Darwin diagnosed

While waiting in lodgings to join H.M.S. Beagle just before Christmas 1831, Charles Darwin suffered chest pain and heart palpitations. On his return to England he began to suffer from a range of gut problems and systemic symptoms around the body, which were to plague him for the rest of his life. At least 40 conditions have been proposed to explain Darwin's illness, which left him disabled, sometimes for weeks on end. Here we show that lactose and food intolerance is the only condition that explains all his symptoms. Furthermore, there is now a molecular basis to account for these, based on metabolic toxins produced by microbes in the intestine. This mechanism has important implications in several other diseases, including diabetes, inflammatory bowel disease, Parkinson's disease and some cancers. Lactose intolerance also has fascinating things to tell us about molecular evolution – the origin of lactose, the unique sugar in milk; why white humans were able to invade the plains of Europe after the last ice thaw, some 10 000 years ago; and one of the most intriguing problems in evolution – the origin of a new enzyme such as lactase, the enzyme responsible for cleaving lactose into its constituents monosaccharides, galactose and glucos

The molecular basis of lactose intolerance

A staggering 4000 million people cannot digest lactose, the sugar in milk, properly. All mammals, apart from white Northern Europeans and few tribes in Africa and Asia, lose most of their lactase, the enzyme that cleaves lactose into galactose and glucose, after weaning. Lactose intolerance causes gut and a range of systemic symptoms, though the threshold to lactose varies considerably between ethnic groups and individuals within a group. The molecular basis of inherited hypolactasia has yet to be identified, though two polymorphisms in the introns of a helicase upstream from the lactase gene correlate closely with hypolactasia, and thus lactose intolerance. The symptoms of lactose intolerance are caused by gases and toxins produced by anaerobic bacteria in the large intestine. Bacterial toxins may play a key role in several other diseases, such as diabetes, rheumatoid arthritis, multiple sclerosis and some cancers. The problem of lactose intolerance has been exacerbated because of the addition of products containing lactose to various foods and drinks without being on the label. Lactose intolerance fits exactly the illness that Charles Darwin suffered from for over 40 years, and yet was never diagnosed. Darwin missed something else - the key to our own evolution - the Rubicon some 300 million years ago that produced lactose and lactase in sufficient amounts to be susceptible to natural selection

Lactose causes heart arrhythmia in the water flea Daphnia pulex

The cladoceran Daphnia pulex is well established as a model for ecotoxicology. Here, we show that D. pulex is also useful for investigating the effects of toxins on the heart in situ and the toxic effects in lactose intolerance. The mean heart rate at 10 °C was 195.9±27.0 beats/min (n=276, range 89.2–249.2, >80% 170–230 beats/min). D. pulex heart responded to caffeine, isoproteronol, adrenaline, propranolol and carbachol in the bathing medium. Lactose (50–200 mM) inhibited the heart rate by 30–100% (K1/2=60 mM) and generated severe arrhythmia within 60 min. These effects were fully reversible by 3–4 h. Sucrose (100–200 mM) also inhibited the heart rate, but glucose (100–200 mM) and galactose (100–200 mM) had no effect, suggesting that the inhibition by lactose or sucrose was not simply an osmotic effect. The potent antibiotic ampicillin did not prevent the lactose inhibition, and two diols known to be generated by bacteria under anaerobic conditions were also without effect. The lack of effect of L-ribose (2 mM), a potent inhibitor of ?-galactosidase, supported the hypothesis that lactose and other disaccharides may affect directly ion channels in the heart. The results show that D. pulex is a novel model system for studying effects of agonists and toxins on cell signalling and ion channels in situ

Systemic lactose intolerance: a new perspective on an old problem

Intolerance to certain foods can cause a range of gut and systemic symptoms. The possibility that these can be caused by lactose has been missed because of “hidden” lactose added to many foods and drinks inadequately labelled, confusing diagnosis based on dietary removal of dairy foods. Two polymorphisms, C/T13910 and G/A22018, linked to hypolactasia, correlate with breath hydrogen and symptoms after lactose. This, with a 48 hour record of gut and systemic symptoms and a six hour breath hydrogen test, provides a new approach to the clinical management of lactose intolerance. The key is the prolonged effect of dietary removal of lactose. Patients diagnosed as lactose intolerant must be advised of “risk” foods, inadequately labelled, including processed meats, bread, cake mixes, soft drinks, and lagers. This review highlights the wide range of systemic symptoms caused by lactose intolerance. This has important implications for the management of irritable bowel syndrome, and for doctors of many specialties

Fermentation product butane 2,3 diol induces Ca2+ transients in E. coli through activation of lanthanum-sensitive Ca2+ channels

The results here are the first demonstration of a physiological agonist opening Ca2+ channels in bacteria. Bacteria in the gut ferment glucose and other substrates, producing alcohols, diols, ketones and acids, that play a key role in lactose intolerance, through the activation of Ca2+ and other ion channels in host cells and neighbouring bacteria. Here we show butane 2,3-diol (5–200 mM; half maximum 25 mM) activates Ca2+ transients in E. coli, monitored by aequorin. Ca2+-transient magnitude depended on external Ca2+ (0.1–10 mM). meso-Butane 2,3-diol was approximately twice as potent as 2R,3R (?) and 2S,3S (+) butane 2,3-diol. There were no detectable effects on cytosolic free Ca2+ of butane 1,3-diol, butane 1,4-diol and ethylene glycol. The glycerol fermentation product propane 1,3-diol only induced significant Ca2+ transients in 10 mM external Ca2. Ca2+ butane 2,3-diol Ca2+ transients were due to activation of Ca2+ influx, followed by activation of Ca2+ efflux. The effect of butane 2,3-diol was abolished by La3+, and markedly reduced as a function of growth phase. These results were consistent with butane 2,3-diol activating a novel La3+-sensitive Ca2+ channel. They have important implications for the role of butane 2,3-diol and Ca2+ in bacterial-host cell signalling

Quantifying the 'hidden' lactose in drugs used for the treatment of gastrointestinal conditions

Background  Lactose intolerance affects 70% of the world population and may result in abdominal and systemic symptoms. Treatment focuses predominantly on the dietary restriction of food products containing lactose. Lactose is the most common form of excipient used in drug formulations and may be overlooked when advising these patients. Aim  To identify and quantify the amount of lactose in medications used for the treatment of gastrointestinal disorders and to identify ‘lactose-free’ preparations. Methods  Medications used for the treatment of gastrointestinal disorders were identified from the British National Formulary (BNF). Their formulation including excipients was obtained from the Medicines Compendium. The lactose content and quantity in selected medications was measured using high-performance liquid chromatography (HPLC). Results  A wide range of medications prescribed for the treatment of gastrointestinal conditions contain lactose. We have quantified the lactose content in a selection of medications using HPLC. Lactose is present in amounts that may contribute towards symptoms. Lactose-free alternatives were also identified. Conclusions  Lactose is present in a range of medications and may contribute towards symptoms. This may not be recognized by the prescribing doctor as excipients are not listed in the BNF, and the quantity of lactose is not listed on the label or in the accompanying manufacturer’s leaflet