of The Nursing Mothers’ Association Of Australia 20(1): 35-47.

Turfkruyer, M. and V. Verhasselt (2015). “Breast milk and its impact on maturation of the neonatal immune system.” Curr Opin Infect Dis 28(3): 199-206.

Uberos, J., E. Aguilera-Rodríguez, A. Jerez-Calero, M. Molina-Oya, A. Molina-Carballo and E. Narbona-López (2017). “Probiotics to prevent necrotising enterocolitis and nosocomial infection in very low birth weight preterm infants.” British Journal of Nutrition 117(7): 994-1000.

Whitten, D. L. and J. A. Hawrelak (2018). “Abstracts from the 19th International Society for Research in Human Milk and Lactation Conference.” Breastfeeding Medicine 13(7): A-1-A-68.

Wickramasinghe, S., A. R. Pacheco, D. G. Lemay and D. A. Mills (2015). “Bifidobacteria grown on human milk oligosaccharides downregulate the expression of inflammation-related genes in Caco-2 cells.” BMC Microbiology 15(1): 172.

Young, W., B. C. Hine, O. A. M. Wallace, M. Callaghan and R. Bibiloni (2015). “Transfer of intestinal bacterial components to mammary secretions in the cow.” PeerJ 3: e888.