Wednesday, August 8, 2018

SIBO & Probiotic Brain Fog in Long-Term Users of Common Probiotic Supplements (Mechanism: D-Lactic Acidosis)

Feeling like your brain veiled in clouds? Could be the D-lactate from the gut bugs overpopulating your small intestine... and you know what: your fancy probiotic may have triggered it or made it worse.
If you remember my article about SIBO, i.e. Small Intestinal Bacterial Overgrowth from March 2017, you will remember that I listed probiotics as "anti-SIBO" tools. Back in the day when I wrote the article that was also the state of the art... pardon, research, which showed a significantly lower SIBO risk in people who consume a probiotic.

Now, with the publication of the latest study from the Digestive Health Clinical Research Center at the Medical College of Georgia at Augusta University (Rao 2018) I will probably have to revise this article, as using a probiotic to prevent or even treat SIBO could very well backfire and make the classic symptoms like brain fog and bloating worse, not better.
Learn more about probiotics and the microbiome a the SuppVersity

Microbiome re-search update '16

BCAAs mess w/ 'ur microbiome

Glutamine your gut + fat loss

'No Sugar' foods mess up 'ur gut

Spore-forming = better probiotics

Sweeteners vs. microbiome?
So what is it that the scientists found that appears to change "everything"? Well, it's as surprising as it is logical. The use of certain probiotics "can result in a significant accumulation of bacteria in the small intestine that can result in disorienting brain fogginess as well as rapid, significant belly bloating" - that's at least how the author of the press release at the Medical College of Georgia at Augusta University put it - and that's not a result from a rodent study.

Brain fog? What is that, anyway? Symptoms are: Mental confusion, cloudiness, impaired judgment, poor short-term memory, and difficulty with concentration.

In order "to determine if BF, gas and bloating are associated with D-lactic acidosis and small intestinal bacterial overgrowth (SIBO)", Rao and his team analyzed data from 30 consecutive adult patients who were referred to their tertiary care center over 3 years. What all of the patients had in common was that they complained about brain fog... i.e. symptoms that included mental confusion, cloudiness, impaired judgment, poor short-term memory, and difficulty with concentration.
Figure 1: Consort flow diagram describing enrollment and disposition of metabolic and breath test results (Rao 2018).
To reduce the likeliness of confounding health conditions, Rao et al. excluded all patients, with abnormal results on an upper endoscopy, duodenal biopsy, colonoscopy or biopsy, as well as abdominal CT imaging. In addition, all had to have normal hematological and biochemical profiles and no a history of small bowel or colonic surgery, intestinal dysmotility (scleroderma or pseudo-obstruction), a history of recent antibiotic use (in the previous 6 weeks), or a history of known neurological or neuropsychiatric problems or celiac disease, Helicobacter Pylori infection, or renal or liver failure. In other words: The patients were brain foggy, but otherwise relatively healthy.
Table 1: Family and Genera of Lactic acid bacteria (LAB) and the type of lactic acid they produce (L-, D- or DL-lactic acid | Vitetta 2017)
The effects are obviously strain- dependent, but... If you've been pondering the question if not simply selecting the "right" probiotics could avoid the problem altogether, you're right - well, sort of. While it is correct that there seem to be certain strains that don't produce D(-)-lactic acid (Carr 2002), it is not clear if D(-)-lactic acid producing bacteria, alone, would be enough to ward off D-lactic acid acidosis, which has by the way also been associated with chronic fatigue syndrome (Sheedy 2009). As Vietta et al. point out in their 2017 paper, the recommendation to use L(+)-lactic acid producing bacteria to displace their D(-)-lactic acid producing cousins, which is propagated by the probiotic producers,  is based on nothing but "unsubstantiated claims" (Vietta 2017).

Eventually, it is even possible that supplementing with commonly used bacteria that produce predominantly L(+)-lactic acid like Bifidobacterium spp. and/or Lactobacillus acidophilus (Gomes 1999) could trigger shifts in the microbial composition of the intestine that will eventually promote not ameliorate an excess production of D(-)-lactic acid and thus brain fog. That it can work has been demonstrated only in case studies, such as Uchida et al. (2004), which reports on a patient with short-bowel syndrome who suffered from D(-)-lactic acidosis was successfully treated with antibiotics and his gut was subsequently recolonized with Bifidobacterium breve, and Lactobacillus casei.
The subjects' symptoms were assessed by the means of a standardized questionnaire for IBS that has been validated by Choi et al. in 2008 and has the patient rate nine classic symptoms, i.e. abdominal pain, belching, bloating, fullness, indigestion, nausea, diarrhea, vomiting and gas, on a scale from 0-3. Next to this rather subjective data, the scientists conducted duodenal aspirate and cultures and glucose breath test on each of the patients. Further testing included an assessment of blood glucose, insulin, ammonia and L-lactate levels and urinary D-lactic acid levels after a carbohydrate challenge, as well as the assessment of gastrointestinal transit + time.
I won't summarize all the demographic features of the subjects. If you're interested you can check them out here in the original article. What I do want to point out, though, are the details the authors provide with respect to the brain fog, about which Rao et al. write:
"Neurocognitive symptoms including BF or mental confusion or impaired judgment, poor short-term memory, and difficulty with concentration were described by all of the patients in the BF group. These symptoms lasted between 30 min to several hours, often post-prandial, and intermittently during the course of the day. Also 28/30 (94%) patients reported post-prandial fatigue and weakness, and 2/30 reported persistent daily fatigue unrelated to meal intake. BF was so severe that 4/30 (13.3%) had quit their jobs" (my emphasis in Rao 2018).
I've already given away the most interesting observation the scientists made: All patients who complained about brain fog 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. And, as it may be of relevance for the interpretation of the results it should be mentioned, that 45.4% of the patients were consuming yogurt daily, 23.3% used opiates to handle the symptoms and 43.3% used PPIs and multivitamins.
Proton pump inhibitors do not cause SIBO, but they sign. increase your risk of developing it: Even though Ratuapli et al. write in their 2012 study that "[i]n [their] large, adequately powered equivalence study, PPI use was not found to be significantly associated with the presence of SIBO as determined by the GHBT", studies using more accurate measures of SIBO than the glucose hydrogen breath test (e.g. duodenal or jejunal aspirate culture) suggest that it clearly predisposes to the development of SIBO - with PPI users being 7-8-fold more likely to develop SIBO than non-users (Lo 2013) - to which extent this may be thwarted by primary diseases, the type of PPI (older studies show much higher SIBO rates) and the administration frequency is unfortunately not addressed in either Lo's meta-analysis or the individual studies.
What all patients with brain fog had in common, though was that they were tested positive for lactic acidosis and/or SIBO. To help them, the researchers treated the patients with various antibiotics (amoxicillin, amoxicillin-clavulanic acid, cotrimoxazole, rifaximin, metronidazole, tinidazole, and ciprofloxacin) based on the individual allergy profile and culture/sensitivity results, and most importantly had them discontinue their probiotics - with quite impressive results in a questionnaire that had the subjects rate their global improvement using a 0–10 visual analog scale:
Figure 2: Improvement in gastrointestinal symptoms after treatment as assessed by Global VAS Score in patients with brain fog (Rao 2018).
"After treatment, 70% of patients reported significant improvement in their symptoms with a significant change in the mean global VAS score (P = 0.005), (Fig. 2). 85% of patients reported complete resolution of BF. There were also significant (p < 0.05) improvements in the individual mean symptom scores [...] for abdominal pain (6.17 vs. 4.17), cramping (3.17 vs. 2.17), bloating (6.5 vs. 4.08), fullness (5.58 vs. 3.5), and distention (5.75 vs. 3.75); but not for other symptoms.

Likewise, in the non-BF group, all 4 patients with SIBO/D-lactic acidosis received antibiotics and reported significant improvement in symptoms at 3-month follow-up; abdominal pain (7.2 vs 2.2), cramping (4.1 vs 2), bloating (7.8 vs 3.1), fullness (4.9 vs 2.4), and distension (6.1 vs 3.2). There was no difference in symptom(s) improvement between the two groups. (p > 0.2). Mean global satisfaction (VAS) score also improved (2.0 ± 1.3 vs. 7.4 ± 2.1, p < 0.05)" (my emphasis in Rao 2018).
The observation that a heavy course of antibiotics and discontinuing the probiotics did the trick in 85% of the patients takes us back to the initially mentioned realization that probiotics can - despite evidence of their SIBO-protective effects - actually cause or at least promote bacterial overgrowth of in the small intestine. That's big news as it implies:

You better think twice before you start supplementing with large numbers of probiotics!

In all fairness, it should be pointed out that the putative mechanism, i.e. "the production of toxic metabolites such as D-lactic acid in the small intestine from bacterial fermentation of carbohydrate substrates" (Rao 2018), occurred as a consequence of "the use of prolonged or excessive probiotics and/or cultured yogurt" and probably only contributed to a pre-existing small intestinal colonization by lactobacilli and other bacteria.

While it appears to be clear that the symptoms were caused by high levels of brain-toxic D-lactic acid being produced by the lactobacillus bacteria, it is not clear how to decide whether patients will see benefits or severe detrimental effects as they were observed for the first time in the study at hand. Accordingly, Rao advises that the excessive and indiscriminate use of probiotics must be avoided. In the corresponding press release, the lead author of the study is even quoted for having said that "Probiotics should be treated as a drug, not as a food supplement" (press release).
Table 2: A selection of reports regarding the administration of specific probiotic strains for specific health indications (Vitta 2017)
So should you stop supplementing probiotics and what about fermented foods? You will remember that I have previously highlighted our lack of understanding when it comes to the complex influence the administration of - at the moment - more or less randomly selected bacteria would have on our microbiome. For the time being, the study at hand is thus not the only reason to stay away from probiotics as a staple supplement, meaning you can still use them temporarily to recolonize your colon after a hefty course of antibiotics.

Don't freak out, though: Food sources of probiotics including yogurt, sauerkraut, kimchi, kefir and even dark chocolate don't pose a problem as they simply contain too small amounts of bacteria to disturb the natural balance of gut bugs in a way that's going to give you brain fog and digestive problems. With respect to high dose probiotics, however, it may be wise to wait for scientists to explore what predisposes certain individuals to develop SIBO with D(-)-lactic acid producing bacteria and/or those bacteria who can produce both L(+)- and D(-)-lactic acid to suddenly spill out tons of the neurotoxic D(-)-form of lactic acid - in view of the fact that numerous clinical studies have reported therapeutic efficacy with the use of D(−), L(+) and DL-Lactic acid producing bacteria without producing D-Lactic acidosis" (see Table 2 | Vietta 2017), it is, after all, very unlikely that D-lactate producing bacteria are innately evil | Comment!
References:
  • Carr, Frank J., Don Chill, and Nino Maida. "The lactic acid bacteria: a literature survey." Critical reviews in microbiology 28.4 (2002): 281-370.
  • Choi, Young K., et al. "Fructose intolerance in IBS and utility of fructose-restricted diet." Journal of clinical gastroenterology 42.3 (2008): 233-238.
  • Lo, Wai–Kit, and Walter W. Chan. "Proton pump inhibitor use and the risk of small intestinal bacterial overgrowth: a meta-analysis." Clinical Gastroenterology and Hepatology 11.5 (2013): 483-490.
  • Rao, et al. "Brain fogginess, gas and bloating: a link between SIBO, probiotics and metabolic acidosis." Clinical and Translational Gastroenterologyvolume 9.162 (2018).
  • Uchida, Hiroo, et al. "D-lactic acidosis in short-bowel syndrome managed with antibiotics and probiotics." Journal of pediatric surgery 39.4 (2004): 634-636.
  • Vitetta, Luis, et al. "Probiotics, D–Lactic acidosis, oxidative stress and strain specificity." Gut microbes 8.4 (2017): 311-322.