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.
