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. 2009 Sep 1;92(3-4):241–287. doi: 10.3184/003685009X12547510332240

The Molecular basis of Lactose Intolerance

Anthony K Campbell a,✉, Jonathan P Waud b, Stephanie B Matthews b
PMCID: PMC10368318  PMID: 19960866

Abstract

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.

Keywords: lactose, lactase, lactose intolerance, milk, hypolactasia, evolution, Darwin, bacterial toxins

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References

  • 1.Matthews S. B., and Campbell A. K. (2000) When sugar is not so sweet. Lancet, 355, 1330. [DOI] [PubMed] [Google Scholar]
  • 2.Matthews S. B., Waud J., Roberts A., and Campbell A. K. (2004) Systemic lactose intolerance: a new perspective on an old problem. Post Grad. Med. J., 81, 167–173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Campbell A. K., and Matthews S. B. (2005) Tony's Lactose Free Cook-book–the science of lactose intolerance and how to live without lactose. (ISBN 0–9540866–1–9).
  • 4.Jacobi A. (1901) Milk-sugar in infant feeding. Trans. Am. Pediat. Soc., 13, 150–160. [Google Scholar]
  • 5.Kretchmer N. (1971) Memorial lecture: lactose and lactase–a historical perspective. Gastroenterology, 61, 805–813. [PubMed] [Google Scholar]
  • 6.Holzel A., Schwarz V., and Sutcliffe K. W. (1959) Defective lactose absorption causing malnutrition in infancy. Lancet, I, 1126. [DOI] [PubMed] [Google Scholar]
  • 7.Cook G. Hypolactasia: geographical distribution, diagnosis, and practical significance. In: Chandra R. K. (ed.) Critical Reviews of Tropical Medicine, 1984, pp. 117–139. Plenum Press, New York and London. [Google Scholar]
  • 8.Brostoff J., and Challacombe S. J. (eds) (2002) Food allergy and intolerance. Saunders, London, 2nd edition. ISBN 0702020389. [Google Scholar]
  • 9.Brostoff J., and Gamlin L. (1989) The complete guide to food allergy and intolerance. ISBN 0–7475–0242–0. Bloomsbury, London. [Google Scholar]
  • 10.Bartoletus F. (1633) Methodus in dyspnoeam seu de respirationibus libri IV, quintus pro colophone accessit de curationibus ex dogmaticorum et hermeticorum poenu depromtis. Bolgna, Boniniae, p. 400.
  • 11.Plimmer R. H. A. (1906. –1907) On the presence of lactase in the intestine of animals and on the adaptation of the intestine to lactose. J. Physiol., 35, 20–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Freund J.-N., Gossé F., and Raul F. (1991) Derivatives of plant beta-glucans are hydrolysed by intestinal lactase-phlorizin hydrolase of mammals. Enzyme, 45, 71–74. [DOI] [PubMed] [Google Scholar]
  • 13.Mackey A. D., Henderson G. N., and Gregory J. F. (2002) Enzymatic hydrolysis of pyridoxine-5'-beta-D-glucoside is catalysed by intestinal lactase-phlorizin hydrolase. J. Biol. Chem., 277, 26858–26864. [DOI] [PubMed] [Google Scholar]
  • 14.Skovbjerg H., Noren O., Sjostrom, Danielsen E. M., and Stig B. (1982) Further characterization of intestinal lactaseyphlorizin hydrolase. Biochim. Biophys. Acta, 707, 89–97. [DOI] [PubMed] [Google Scholar]
  • 15.Ramaswamy S., and Radhakrishn A. N. (1975) Lactase-phlorizin hydrolase complex from monkey small intestine: purification, properties and evidence for two catalytic sites. Biochim. Biophys. Acta, 403, 446–455. [DOI] [PubMed] [Google Scholar]
  • 16.Aribas J. C. D., Herrero A. G., Martin-Lomas M., Canada F. J., He S., and Withers S. G. (2000) Differential mechanism-based labeling and unequivocal activity assignment of the two active sites of intestinal lactaseyphlorizin hydrolase. Eur. J. Biochem., 267, 6996–7005. [DOI] [PubMed] [Google Scholar]
  • 17.Swallow D. M. (2003) Genetics of lactase persistence and lactose intolerance. Ann. Rev. Genet., 37, 197–219. [DOI] [PubMed] [Google Scholar]
  • 18.Troelsen J. T., Mitchlemore C., Spodsberg N., Jensen A. M. J., Noren O., and Sjostrom H. (1997) Regulation of lactase-phlorizin hydrolase gene expression by the caudal-related homeodomain protein cdx-2. Biochem. J., 322, 833–838. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Fang R., Olds L., Santiago A., and Sibley E. (2001) GATA family of transcription factors activate lactase gene promoter in intestinal Caco-2 cell. Am. J. Physiol., 280, G58–G67. [DOI] [PubMed] [Google Scholar]
  • 20.Radebach J. R., Wurthrich M., Grunberg J., Sterchi E. E., and Naim H. Y. (1996) Maturation of human intestinal lactase-phlorizin hydrolase: generation of the brush border form of the enzyme involves at least two proteolytic cleavage steps. Eur. J. Biochem., 236, 789–795. [DOI] [PubMed] [Google Scholar]
  • 21.Mantei N., Villa M., Enzler T., Wacke H., Boll W., James P., Hunziker W., and Semenza G. (1988) Complete primary structure of human and rabbit lactase-phlorizin hydrolase: implications for biosynthesis, membrane anchoring and evolution of the enzyme. EMBO J., 7, 2705–2713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Wuthrich M., Grunberg J., Hahn D., Jacob R., Radebach I., Naim H. Y., and Sterchi E. E. (1996) Proteolytic processing of human lactase-phlorizin hyrolase is a two-step event: indentification of the cleavage sites. Arch. Biochem. Biophys., 336, 27–34. [DOI] [PubMed] [Google Scholar]
  • 23.Waud J., Bermudez-Fajardo A., Sudadhaharan T., Jefferies J., Jones A., and Campbell A. K. (2001) Measurement of proteases using chemiluminescence resonance energy transfer chimaeras between green fluorescent protein and aequorin. Biochem. J., 357, 687–697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Jacob R., Peters K., and Naim H. Y. (2002) The prosequence of human lactase-phlorizin hydrolase modulates the folding of the mature enzyme. J. Biol. Chem., 277, 8217–8225. [DOI] [PubMed] [Google Scholar]
  • 25.Maiuri L., Rossi M., Raia V., Paparo F., Garipoli V., and Auricchio S. (1993) Surface staining on the villus of lactase protein and lactase activity in adult-type hypolactasia. Gastroenterology, 105, 708–714. [DOI] [PubMed] [Google Scholar]
  • 26.Lifshitz F. (1996) Congenital lactose deficiency. J. Pediatr., 69, 229–237. [DOI] [PubMed] [Google Scholar]
  • 27.Kuokkanen M., Kokkonen J., Enattah N. S., Ylisaukko-Oja T., Koma H., Varilo T., Peltonen L., Savilahti E., and Jarvela I. (2006) Mutations in the Translated Region of the Lactase Gene (LCT) Underlie Congenital Lactase Deficiency. Am. J. Hum. Genet., 78, 339–44. Epub 2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Tivey D. R., Morovat A., and Dauncey M. J. (1993) Administration of 3, 5, 3'-triiodothyronine induces a rapid increase in enterocyte lactase-phlorizin hydrolase activity of young pigs on a low energy intake. Exp. Physiol., 78, 337–346. [DOI] [PubMed] [Google Scholar]
  • 29.Matosin-Matekalo M., Meseron J. E., Delezay O., Poiree J. C., Ilundain A. A., and Brot-Laroche E. (1998) Thyroid hormone regulation of the Na+/yglucose cotransporter SGLT1 in caco-2 cells. Biochem. J., 334, 633–640. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Srinivasan D., and Minocha A. (1998) When to suspect lactose in tolerance. Symptomatic, ethnic, and laboratory clues. Postgraduate Med., 104, 109–123. [DOI] [PubMed] [Google Scholar]
  • 31.Llewellyn D. H., Roderick L., Sheik N., and Campbell A. K. (1996) Calcium stress induces calreticulin gene expression. Biochem. J., 318, 400–410. [Google Scholar]
  • 32.Flatz G. (1987) Genetics of lactose digestion in humans. Adv. Hum. Genet., 16, 1–77. [DOI] [PubMed] [Google Scholar]
  • 33.Enattah N. S., Sahi T., Savilahti E. et al. (2002) Identification of a variant associated with adult-type hypolactasia. Nature Genetics, 30, 233–237. [DOI] [PubMed] [Google Scholar]
  • 34.Kuokkanen M., Enattah N. S., Oksanen A., Savilahti E., Orpana A., and Jarvela I. (2003) Transcriptional regulation of the lactase phlorizin-hydrolase gene by polmorphisms with adult-type hypolactasia. Gut, 52, 647–652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Campbell A. K. (1994) Rubicon: the fifth dimension of biology. Duckworth, London. Now available from Welston Press on CD. [Google Scholar]
  • 36.Sharpe P. T. (2000) Homeobox genes in initiation and shape of teeth during development in mammalian embryos. In: Teaford M. F., Smith M. M., and Fergusin F. W. (eds.) Development, function and evolution of teeth, pp. 3–12. Cambridge University Press, Cambridge. [Google Scholar]
  • 37.Sosulski F. W., Elkowicz L., and Reichart R. D. (1982) Oligosaccharides in eleven legumes and their classified protein and starch fractions. J. Food Sci., 47, 498–502. [Google Scholar]
  • 38.Bock A., and Sawers G. (1996) Fermentation. In: Neidhardt F. C. (ed.), Escherichia coli and Salmonella: cellular and molecular biology. 2nd edn. Vol 1, Chap. 18, pp. 262–282. [Google Scholar]
  • 39.Harden A., and Walpole G. S. (1906) Chemical action of Bacillus lactose aerogenes (Escheris) on glucose and mannitol: production of 2, 3-butyl-glycerol and acetyl-methylcarbinol. Proc. R. Soc. Lond. SerB, 77, 399–404. [Google Scholar]
  • 40.Campbell A. K. (1983) Intracellular calcium: its universal role as regulator, pp. 556, Chichester, John Wiley and Sons. [Google Scholar]
  • 41.Jones H. E., Holland I. B., Baker H. L., and Campbell A. K. (1999) Slow changes in cytosolic free Ca2+ in Escherichia coli highlight two putative influx mechanisms in response to changes in extracellular calcium. Cell. Calcium, 25, 265–274. [DOI] [PubMed] [Google Scholar]
  • 42.Campbell A. K., Matthews S. B., and Wann K. T. (2004) Lactose causes heart arrhythmia in the water flea Daphnia pulex. Comp. Biochem. Physiol., B 139, 225–234. [DOI] [PubMed] [Google Scholar]
  • 43.Metchnikoff E. (1900) Sur les cytotoxines. Annales Institute Pasteur xiv, 402. [Google Scholar]
  • 44.Metchnikoff E. (1908) The Nature of Man: Studies in optimistic philosophy, pp. 73. English Translation Chalmers Mitchell, P. Putnam's and Son, New York and London. [Google Scholar]
  • 45.Frissora C. L., and Koch K. L. (2005) Symptom overlap and comorbidity of irritable bowel syndrome with other conditions. Curr. Gastroenterol. Rep., Aug; 7(4), 264–271. [DOI] [PubMed] [Google Scholar]
  • 46.Szilagyi A., Malolepszy P., Yesovitch S., Nathwani U., Vinokuroff C., Cohen A., and Xue X. (2005) Inverse dose effect of pretest dietary lactose intake on breath hydrogen results and symptoms in lactase nonpersistent subjects. Dig. Dis. Sci., Nov; 50(11), 2178–2182. [DOI] [PubMed] [Google Scholar]
  • 47.Campbell A. K., and Matthews S. B. (2005) Darwin's illness revealed. Post. Grad. Med. J., 81, 248–251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Campbell A. K. (2003) What Darwin missed. Astrophys. Space Sci., 285, 1–5. [Google Scholar]
  • 49.Campbell A. K. (2003) Save those molecules! Molecular biodiversity and life. J. Appl. Ecol., 40, 193–203. [Google Scholar]
  • 50.Simoons F. J. (1971) The antiquity of dairying in Asia and Africa. Geogr. Rev., 61, 431–439. [Google Scholar]
  • 51.Feldman M. W., and Cavalli-Sforza L. L. (1989) On the theory of evolution under genetic and cultural transmission with application to the lactose absorption problem, Chap. 8, pp. 145–173. In: Feldman M. W. (ed.), Mathematical Evolutionary Theory. Princeton University Press, Princeton. [Google Scholar]
  • 52.Heilskow N. S. C. (1951) Studies on animal lactase. II. Distribution in some of the glands of the digestive tract. Acta Physiol. Scand., 24, 84–89. [DOI] [PubMed] [Google Scholar]
  • 53.Elwood P. C. (2005) Milk and cardiovascular disease: a review of the evidence. Am. J. Dairy Technol., 59, 502–505. [Google Scholar]
  • 54.Moss M., and Freed D. (2002) The cow and the coronary: epidemiology, biochemistry and immunology. Int. J. Cardiol., 87, 203–216. [DOI] [PubMed] [Google Scholar]
  • 55.Williams R. (1985) Biochemical individuality: the basis of the genetotrophic concept. Keats Publishing, Connecticut. [Google Scholar]
  • WEB SITES
  • 1.www.lactose.co.uk, Conventional information about lactose intolerance and selling products.
  • 2.www.lactoseintolerance.co.uk, Conventional information about lactose intolerance and milk allergies, with symptoms, treatments, and ‘hidden’ milk products.
  • 3.www.lactoseintolerant.org, Conventional information only about lactose intolerance and milk allergies.
  • 4.www.welstonpress.com, The only one at present that deals with systemic symptoms caused by lactose

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