Probiotics can Cause D-Lactic Acidosis and Brain Fogginess: Reply to Quigley et al.

We thank the authors for their interest in our article. As they would appreciate, the realm of probiotics in health and disease is important to understand mechanistically and from a precision medicine perspective. Clearly, some people benefit from probiotics, others are unaffected, while still others have unexpected deleterious effects. Our research focused on a group of patients with unexplained brain fogginess, gas and bloating, and to determine the underlying mechanism(s). We have identified probiotics as one plausible factor in the pathogenesis of their problem among others. The report has received both praise and criticism from manufacturers of probiotics, as well as from Dr Quigley and colleagues, who have significant personal and scientific interests in probiotics. We are happy to respond to these criticisms, especially when approached from the perspective of average effects in average populations, and clarify what was clearly demonstrated in the subset of patients who experienced “brain fogginess”.

1. “Probiotics are safe”: Studies on probiotics have inadequate record of safety assessment, as concluded by the Agency for Healthcare Research and Quality[1], or carry risks[2,3]. Hence, more safety studies are needed. 2. “Probiotics and SIBO are not equally culpable”: We found evidence for SIBO in 68% with either duodenal aspirate or breath test in a group of patients with brain fogginess (BF) and significant gas/bloating, all of whom took probiotics, compared to 28% in a control group without BF. Duodenal aspirates grew lactobacilli incriminating probiotics, among other bacteria. Because distal small bowel was not evaluated, where colonization is more likely, we may have detected fewer subjects. Thus, probiotics cause SIBO, but not all SIBO is from probiotics. 3. “Bifidobacteria don’t produce d-lactate”: They quote a 1968 paper as evidence[4], in which the authors did not measure d-lactate, because “Bifidobacterium did not produce CO2”, and substantiate this with an unpublished observation[4]. In contrast, Bifidobacterium longum subsp. infantis does produce d- and l-lactate, but in lower amounts compared to Lactobacillus rhamnosus[5]. Thus, Bifidobacteria produce d-lactate, albeit less than Lactobacillus[6]. 4. “d-lactic acidosis can be treated by probiotics”: The authors describe a recent case report, but there are other case reports where d-lactic acidosis was treated with antibiotics and probiotics but these authors were unsure which treatment conferred benefit[7,8]. In another report, d-lactic acidosis was provoked twice by probiotics[9]. Hence, probiotics should be avoided in d-lactic acidosis. 5. “Rao and colleagues equate all probiotics which is misleading”: We found that 15/30 patients took OTC generic probiotics (Walmart, Walgreens, CVS etc) and 15 took named brands (Culturelle®, Jarodophilus®, VSL#3®, Align®, Nature’s®, Colonsense®, Ultimate Care®). Our study was not designed to address which probiotic or its contents either caused SIBO or was safer, but to identify why our patients developed debilitating gastrointestinal symptoms and BF. 6. “Is it d-Lactic acidemia or acidosis?”: d-Lactic acidosis describes elevated d-lactic acid levels with neurocognitive symptoms, and misdiagnosis is common[10]. In our series, 23/30 patients with BF had elevated d-lactic acid with mild to moderate symptoms, and BF was reproduced in 20/30 (66%) patients, but not severe enough for hospitalization. Thus, it is a matter of semantics. 7. “Patient’s response to antibiotic and probiotic cessation is not conclusive”: Our scientific paper was intended to raise awareness that probiotics may colonize small bowel and cause SIBO. If so, because they produce d-lactic acid (especially Lactobacillus and Streptococcus sp.), they may cause BF and clinicians should recognize this association and treat appropriately. We intend conducting future studies using more validated parameters for BF, and testing for SIBO and d-lactate resolution. 8. “Questionable diagnosis of SIBO especially with mild increased counts”: The methodology we used for identifying SIBO with either glucose breath test or duodenal aspirate/culture conforms with the recommendations of the North American Consensus[11]. Hence, the diagnosis was accurate and based on current established criteria.