Friday, 3 June 2016

Dysbiosis and D-lactate

Lactate (C3H6O3) is an intermediate of carbohydrate metabolism, produced from pyruvate during lactic acid fermentation. Lactate can exist as two enantiomers/stereoisomers, L- and D-lactate, with L-lactate being the main form present in the body. Human cells produce L-lactate from glucose and alanine, while a small amount of D-lactate can be produced via the methylglyoxal pathway 1. However gut microbes can produce both L- and/or D-lactate as major metabolic by-products 2.

Elevated gut and/or blood levels of D-lactate are seen in several conditions and may be harmful 1–3. An overgrowth of D-lactate-producing gut bacteria has also been implicated in ME/CFS 4–6; although blood levels and biological interactions/associations have not yet been investigated, making the relevance unclear. Still, I think we can learn something from general research on D-lactate production by the gut microbiota.

In the gut, dietary carbohydrates provide fuel for microbial fermentation. Normally this should occur predominantly in the colon, where indigestible carbs accumulate and are slowly broken down into sugars. Many gut microbes (e.g. Lactobacilli, Streptococci, Bifidobacteria, etc.) can subsequently perform lactic acid fermentation and release lactate as metabolic waste 7. Some microbes express D-lactic acid dehydrogenase (DDH) allowing them to produce D-lactate 2. Gut lactate levels normally remain extremely low or undetectable, since both L- and D-lactate are intermediate substrates for the production of SCFAs (mainly butyrate) 8–10, the normal end-products of carbohydrate fermentation. However, large amounts of indigestible sugars (e.g. lactulose 10 or FOS 11) have been shown to increase colonic lactate levels in healthy individuals, likely due to production outpacing utilisation.

In many diseases there may be highly abnormal patterns of carbohydrate fermentation. This may involve excessive fermentation in the small intestine (e.g. SIBO) or dysregulated fermentation in the large intestine (colonic dysbiosis). Several gut conditions (e.g. IBD, intestinal ischemia and short bowel) have been associated with elevated colonic lactate and blood D-lactate levels, as a result of changes to the intestinal environment (substrate availability, pH, blood flow, etc.) and bacterial abundance 3.

Humans have some ability to metabolise D-lactate via DDH/D-2-HDH (highest expression in liver and kidneys) 1,2,12. However, at high production rates, D-lactate can accumulate in blood. D-lactate may exert toxic effects. D-lactate can directly interfere with pyruvate/lactate metabolism and mitochondrial function in brain and heart tissue 12. If levels get high enough (>3 mmol/L) this can cause D-lactic acidosis, which is associated with an array of neurological symptoms (e.g. encephalopathy, slurred speech, ataxia, etc.) 2. Notably, blood D-lactate levels may only poorly correlate with neurological symptoms, suggesting other factors are also involved 2.

D-lactic acidosis typically occurs as a rare complication of short bowel syndrome. Here, a shortened small intestine enables dietary sugars to reach the colon, where they are rapidly fermented, resulting in a bloom of bacteria (i.e. Lactobacilli) which produce lactate, overwhelming its utilisation 2. In these cases, meals high in carbohydrates can promote acidosis. Therefore restriction of dietary carbohydrate is important for management 2. Interestingly however, the type of dietary carbohydrate also seems crucial. A couple of detailed case reports, on people with short bowel and recurrent episodes of D-lactic acidosis, have assessed the ability of their bacteria to produce D-lactate in response to different carbohydrates 10,13. They found that simple sugars (e.g. glucose, lactose, maltose, sucrose, etc.) promote D-lactate production, whereas long-chain starch polysaccharides did not. Therefore manipulation of dietary carbs to be low in sugars and high in starch eliminated episodes of D-lactic acidosis 10,13. This may be because D-lactate-producing bacteria cannot effectively break down starch, or just that simple sugars can be metabolised far more rapidly 2. Also of interest, another short bowel patient with recurrent D-lactic acidosis, was apparently successfully treated long-term with a standalone synbiotic therapy, consisting of probiotic bacteria and the prebiotic fibre GOS 14. In humans GOS mainly supports the growth of Bifidobacteria 15, which can alter fermentation patterns and lower D-lactate levels in vitro 16.

Back to ME/CFS. There is evidence of SIBO 17,18 and dysbiosis, including an overgrowth of D-lactate producing bacteria (e.g. Streptococci and Enterococci) 4. Levels of several lactic acid bacteria also correlate with symptoms 5,6. However there is still no measurement of gut microbiota DDH expression or gut and blood D-lactate. Also, if D-lactate is an issue, then is carbohydrate type important? Notably, the D-lactate-producing ability of bacteria elevated in ME/CFS was only tested with glucose 4, which at least implicates sugars. However, since simple sugars are normally absorbed high up the intestine, for them to be an issue implies malabsorption and/or SIBO.

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3.         Verbeke, K. A. et al. Towards microbial fermentation metabolites as markers for health benefits of prebiotics. Nutr Res Rev 28, 42–66 (2015).
4.         Sheedy, J. R. et al. Increased d-lactic Acid intestinal bacteria in patients with chronic fatigue syndrome. In Vivo 23, 621–8 (2009).
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9.         Bourriaud, C. et al. Lactate is mainly fermented to butyrate by human intestinal microfloras but inter-individual variation is evident. J. Appl. Microbiol. 99, 201–12 (2005).
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12.       Ling, B. et al. D-Lactate altered mitochondrial energy production in rat brain and heart but not liver. Nutr. Metab. (Lond). 9, 6 (2012).
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14.       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. 98, 110–3 (2013).
15.       Davis, L. M. G., Martínez, I., Walter, J., Goin, C. & Hutkins, R. W. Barcoded pyrosequencing reveals that consumption of galactooligosaccharides results in a highly specific bifidogenic response in humans. PLoS One 6, e25200 (2011).
16.       Jiang, T. & Savaiano, D. A. Modification of colonic fermentation by bifidobacteria and pH in vitro. Impact on lactose metabolism, short-chain fatty acid, and lactate production. Dig. Dis. Sci. 42, 2370–7 (1997).
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