Probiotic Supplements and The Breastfeeding Infant  – Why Not

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

By Dawn Whitten BNat(Hons) IBCLC Researcher, Clinician and Lactation Consultant

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.

Codonopsis: A Novel Herbal Approach to Hydrogen Sulphide Gas-Producing Bacteria

When preparing for my recent lecture at the 11th Herbal & Naturopathic International Conference – Using Herbal Medicines to Modify the Microbiota – I came across an interesting study that looked at the impact of dang shen (Codonopsis pilosula) on the gut microbiota – and specifically gastrointestinal concentrations of Desulfovibrio spp. – a key gastrointestinal hydrogen-sulphide gas-producer.

Most species of bacteria in the colon produce hydrogen gas as a byproduct of fermentation. Some of this microbially-produced hydrogen stays as hydrogen, but some is consumed by other bacteria or archaea. These hydrogen consumers are termed hydrogenotrophs. Hydrogen is shunted down one of three pathways, into methane (by methanogens), acetate (by acetogens), and hydrogen sulphide (via sulphate-reducing bacteria).

This hydrogen pathway is important because excess production of hydrogen sulphide gas has been linked to colonic inflammation, increased gut permeability, visceral hypersensitivity (one of the main drivers of IBS), inflammatory bowel disease (IBD), and colorectal cancer. Sulphate-reducing bacteria (SRB) are also postulated to play a causative role in some cases of small intestinal bacterial overgrowth (SIBO) – commonly referred to as hydrogen-sulphide SIBO.

Agents capable of reducing populations of these bacteria are sorely needed, and to date there has been little research done into agents proficient at decreasing SRB populations. So, I was super excited to come across this study that looked at the impact of dang shen on one of the main hydrogen-sulphide gas producers in the human gastrointestinal tract – the Proteobacteria Desulfovibrio spp..

Dang shen is commonly referred to as “poor man’s ginseng”, as it is used for similar purposes as Korean ginseng, but is far less costly and easy to come by. This study utilised a mouse model of IBD to investigate the impact of Codonopsis on the microbiota (Jing et al., 2018). The polysaccharide components were isolated from dang shen roots and administered to the mice. The dose used was equivalent to the high end of the traditionally recommended dose for this herb – 30g/day. Clear prebiotic-like effects were observed, such as increases in concentrations of beneficial members of the gastrointestinal ecosystem, such as Bifidobacterium spp., Akkermansia spp., and Lactobacillus spp.. Conversely, populations of pathobionts like Alistipes spp., and Desulfovibrio spp. were inhibited.

As pointed out, it was the polysaccharides of Codonopsis that demonstrated this capacity to reduce populations of SRB, whilst concurrently increasing beneficial bacteria populations. Thus, we need to use extraction techniques that are capable of extracting the water-soluble dang shen polysaccharides. Customarily in Traditional Chinese Medicine (TCM), Codonopsis is extracted via decoction. This preparation technique would undoubtedly work well to extract out the polysaccharides. Other suitable options would include just chewing up and consuming the root chunks (luckily they taste quite pleasant), adding the root to soups and stews, or grinding the chunks into a powder and using this in smoothies etc…

I have only just started using Codonopsis for this application in clinic, so I haven’t yet had the opportunity to systematically observe the impact on GIT concentrations of SRB. But I wanted to get this research out there so that others could start trialling this herb – as tools to address an overgrowth of hydrogen sulphide-producing bacteria are few and far between.

I am very curious to get others feedback on the prescription of Codonopsis as an anti-Desulfovibrio agent. Feel free to post your experiences below.

Note: For a limited time, Probiotic Advisor is offering FREE access to Dr Hawrelak’s 1-hour webinar on Using Herbal Medicines to Modify the Microbiota – enrol today!

Jason Hawrelak
ND, BNat (Hons), PhD, FNHAA, MASN, FACN
Chief Research Officer
Probiotic Advisor

References
Jing, Y., Li, A., Liu, Z., Yang, P., Wei, J., Chen, X., … Zhang, C. (2018). Absorption of Codonopsis pilosula Saponins by Coexisting Polysaccharides Alleviates Gut Microbial Dysbiosis with Dextran Sulfate Sodium-Induced Colitis in Model Mice. BioMed Research International, 2018, 1–18. https://doi.org/10.1155/2018/1781036

Probiotics Cause SIBO and Brain Fog – Really?!

I’ve been meaning to critique this study for some months. With the bulk of my teaching done for the year (and my grading), I’ve finally found some time to have a good look at this study linking probiotic use and brain fog:

Rao SSC, Rehman A, Yu S, et al. Brain Fogginess, Gas and Bloating: A Link Between SIBO, Probiotics and Metabolic Acidosis. Clinical and Translational Gastroenterology 9, 162 (2018). DOI: 10.1038/s41424-018-0030-7

Published just a few months ago, the conclusions of the study, that brain fog is caused by probiotics and that probiotics can cause small intestinal bacterial overgrowth (SIBO), have been widely disseminated throughout the blogosphere. But, in my opinion, a number of significant issues with this study have rarely been highlighted.

Firstly, let’s take a look at what the test subjects in the study were taking:

“All patients in the BF (brain fog) group were taking probiotics (range 3 months to 3 years), some were taking 2–3 different varieties containing lactobacillus species, and/or bifidobacterium species or streptococcus thermophillus and others. Additionally 11 (36.7%) were using cultured yogurt daily, and 2 (6.7%) large amounts (20 oz.) of homemade cultured yogurt daily. Opioid use was found in 7/30 (23.3%), and PPI use and multivitamins in 13/30 (43.3%). Fish Oil and Biotin supplementation in 4/30 patients and 1/30 (3.3%) were taking ubiquinone, dessicated thyroid, simethicone, melatonin, curcumin, saw palmetto, samento extract, and artemisinin extract. One patient (12%) in the non-BF group took probiotics (Lactobacillus rhamnosus), 3/8 (37%) were using PPI, 3/8 (37%) multivitamin and fish oil supplements, and one opioids.”

The description of the probiotic products was immensely vague. What was being taken by these patients was not clear. It appears, however, that most of the consumed products purported to contain lactobacilli, bifidobacteria, and Streptococcus thermophilus. Yoghurt, by definition, contains strains of both S. thermophilus and Lactobacillus delbrueckii ssp bulgaricus.

What’s never discussed in the article is the idea that subjects in the BF group may have been self-medicating with probiotics and yoghurt as a way of treating their gut symptoms and even brain fog – essentially that these symptoms pre-dated probiotic use and therefore couldn’t be causative.

It is also worth noting that the BF group had a high incidence of opioid (23%) and proton pump inhibitor use (43%). Both of which are well-known risk factors for SIBO development. The non-BF control group is also very small – only 8 people – and had about half the rate of opioid use. Opiates are well-known for their ability to impact cognitive functioning.

Secondly, let’s now look at the results from duodenal aspirate and culture:

“In the BF group, cultures for SIBO were positive in 14 (46.7%) patients and negative in 14 patients (46.7%) (Fig. 2); 2 patients did not have duodenal aspiration. Aerobic strains were grown in 22 (64.7%), and anaerobic bacteria in 9 (26.5%) patients. The predominant aerobic organisms were Streptococcus species, Staphylococcus species, Neisseria species, and Hemophilus species, and the predominant anaerobic organisms were gram negative rods, and cocci, gram positive rods – lactobacillus species, and prevotella species. The disposition of D and/or L-lactic acidosis is summarized in Fig. 2. In the non-BF group, 2/8 (25%) had positive culture for SIBO and one subject grew streptococcus species, and neisseria, and second subject grew rothia species and pseudomonas, and 1/8 (14%) grew candida species.”

What this tells us is that less than half the subjects with brain fog were positive for SIBO on aspirate and culture (debatably the gold-standard for SIBO diagnosis). And importantly, what researchers didn’t find in the small bowel of these SIBO positive patients with brain fog were lactobacilli or bifidobacteria – the two main genera of probiotic bacteria. The ones these patients were apparently taking!

If bacteria from probiotic supplements colonised and were the cause of the overgrowth, then it follows that they would be found in the small intestine. But we can clearly see that this was not the case! Not even a single patient was found to have bifidobacteria growing in their small intestine and only 3 patients were reported to have “Lactobacilli and/or Prevotella” species present. The latter phrasing, taken from the article itself, suggests that perhaps only one or two patients actually had lactobacilli found in their small intestine!

These microbiology results clearly do not support the idea that probiotics were the cause of their SIBO and brain fog.

The most common organisms found in the small intestine were the aerobic species Streptococcus, Staphylococcus, Neisseria, and Haemophilus. All of these species are common members of the oral microbiota, as are Prevotella spp. I think this is important as we’ll highlight below.

Some sections from the article are worth highlighting and discussing in more depth:

“Here, the BF was likely induced by the production of toxic metabolites such as D-lactic acid in the small intestine from bacterial fermentation of carbohydrate substrates. The use of prolonged or excessive probiotics and/or cultured yogurt further contributed to the small intestinal colonization by lactobacilli and other bacteria.”

There was no evidence of colonisation in their study – lactobacilli were very rare in the small bowel of patients with BF and bifidobacteria non-existent in their culture samples.

Streptococcus species were common in the small intestine of these patients, however. So, one could make an argument that these streptococci came from the yoghurt consumed by many of these patients. Given that the authors did not detail the exact species found in the aspirates, it is not possible to know if this was the case or not. It is worth noting here though, that Streptococcus thermophilus (the sole Streptococcus spp. found in yoghurt) is a known L-lactate producer, incapable of producing D-lactate. So, this further refutes their arguments linking ingestion of yoghurt and probiotic supplements with D-lactic acidosis.

“Lactobacillus species and bifidobacterium are the most common bacteria in probiotic formulations, and are felt to be useful in the treatment of irritable bowel syndrome, inflammatory bowel disease, and other intestinal problems. Both bacteria produce D-lactic acid.”

Bifidobacteria do not produce D-lactate and only some lactobacilli do. The article itself did not even specify the species of lactobacilli that were found in the small bowel of those 1 or 2 BF subjects to determine whether they were even theoretically capable of producing D-lactate. Nor did the authors check if the lactobacilli species found on aspirate matched those found in their supplement or yoghurt. These may well have been indigenous lactobacilli that were found in these few people, not exogenously provided by probiotics or yoghurt!

“Additionally, opioids and PPI use may have predisposed patients to SIBO as 78% of PPI users had D-lactic acidosis.”

For me, this should have been the major highlight of the paper! Read that last bit again – 78% of PPI users had D-lactic acidosis. Reflect on this in the context of how frequently PPIs are used in Western nations and its possible significance is staggering.

So, what is the probable mechanism behind this observed link between D-lactic acidosis and PPI use? On average, we swallow 1 litre of saliva daily with each mL of saliva containing ~108 CFU/mL of bacteria. Hence, in a given 24-hour period, we swallow about 100 billion salivary microbes. This equates to a far greater amount of bacteria than we’ll get in many probiotic supplements and substantially more than a bowl of yoghurt. The oral microbiota is often dominated by species of streptococci. The PPI-induced hypochlorhydria means that these swallowed oral microbes have the opportunity to reach the small intestine in large numbers – where they could potentially colonise or just be continually replaced (as a constant supply of oral microbes makes its way down the GIT). This mechanism of D-lactic acidosis fits the data observed in this study far better than the idea of probiotic/yoghurt use as the cause of the observed D-lactic acidosis. The majority of SIBO positive subjects with BF were colonised by oral cavity bacteria, like Streptococcus spp., and very few had species found in probiotic supplements. And we know the species of Streptococcus found in yoghurt (S. thermophilus) is incapable of producing D-lactate, unlike many Streptococcus species found in the oral cavity.

Finally, this was an observational study only – this study could never prove causation. If a possible link between probiotic usage and SIBO and brain fog wanted to be properly explored, then the study needed some major changes in design. Some basic questioning around symptom onset vs length of probiotic use would have been helpful. It would also have been a good idea to check if the contents of the probiotics matched what was on the label and what was found in the small intestine. The treatment intervention should not have been antibiotics and probiotic withdrawal, but solely the withdrawal of the probiotic product to see how it impacted both gut and BF symptoms; followed by a blinded probiotic re-introduction to assess for symptom return.

In the end, we’re left with a study that doesn’t actually show what it purports – that probiotics cause SIBO or brain fog. But it does throw up some interesting hypotheses that need further study – especially around the area of PPI use, oral streptococci colonisation of the small bowel, and D-lactic acidosis.

Jason Hawrelak
ND, BNat (Hons), PhD, FNHAA, MASN, FACN
Chief Research Officer
Probiotic Advisor

Probiotics Prevent SIBO in Proton Pump Inhibitor Users

Proton pump inhibitor (PPI) medications are one of most frequently utilised classes of medicines. Primarily used to treat gastro-oesophageal reflux disease (GORD), gastritis and peptic ulcer disease, use of these medications has risen sharply over the past two decades. In fact, utilisation has increased by over 1300% over this time! Commonly used PPIs include omeprazole (Losec), lansoprazole (Zoton), esomeprazole (Nexium), pantoprazole (Somac) and rabeprazole (Pariet). Nexium alone accounts for over 19 million prescriptions in the US annually. In Australia, during 2013-14 there were over 19 million prescriptions written for PPIs – quite impressive for a nation of only 24 million people!

The capacity of PPIs to increase risk of Small Intestinal Bacterial Overgrowth (SIBO) had been debated (at least in some circles) until a meta-analysis published in 2013 showed conclusively that PPI use increased the odds of developing SIBO. Pooled data showed over a 7.5-fold increased risk of SIBO development in PPI users.

Given the substantial SIBO-risk associated with their use and the massive frequency of utilisation, it is not surprising that SIBO diagnosis and awareness has increased dramatically over the past decade. This is even more worrying in light of data suggesting that up to 70% of patients taking PPIs are doing so inappropriately!

So, is there anyway to decrease the risk of SIBO development in those patients taking PPIs? It turns out that the right probiotic preparation is indeed capable of reducing the risk of SIBO development.

In a very recent randomised, controlled trial, 128 patients with GORD were allocated to receive either a probiotic supplement or placebo alongside their PPI over a 12-week period. The probiotic group received the strain Lactobacillus reuteri DSM 17938 at a dose of 5 drops per day of an oil preparation (containing a total of 1 x 10^8 CFU/day). SIBO assessment was done (via the Glucose Breath Test) at baseline and again after 12 weeks PPI treatment (esomeprazole). No patients tested positive for SIBO at baseline. Amazingly, SIBO developed in over 56% of patients taking the PPI in the placebo group in just 12 weeks! On the other hand, SIBO only developed in 6% of subjects in the PPI + probiotic group (group difference P<0.001). Additionally, significantly more children in the placebo group developed new gastrointestinal symptoms compared to those in the probiotic group (P=0.026).

This study clearly showed that the co-ingestion of this specific probiotic strain was capable of preventing SIBO from developing in patients taking PPIs. Is this something we could expect from just any probiotic preparation? The research suggests not, with a previous study finding an alternative probiotic preparation comprised of two probiotic strains (Lactobacillus rhamnosus R0011 & L. acidophilus R0052) prescribed at a higher dose (2.0 x 10^9 CFU/day combined) was unable to prevent SIBO development in PPI users. So, at this point, we’d have to conclude that this is an action potentially unique to the L. reuteri DSM 17938 strain.

So, how does this strain work to prevent SIBO from developing? It may have to do with the ability of this strain to produce an anti-microbial compound called reuterin. Reuterin has demonstrated broad action against a range of microorganisms that are commonly found to be overgrown in patients with SIBO – Escherichia, Proteus, Pseudomonas, Staphylococcus, Streptococcus, Enterococcus and Bacteroides spp..

I’ve always argued that probiotics can play pivotal roles in the treatment of SIBO and now we have excellent evidence showing that the right probiotic can prevent its development too.

Jason Hawrelak
ND, BNat (Hons), PhD, FNHAA, MASN, FACN
Chief Research Officer
Probiotic Advisor

Selected references:
Axelsson LT, Chung TC, Dobrogosz WJ, et al. (1989). Production of a broad spectrum antimicrobial substance by Lactobacillus reuteri. Microbial Ecology in Health and Disease 2(2):131-136.

Belei O, Olariu L, Dobrescu A, et al. (2018). Is it useful to administer probiotics together with proton pump inhibitors in children with gastroesophageal reflux? J Neurogastroenterol Motil 24(1):51-57. PMID: 29291607

Forgacs, I., & Loganayagam, A. (2008). Overprescribing proton pump inhibitors. BMJ, 336(7634), 2-3. doi: 10.1136/bmj.39406.449456.BE
Hollingsworth S, Duncan EL, Martin JH. (2010). Marked increase in proton pump inhibitors use in Australia. Pharmacoepidemoil Drug Saf 19(10):1019-1024.

Lo, W. K. and W. W. Chan (2013). “Proton Pump Inhibitor Use and the Risk of Small Intestinal Bacterial Overgrowth: A Meta-analysis.” Clinical Gastroenterology and Hepatology 11(5): 483-490.

Just what is a “leaky vagina”? And why we should care about it…

I’ve just returned from the MINDD Conference in Sydney where I was invited to present lectures to both health professionals, and the general public, on the functions and importance of the vaginal microbiota.

One of the concepts I brought up at the conference was the idea of a “leaky” vagina. Many of us are very aware of the consequences of a leaky gut or leaky blood-brain barrier. But few of us have considered the concept of a leaky vagina – or what impact this may have on a woman’s health.

What are the known risks? Well increased risk of genital herpes infection, as well as human papilloma virus (HPV) infection and its sequelae cervical cancer, for two. Given this, I wonder why optimisation of the vaginal ecosystem is not a core component of a women’s preventative healthcare strategy.

The vaginal microbiota is the “poor cousin” of the GIT microbiota – it has only just begun to get the research interest it deserves. Research conducted over the last 5 years has clearly shown that an optimal vaginal ecosystem (i.e., an ecosystem dominated by D-lactate-producing lactobacilli species) is associated with enhanced fertility, better birth outcomes, and reduced risk of sexually transmitted diseases and recurrent urinary tract infections, as well as reduced HPV infection rates (a necessary precursor to cervical cancer).

So how many women have an optimal vaginal microbiota? Sadly, research suggests not that many – with some research finding only about 40% of women having ecosystems dominated by D-lactic acid-producing species (Lactobacillus crispatus, L. gasseri, and L. jensenii).

One final consideration is that we are only now finding out some of the ramifications of having a “leaky” vaginal wall. Other consequences will surely be teased out in the upcoming years. We know a dysbiotic vaginal microbiota containing large numbers of Gram-negative bacteria and a deficiency of lactic acid-producing lactobacilli leads to a leaky vagina. This is due to the vital role of lactic acid, specifically D-lactic acid, in the growth and repair of vaginal epithelial cells.

Undoubtedly, the combination of dysbiosis and increased permeability to bacterial by-products like endotoxins (from Gram-negative bacteria) will add to a woman’s inflammatory load. This may directly impact reproductory organs and contribute to diseases like endometriosis (see the paper on the bacterial contamination hypothesis below), but also have systemic sequalae. With inflammation now seen to be a key driver of most, if not all, chronic Western diseases, it is about time to highlight this issue.  We know that GIT dysbiosis can contribute to systemic inflammatory load, but we now need to consider that vaginal dysbiosis can do likewise in women.

We, as clinicians, need to start assessing the health of this ecosystem in all of our female patients. A simple pH test strip (with accurate gradations between pH 3.5-5.5) is all that is needed for an initial screen for vaginal dysbiosis – with a pH >4.5 a clear indication of a dysbiotic ecosystem in pre-menopausal women.

To learn more about this vital, yet under-appreciated ecosystem, as well as learn techniques to optimise the vagina microbiome, have a look at our new course covering these topics (and more!).

Jason Hawrelak
ND, BNat (Hons), PhD, FNHAA, MASN, FACN
Chief Research Officer
Probiotic Advisor

Select References:

Borgdorff H, Tsivtsivadze E, Verhelst R, Marzorati M, Jurriaans S, Ndayisaba GF, et al. Lactobacillus-dominated cervicovaginal microbiota associated with reduced HIV/STI prevalence and genital HIV viral load in African women. ISME J. 2014;8(9):1781-93

Hyman, R. W., Herndon, C. N., Jiang, H., Palm, C., Fukushima, M., Bernstein, D., . . . Giudice, L. C.. The dynamics of the vaginal microbiome during infertility therapy with in vitro fertilization-embryo transfer. J Assist Reprod Genet. 2012; 29(2), 105-115.

Khan KN, Fujishita A, Hiraki K, et al. Bacterial contamination hypothesis: a new concept in endometriosis. Reprod Med Biol 2018;17(2):125-33. doi: 10.1002/rmb2.12083

Kirjavainen, P. V., Pautler, S., Baroja, M. L., Anukam, K., Crowley, K., Carter, K. & Reid, G. 2009. Abnormal Immunological Profile and Vaginal Microbiota in Women Prone to Urinary Tract Infections. Clin. Vaccine Immunol. 2009; 16, 29-36.

Mitra A, MacIntyre DA, Marchesi JR, Lee YS, Bennett PR, Kyrgiou M. The vaginal microbiota, human papillomavirus infection and cervical intraepithelial neoplasia: what do we know and where are we going next? Microbiome. 2016;4(1):58

Petrova MI, Lievens E, Malik S, Imholz N, Lebeer S. Lactobacillus species as biomarkers and agents that can promote various aspects of vaginal health. Front Physiol. 2015;6:81.

Younes, J. A., Lievens, E., Hummelen, R., van der Westen, R., Reid, G., & Petrova, M. I. Women and Their Microbes: The Unexpected Friendship. Trends in Microbiology. 2017;26(1), 16-32.