Rao S, Rehman A, Yu S, Andino NM. Brain fogginess, gas and bloating: a link between SIBO, probiotics and metabolic acidosis. Clin Transl Gastroenterol. 2018;9(6):162.
Prospective observational study
To determine if there are any associations between brain fogginess, abdominal symptoms, positive small intestinal bacterial overgrowth (SIBO) tests, and acidosis caused by circulating L-lactic acid or urinary D-lactic acid
Participants included consecutive adult patients referred to the authors’ specialty clinic at the Medical College of Georgia at Augusta University over a 3-year period. Thirty-eight patients were evaluated. All patients presented with unexplained abdominal gas, bloating, and distension; 30 had brain fogginess (BF) and 8 did not. Brain fogginess was defined as presence of 2 or more of the following symptoms for more than 3 months during their initial clinic visit: mental confusion, cloudiness, impaired judgment, poor short-term memory, and difficulty with concentration. All participants had negative endoscopic and radiological tests.
Study Parameters Assessed
Participants were evaluated for SIBO with a glucose breath test (GBT) and duodenal aspiration/culture. Bowel symptoms and gastrointestinal transit were also assessed. Metabolic assessments included levels of L-lactic acid and ammonia in the blood and levels of D-lactic acid in the urine.
Testing for lactic acid is still considered a novel assessment test. Blood and urine lactic acid levels were measured after an oral glucose challenge (simultaneous with the GBT). Blood levels of L-lactic acid ≥2.2 mmol/L were considered positive and indicative of acidosis. Urine samples for D-lactic acid were collected at baseline, 1 hour, and 3 hours during and after the GBT and analyzed in a specialist lab (Mayo Clinic Laboratories, Rochester, MN). D-lactic acid levels ≥0.22 mmol/L were considered abnormal and indicative of acidosis.
Abdominal bloating, pain, distension, and gas were the most severe symptoms and their prevalence was similar between groups. All 30 of the patients in the BF group had consumed probiotics. Small intestinal bacterial overgrowth was more prevalent in BF than non-BF group (68% vs 28%; P=0.05). D-lactic acidosis was more prevalent in BF compared to non-BF group (77% vs 25%; P=0.006). Brain fog was reproduced in 66% (20/30) of patients during the GBT. Gastrointestinal transit was slow in 33% (10/30) of patients with BF and 25% (2/8) without. Other metabolic tests were unremarkable. After discontinuation of probiotics and a course of antibiotics, BF resolved and gastrointestinal symptoms improved significantly in 77% (23/30) of the symptomatic group (P=0.005).
If the term D-lactic acidosis doesn’t ring many bells in your memory do not worry; until very recently the condition was thought to be rare in humans,1 something only occasionally seen in ruminant animals, in particular baby cows.2 It’s not something you’ve forgotten about; rather, it’s something you’ve never heard of.
Bottom line: If your patients are complaining of gas, bloating, and brain fog, ask if they are taking probiotics.
A single human case was first described by Oh et al in 1979 in a patient with short bowel syndrome who presented with psychoneurologic symptoms.3 Over the years occasional reports have been published, the condition occurring as a complication of bariatric surgery,4 or, most often, short bowel syndrome.5 The condition was considered to be very rare, one of those zebra diagnoses to consider in cases of metabolic acidosis characterized by encephalopathy with a high anion gap.1 It was not something one needed to keep on the radar, at least not until this paper.
The current paper by Rao et al follows a preliminary study by the same authors. In a 2014 report, Rao and colleagues described 7 patients who had presented with both unexplained abdominal bloating and BF and who were consuming probiotics.6 This new prospective study, which builds on the 2014 report, suggests that D-lactic acidosis may be much more common than suspected, in part self-induced or self-inflicted by people supplementing with over-the-counter (OTC) probiotics—the ubiquitous Lactobacillus and Bifidobacterium species we have long promoted.
We need to back up a second and review a little chemistry. Lactate in nature exists in 2 optical isomers, D-lactate or L-lactate. L-lactate is much more abundant in humans and other mammals, with blood concentrations 100 times that of D-lactate. L-lactate is the only form made in mammals. The trace amounts of D-lactate found in the blood are actually made by carbohydrate-fermenting gut bacteria, including Lactobacillus spp and Bifidobacterium spp, which are able to produce both stereoisomers in varying proportions.7 L-lactate is efficiently metabolized and broken down in the body, while D-lactate is not readily broken down and accumulates.8
Normal blood levels of D-lactate in healthy adults are low, ranging from 11 to 70 nmol/L. At elevated levels defined as acidosis (>2.5-3.0 mmol/L; note difference nanomole vs millimole) patients display symptoms of ataxia, slurred speech, and confusion. Standard management consists of restricting oral carbohydrates or fasting and using nonabsorbable antibiotics to eliminate D-lactate–producing bacteria. However, D-lactic acidosis usually recurs, and patients must fast repeatedly to keep the problem at bay, which interferes with quality of life.9,10
A 2010 report describing a case of a 5-year-old girl in which ingestion of supplemental probiotics was associated with D-lactate acidosis is perhaps the first mention of this potential possibility in the literature.11 Until this report no one was thinking about this.
What this paper tells us is that this condition, D-lactic acidosis, may occur more often than we would have ever suspected. No one would think of probiotics as a cause of illness—we think of them as a cure for many things. In particular, we would think of them as useful for patients with gas and bloating. Obviously taking probiotics does not cause D-lactate acidosis in all the people who take them.
The National Institutes of Health (NIH) reports that in 2017, 1.6% of US adults, or about 3.9 million people, take probiotics.12 Clearly this problem, if it really exists at all, is still rare. There are those who express their doubts whether this D-lactate acidosis is really a problem. A literature review published in August was unable to find records of infants made ill by probiotic supplementation.13
On the other hand, we are now obligated to be aware of this symptom picture and include it in our differential diagnosis.
I find myself thinking about past patients. As my practice is oncology-focused, most of our patients have been treated with chemotherapy at some point; many of them complain of brain fog. A fair percentage of them, in an attempt to improve their health, take probiotics regularly. Could we be mistaking D-lactate acidosis for “chemo brain”? One distinct symptom worth remembering, reported by Rao et al, was that the brain fog was worsened by ingestion of sugar, in this case the glucose load used in the SIBO breath test. That symptom is so familiar that I wonder how many cases of D-lactic acidosis I may have missed over the years. In a bygone era we would have assumed that symptom was due to Candida. Now we blame it on SIBO. In both cases we would prescribe probiotics.
We should note that the current study used a slightly lower threshold of D-lactate to define the condition (2.5 vs 3.0 mmol) than most reports, but keep in mind normal body levels are measured in nanomoles not millimoles.14
Antibiotics have been the standard treatment for D-lactic acidosis in the past. The condition has tended to recur or proven resistant to antibiotics in some patients. There have been reports of successful and lasting improvements following fecal transplants15,16 or cocktails using specific strains of probiotic bacteria.17,18 We have no easy way of discriminating between probiotic products to determine whether they produce D-lactate or not, so simply supplementing with more probiotics seems unwise.
Many patients, and many colleagues as well, are going to find this information challenging to accept. It is a new idea and we have for many years promoted probiotic bacteria as such purely beneficent agents that it will be hard for many to accept that they could have negative consequences.
Bottom line: If your patients are complaining of gas, bloating, and brain fog, ask if they are taking probiotics. If yes, then ask if their symptoms are worse after eating sugar. If their answer is again yes, include D-lactic acidosis in your differential. One fault of this current study is that they did not have the patients stop taking probiotics to see if they improved without antibiotics. Knowing my patient population, antibiotic treatment may not be their first choice. Still, stopping the probiotics and taking antibacterial herbs may be a reasonable first line of treatment to see if it controls the symptoms.
- Kang KP, Lee S, Kang SK. D-lactic acidosis in humans: review of update. Electrolyte Blood Press. 2006;4(1):53-56.
- Lorenz I, Gentile A. D-lactic acidosis in neonatal ruminants. Vet Clin North Am Food Anim Pract. 2014;30(2):317-331.
- Oh MS, Phelps KR, Traube M, Barbosa-Saldivar JL, Boxhill C, Carroll HJ. D-lactic acidosis in a man with the short-bowel syndrome. N Engl J Med. 1979;301(5):249-252.
- Traube M, Bock J, Boyer JL. D-lactic acidosis after jejunoileal bypass. N Engl J Med. 1982;307(16):1027.
- Kowlgi NG, Chhabra L. D-lactic acidosis: an underrecognized complication of short bowel syndrome. Gastroenterol Res Pract. 2015;2015:476215.
- Rehman A. Brain fogginess, gas, bloating and distension: a link between SIBO, probiotics and metabolic acidosis. Gastroenterology. 2014;146:S850-S851.
- Hove H, Mortensen PB. Colonic lactate metabolism and D-lactic acidosis. Dig Dis Sci. 1995;40:320-330.
- Oh MS, Uribarri J, Alveranga D, Lazar I, Bazilinski N, Carroll HJ. Metabolic utilization and renal handling of D-lactate in men. Metabolism. 1985;34:621-625.
- Ewaschuk JB, Naylor JM, Zello GA. D-lactate in human and ruminant metabolism. J Nutr. 2005;135(7):1619-1625.
- Seheult J, Fitzpatrick G, Boragn G. Lactic acidosis: an update. Clin Chem Lab Med. 2017;55(3):322-333.
- Munakata S, Arakawa C, Kohira R, Fujita Y, Fuchigami T, Mugishima H. A case of D-lactic acid encephalopathy associated with use of probiotics. Brain Dev. 2010;32(8):691-694.
- National Center for Complementary and Integrative Health, National Institutes of Health. Use of complementary health approaches in the US. https://nccih.nih.gov/research/statistics/NHIS/2012/natural-products/biotics. Modified September 24, 2017. Accessed October 25, 2018,
- Łukasik J, Salminen S, Szajewska H. Rapid review shows that probiotics and fermented infant formulas do not cause D-lactic acidosis in healthy children. Acta Paediatr. 2018;107(8):1322-1326.
- Fabian E, Kramer L, Siebert F, et al. D-lactic acidosis - case report and review of the literature. Z Gastroenterol. 2017;55(1):75-82.
- Bulik-Sullivan EC, Roy S, Elliott RJ, et al. Intestinal microbial and metabolic alterations following successful fecal microbiota transplant for D-lactic acidosis. J Pediatr Gastroenterol Nutr. 2018;67(4):483-487.
- Davidovics ZH, Vance K, Etienne N, Hyams JS. Fecal transplantation successfully treats recurrent D-lactic acidosis in a child with short bowel syndrome. JPEN J Parenter Enteral Nutr. 2017;41(5):896-897.
- Takahashi K, Terashima H, Kohno K, Ohkohchi N. A stand-alone synbiotic treatment for the prevention of D-lactic acidosis in short bowel syndrome. Int Surg. 2013;98(2):110-113.
- Yilmaz B, Schibli S, Macpherson AJ, Sokollik C. D-lactic acidosis: successful suppression of D-lactate–producing Lactobacillus by probiotics. Pediatrics. 2018;142(3):e20180337.