No Dose of Lactose

Grace Huang and Anjali Pagidi Thomas Jefferson High School for Science and Technology

“Do you have almond milk instead?” When somebody asks a question like this, one can almost be certain that this person is lactose intolerant. About 65% of the world’s population suffers from some degree of lactose intolerance, or the weakened ability to digest lactose, a sugar most commonly found in dairy products [5]. However, did you know that, in fact, lactose intolerance is the “default,” meaning that the entire human race started off without the ability to digest lactose?

Before we discuss the evolutionary history of lactose intolerance, we must define the basics of this condition. The most common type of intolerance is primary lactose intolerance [4]. Individuals with this condition can produce lactase as an infant since lactase digests milk, the main source of nutrition for infants. As they continue to grow, however, the amount of milk products they consume decreases, along with the amount of lactase their body produces. By the time they reach adulthood, their body makes so little lactase that they have difficulty digesting milk and other dairy products. The second most common form of intolerance is secondary lactose intolerance, which occurs when some external factor lowers the small intestine’s ability to produce lactase. These factors can include surgeries or illnesses, such as intestinal infection, celiac disease, bacterial overgrowth, and Crohn's disease [4]. The third type of lactose intolerance is called congenital lactase deficiency, in which an individual is intolerant from infancy [5].

When lactose-intolerant individuals consume products that contain the sugar, they can experience a variety of symptoms including diarrhea, stomach cramps, bloating, gas, nausea, and vomiting [4]. Based on a person’s symptoms, doctors can perform tests to confirm their intolerance [3]. The hydrogen breath test is conducted by measuring the amount of hydrogen in one’s breath after drinking a liquid with high lactose levels. If their breath contains a high amount of hydrogen, they are not fully digesting the lactose. The lactose intolerance test measures the amount of glucose in one’s blood two hours after drinking a liquid with high lactose levels. Since lactose breaks down into glucose, a low amount of glucose in their blood indicates that they have not properly digested all the lactose [3].

At this point, you must be wondering how lactose digestion occurs in the first place. The energy-containing compound lactose is a disaccharide sugar made up of two monosaccharides, glucose and galactose [1]. The corresponding enzyme lactase is produced by intestinal epithelial cells, which line the walls of the small intestine. These cells have little projections called microvilli that absorb nutrients that pass through the intestine. A group of microvilli is known as a brush border. Lactase works at brush borders to break down lactose into its simple sugars: glucose and galactose [6]. Lactase has a β-galactosidase site to carry out its enzymatic function [1]. This site binds lactose as a substrate (reactant) and releases glucose and galactose as products, which can be processed by humans to obtain energy.

Human expression of lactase is regulated by development throughout one’s lifetime [1]. Intestinal lactase production begins to increase during the third trimester, eventually reaching its peak at birth. After breastfeeding stops, lactase production starts to differ in babies with different gene expressions. Some infants experience some degree of lactase deficiency while other infants experience lactase persistence. When intestinal lactase production drops, infants may exhibit symptoms mentioned above. In normal infants, when lactose intake increases, the high concentration of lactase will carry out their function, resulting in small amounts of lactose entering the colon (large intestine). In contrast to these infants, lactose intolerant patients have relatively low concentrations of lactase, causing the majority of the ingested lactose to escape to the colon. In human bodies, some colonic microbes, such as Lactobacillus and Bifidobacterium, can also break down lactose. However, they eventually conduct fermentation to convert the products to lactate for their own use [9]. When colonic fermentation occurs as a result of lactase deficiency, the fast accumulation of fermentation products causes the symptoms described above and is also the basis of the hydrogen breath test [8, 9].

After geneticists noticed the phenotypic symptoms associated with lactose intolerance, they began to explore the genotypes involved that result in this particular phenotype [2]. To understand the variation in the degree of lactose tolerance among different populations, geneticists compared the DNA sequence of the gene that codes for lactase. Nonetheless, they did not find a consistent pattern until a breakthrough occurred in 2002. When a group of Finnish researchers analyzed not only genes encoding lactase but other genes in that region as well, he discovered a mutation in one of the possible regulatory sequences of the lactase gene. This mutated sequence was only present in the lactose tolerant population. Adults possessing this mutation can produce high levels of lactase, while people without this mutation can only produce relatively small amounts of lactase [2].

After scientists studied the DNA sequences involved in lactose intolerance, they discovered that the two main genes are the LCT gene and the MCM6 gene. The LCT gene, located on chromosome 2, provides instructions for making the lactase enzyme [6]. The MCM6 gene involved, also located on chromosome 2, contains the instructions to make an MCM complex, a group of proteins that function as helicases. Helicases are used to “unzip” DNA so that it can be duplicated or transcribed into proteins [7].

In infants, lactose intolerance is caused by mutations, or changes, in the LCT gene [5]. Mutations in this gene cause lactase to function improperly, hindering the infant’s ability to digest lactose. Lactose intolerance in adults is caused by decreased expression of the LCT gene. LCT gene expression is controlled by a regulatory sequence located on the MCM6 gene. The presence of mutations on the MCM6 gene determines one’s lactose tolerance in adulthood [5]. Scientists have recognized at least four variations that have to do with lactose intolerance [7]. To inherit lactose intolerance as an infant, both parents must have at least one copy of the mutated LCT gene, although they may not display this trait [5]. Congenital lactase deficiency is inherited in an autosomal recessive pattern. In other words, to be affected with this condition, the infant must contain two mutated versions of LCT. The ability to digest lactose as an adult is dependent on variations in the MCM6 gene. These mutations are passed on following an autosomal dominant pattern. The individual only needs one copy of the mutated MCM6 gene to have sustained lactose production [5].

Discovery of the lactose intolerance genes not only led to close analysis of their functions, but also drew the attention of evolutionists to study its origin. Since the original gene for lactose intolerance is present across a wide range of ethnic groups, it provides evidence that all humans were once lactose intolerant [2]. However, about 10,000 years ago, people began raising livestock and obtaining milk for nutrition in different locations of the world [9]. During the early phase of this change, people had to ferment milk to remove the lactose in it, which also removes 20 to 50 percent of its calories. Therefore, the small portion of the population that gained lactose tolerance by mutation some time during those 10,000 years possessed a great evolutionary advantage. Since those people could extract more energy from milk, they were more likely to survive natural disasters that could cause famine. In fact, the trait of lactose intolerance evolved independently at four different locations in the world, possibly providing explanation for the variation in genes encoding lactose tolerance [9].

Next time you complain that you can’t eat ice cream without taking a pill, remember that all of our ancestors were lactose intolerant. Ever since humans appeared on this planet several million years ago, the massive wheel of evolution for survival has not stopped turning. The nano-sized lactose’s seemingly prolonged story is but a piece of dust in the evolution of our planet, just like how miniscule humans stand in awe of the unimaginable force of nature.

References

[1] Forsgard, R. A. (2019). Lactose digestion in humans: Intestinal lactase appears to be constitutive whereas the colonic microbiome is adaptable. The American Journal of Clinical Nutrition, 110(2), 273-279. https://doi.org/10.1093/ajcn/nqz104

[2] Gajdos, Z. (2007, March 15). Got lactase? How (some of ) our bodies evolved to enjoy milk with cookies [Blog post]. Retrieved from http://sitn.hms.harvard.edu/flash/2007/issue28/

[3] Mayo Clinic Staff. (2020, April 7). Lactose intolerance - diagnosis & treatment. Retrieved from https://www.mayoclinic.org/diseases-conditions/lactose-intolerance/diagnosis-treatment/drc-20374238

[4] Mayo Clinic Staff. (2020, April 7). Lactose intolerance - symptoms & causes. Retrieved from https://www.mayoclinic.org/diseases-conditions/lactose-intolerance/symptoms-causes/syc-20374232

[5] National Institute of Health. (2020, May 26). Lactose intolerance. Retrieved from https://ghr.nlm.nih.gov/condition/lactose-intolerance

[6] National Institute of Health. (2020, May 26). LCT gene. Retrieved from https://ghr.nlm.nih.gov/gene/LCT#location

[7] National Institute of Health. (2020, May 26). MCM6 gene. Retrieved from https://ghr.nlm.nih.gov/gene/MCM6

[8] Rana, S. V., & Malik, A. (2014). Hydrogen breath tests in gastrointestinal diseases. Indian Journal of Clinical Biochemistry, 29(4), 398-405. https://doi.org/10.1007/s12291-014- 0426-4

[9] Smithsonian Magazine. (2009, April 7). Lactose tolerance and human evolution. Retrieved from https://www.smithsonianmag.com/arts-culture/lactose-tolerance-and-human-evolution-56187902/