D-Lactic acid-induced neurotoxicity in a calf model

College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
AJP Endocrinology and Metabolism (Impact Factor: 3.79). 08/2007; 293(2):E558-65. DOI: 10.1152/ajpendo.00063.2007
Source: PubMed


Lactic acidosis (DAC) occurs as a complication of short-bowel syndrome in humans and in a variety of other gastrointestinal disorders in monogastrics and ruminants. DAC is associated with signs of impaired central nervous system (CNS) function including ataxia and coma. The objective of this experiment was to determine whether either acidification of nervous tissue or d-lactic acid is responsible for decreased neurological function. Eight Holstein calves (32 +/- 11 days, 70 +/- 10 kg) were surgically catheterized with indwelling intravenous jugular and atlanto-occipital space cerebrospinal fluid (CSF) catheters and infused for 6 h in random order with isomolar dl-lactic acid (dl-LA), l-lactic acid (l-LA), hydrochloric acid (HCl), or saline. dl-LA induced ataxia after 4 h of infusion and produced the greatest obtunding of CNS function (at 7 h, score 8.0 +/- 0.4), whereas the other infusions caused neither ataxia nor scores over 1.5 (P < 0.01 from dl-LA). dl-LA induced significantly less acidemia than HCl (at 6 h pH 7.13 +/- 0.06 and 7.00 +/- 0.04, base excess -16 +/- 1 and -23 +/- 3 mmol/l, bicarbonate 11 +/- 1 and 8 +/- 1 mmol/l respectively, all P < 0.01) but greater than l-LA and saline (P < 0.01). CSF changes followed a similar but less pronounced pattern. Although HCl infusion produced a severe acidemia and CSF acidosis, only minor effects on neurological function were evident suggesting that d-lactate has a direct neurotoxic effect that is independent of acidosis. Conversely, l-LA produced only minor neurological changes.

Download full-text


Available from: Saman Abeysekara,
  • Source
    • "It is important to point out that many of the neurologic signs are not promoted by thiamine deficit, because the serum D-lactic acid increase allows it to cross the blood-brain barrier by monocarboxylate protons transporters. The majority of neurological disturbances (i.e., ataxia and depressed menace, palpebral, and tactile reflexes) are related to D-lactate accumulation in cerebrospinal fluids rather than in blood [15] "
    [Show abstract] [Hide abstract]
    ABSTRACT: Acute ruminal acidosis is a metabolic status defined by decreased blood pH and bicarbonate, caused by overproduction of ruminal D-lactate. It will appear when animals ingest excessive amount of nonstructural carbohydrates with low neutral detergent fiber. Animals will show ruminal hypotony/atony with hydrorumen and a typical parakeratosis-rumenitis liver abscess complex, associated with a plethora of systemic manifestations such as diarrhea and dehydration, liver abscesses, infections of the lung, the heart, and/or the kidney, and laminitis, as well as neurologic symptoms due to both cerebrocortical necrosis and the direct effect of D-lactate on neurons. In feedlots, warning signs include decrease in chewing activity, weight, and dry matter intake and increase in laminitis and diarrhea prevalence. The prognosis is quite variable. Treatment will be based on the control of systemic acidosis and dehydration. Prevention is the most important tool and will require normalization of ruminal pH and microbiota. Appropriate feeding strategies are essential and involve changing the dietary composition to increase neutral detergent fiber content and greater particle size and length. Appropriate grain processing can control the fermentation rate while additives such as prebiotics or probiotics can help to stabilize the ruminal environment. Immunization against producers of D-lactate is being explored.
    The Scientific World Journal 11/2014; 2014. DOI:10.1155/2014/702572 · 1.73 Impact Factor
  • Source
    • "d-lactate concentration increases significantly secondary to infection, trauma and damage to the digestive barrier by ischaemia and necrosis (Smith et al. 1989, Sun et al. 2001). d-lactate concentrations were reported to be strongly associated with acute neuropathy in humans and a calf model (Uribarri et al. 1998, Abeysekara et al. 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Objectives: To determine whole blood and serum concentrations of l-lactate and serum concentrations of d-lactate in healthy rabbits and compare three methods of analysis for l-lactate measurement. Methods: Prospective study using 25 rabbits. Concentrations of whole blood l-lactate were measured using a portable analyser and a blood gas analyser. The remainder of the sample was allowed to clot for centrifugation. Serum was stored at -20°C for determination of l- and d- lactate by high-performance liquid chromatography. Results: d-lactate values by high-performance liquid chromatography were 0 · 17 ± 0 · 08 mmol/L. l-lactate values were 5 · 1 (±2 · 1) mmol/L by high-performance liquid chromatography, 6 · 9 (±2 · 7) mmol/L with the portable analyser and 7 · 1 (±1 · 6) mmol/L with the blood gas analyser. No significant difference (P > 0 · 05) was found between the two analysers. Significant difference existed between serum l-lactate values obtained by high-performance liquid chromatography and the whole blood values obtained with the blood gas analyser (P < 0 · 01) and portable analyser (P < 0 · 05). Clinical significance: Serum concentrations of d-lactate in healthy rabbits are in the range of those of other mammals. l-lactate values in healthy rabbits are higher compared with other mammals. Good correlation was found between the portable and blood gas analysers for whole blood l-lactate measurement in healthy rabbits.
    Journal of Small Animal Practice 07/2014; 55(9). DOI:10.1111/jsap.12247 · 1.09 Impact Factor
  • Source
    • "We found, coherently with the literature, that faecal D-lactate was undetectable in healthy human faeces and the faecal L-lactate was around 1.5 mM [41], [47], [48]. D-lactate enantiomer is toxic for neurons in a manner that is independent of acidosis [49] while L-lactate is metabolized at high level by neurons. D-and L-lactate share similar pathways of transport and metabolism in the digestive tract, but in human brain tissue, D isoform seems to impair the L lactate availability, thus provoking energy deficit in neurons [23], [50]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Our objective was to understand the functional link between the composition of faecal microbiota and the clinical characteristics of adults with short bowel syndrome (SBS). Sixteen patients suffering from type II SBS were included in the study. They displayed a total oral intake of 2661±1005 Kcal/day with superior sugar absorption (83±12%) than protein (42±13%) or fat (39±26%). These patients displayed a marked dysbiosis in faecal microbiota, with a predominance of Lactobacillus/Leuconostoc group, while Clostridium and Bacteroides were under-represented. Each patient exhibited a diverse lactic acid bacteria composition (L. delbrueckii subsp. bulgaricus, L. crispatus, L. gasseri, L. johnsonii, L. reuteri, L. mucosae), displaying specific D and L-lactate production profiles in vitro. Of 16 patients, 9/16 (56%) accumulated lactates in their faecal samples, from 2 to 110 mM of D-lactate and from 2 to 80 mM of L-lactate. The presence of lactates in faeces (56% patients) was used to define the Lactate-accumulator group (LA), while absence of faecal lactates (44% patients) defines the Non lactate-accumulator group (NLA). The LA group had a lower plasma HCO3− concentration (17.1±2.8 mM) than the NLA group (22.8±4.6 mM), indicating that LA and NLA groups are clinically relevant sub–types. Two patients, belonging to the LA group and who particularly accumulated faecal D-lactate, were at risk of D-encephalopathic reactions. Furthermore, all patients of the NLA group and those accumulating preferentially L isoform in the LA group had never developed D-acidosis. The D/L faecal lactate ratio seems to be the most relevant index for a higher D- encephalopathy risk, rather than D- and L-lactate faecal concentrations per se. Testing criteria that take into account HCO3− value, total faecal lactate and the faecal D/L lactate ratio may become useful tools for identifying SBS patients at risk for D-encephalopathy.
    PLoS ONE 01/2013; 8(1):e54335. DOI:10.1371/journal.pone.0054335 · 3.23 Impact Factor
Show more