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At birth, nearly all human beings, as well as most mammals, are able to digest lactose, a disaccharide present in their mothers’ milk. This is a critical ability, since newborns obtain a large amount of their energy from digesting the lactose in milk. During digestion, lactose is first split into 2 monosaccharides, glucose and galactose, by the lactase enzyme in the small intestine. See Fig. 1. The monosaccharides are then absorbed by the small intestine and enter into the bloodstream.
Lactase is found in the microvilli (small fingerlike projections) of the cells lining the small intestine. The environment in the small intestine where the enzyme is made ranges from pH 6 to 8, with the pH being 6 to 6.5 in the part of the intestine closest to the stomach. The optimal pH for human lactase is 6.0. At pH 8 to 9, it exhibits 50% of its maximum activity and has little activity below pH 3.
In most people, lactase expression diminishes between the ages of 2 and 12. As most people mature to adulthood, the cells that produce lactase are programmed to stop making significant amounts of the enzyme. The lactase gene is still intact, but is no longer expressed or is expressed only at very low levels. Once people stop producing lactase, they become lactose intolerant. They cannot comfortably digest dairy products that contain lactose, or are limited in the amount of dairy they can comfortably consume.
People can also become lactose intolerant because they have a condition that damages the lactase-producing cells in their intestines. For example, people with celiac disease have an immune reaction to the gluten protein found in some grain. Over time, this immune reaction damages the intestinal lining to the point that it no longer produces lactase.
Lactose intolerance should not be confused with lactase deficiency, which is relatively rare. People who are lactase deficient are said to have a “congenital lactase deficiency"; throughout their lives they are unable to make any functional lactase enzyme. The presence of a mutation that creates a stop codon in the lactase gene is one example of how this type of lactase deficiency occurs.
Lactose intolerance is marked by the production of excessive gas, bloating, and abdominal pain. In some lactose intolerant people, ingesting lactose causes diarrhea, as well as a variety of other symptoms throughout their bodies. Most of the intestinal symptoms that mark lactose intolerance occur as a result of bacteria in the large intestine digesting lactose.
As the bacteria in the large intestine ferment lactose, they produce hydrogen, methane, and carbon dioxide gas. This excess gas causes bloating and abdominal pain. The hydrogen produced by the bacteria acidifies the intestine and the lactose present increases osmotic pressure in the intestine. The increased acid and osmotic pressure lead to the flow of fluid and ions into the intestine, causing diarrhea. In contrast, people who make lactase are able to digest the lactose in their small intestines before it has a chance to reach their large intestines and cause discomfort.
As mentioned, there are people with lactose intolerance who experience symptoms that are more systemic, meaning that other parts of their bodies (besides their intestines) are affected. Some scientists hypothesize that these symptoms may be linked to compounds produced by lactose-fermenting bacteria in these individuals’ large intestines.
It is estimated that approximately 75% of the adult world population is not able to digest lactose, the main carbohydrate in milk.
The ability to make lactase as an adult varies between populations. Populations of northern Europeans or of northern European descent and those from some African tribes are among the groups with the greatest number of people who continue to make lactase even after they are adults. The ability to express lactase into adulthood has been most commonly linked with 2 single base pair changes that are most commonly found in northern Europeans or in people of northern European descent.
These 2 mutations are found in the same region of the human genome. One of these 2 base pair changes, the one most closely associated with adult lactase expression in Europeans, changes a cytosine 13,910 base pairs upstream of the lactase gene to a thymine. Although this cytosine-to-thymine change is in a different gene from the lactase gene, evidence suggests that the mutation effects the regulation of lactase gene transcription.
In addition to the 2 commonly found single base pair mutations mentioned above, multiple different single base pair changes linked to the ability of adults to express lactase have been found throughout the world. Examination of the sequence of the genomic DNA surrounding these different single base pair changes suggests that at least some of the changes arose independently in different populations.
From studying the DNA sequence of the human genome, scientists have been able to determine where many of these mutations originally occurred. Some of these mutations are found not only in populations located where the mutation originally arose, but in other populations as well. For example, the most common mutation conferring the ability to express the lactase enzyme into adulthood first arose in northern Europe, most likely in the region that is now Sweden, but it is also found in populations in other parts of the world. Studying the frequency of each of these mutations in different populations around the world reveals interesting information about the migration of people.
For instance, the most common mutation referred to above is found at fairly high frequency in Swedish populations. However, in general, as you move further east and south in Europe, the frequency of the mutation in populations decreases, suggesting that the population in which the mutation arose has not spread itself evenly across Europe.
Archeologic evidence suggests that humans began to collect and drink milk from other animals in the Middle East around 9,000 years ago. Evidence also suggests that early dairying practices may have involved making cheese. Some cheeses contain little or no lactose and thus could have been eaten by people producing low levels of lactase.
Current evidence suggests that the ability of humans to express the lactase enzyme into adulthood did not arise until after dairying practices had begun. In the presence of cheeses with no or only a little lactose, even those not making lactase could benefit from dairying practices. However, those that continued to express lactase into adulthood would have also had access to the milk as well as a broader variety of cheeses. This access could have given them and their offspring a selective advantage, which would have selected for the spread of the allele in the population.