Category Archives: Probiotics

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.

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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