Evolution of Lactase Persistence and Non-Persistence

Introduction

Lactose intolerance is the inability to digest lactose and is the most common intestinal malabsorption disorder. Lactose is a sugar that is often found in dairy products, and most mammals lose the ability to digest this sugar post weaning. On the other hand, those with lactase persistence are able to continue digesting lactose into their adulthood through the production of an enzyme called lactase. The production of this enzyme is an inheritable trait most commonly found amongst European populations and pastoralist communities.

Genetics

Figure 2. Bacteria that is commonly found in the small intestine. This image displays a specific metabolic interaction between the host and various species of bacteria.

Lactose intolerance is a genetic condition also referred to as ‘lactase non-persistence (LNP)’. This condition is the result of a decline in lactase production after weaning. Lactase is the enzyme that is responsible for the degradation of the sugar (lactose) found in milk and other dairy products into glucose and galactose. This decline is typically a normal trait in the developmental process of mammals into adulthood. Those with LNP will unfortunately suffer from side effects from incomplete digestion in the small intestine. These side effects include bloating, flatulence, diarrhea, and abdominal pain.

Those with lactase persistence (LP) have inherited the ability to produce lactase in adulthood through a T-mutation. The inheritable trait is then passed down as an autosomal dominant trait, noted as the lactase gene (LCT). Research shows that LP is heavily associated with single nucleotide polymorphisms (SNPs) that are located in the enhancer region which regulates lactase expression. This observation is most commonly found in European populations regarding the -13910T*-mutation. The LCT gene is found in the intron of the MCM6 gene, located upstream of the LCT gene. Among individuals of European descent, the A-allele of the SNP is associated with LP, while the G allele is associated with LNP. Since LP is observed to be a dominant trait, individuals with heterozygous alleles are observed to inherit the LP trait. Other than the -13910*T-mutation, other closely related mutations were also found to be associated with LP, however these were found commonly in populations in East Africa.

Studies have found that the -13910*T-mutation acts as a stimulus towards lactase production. Binding sites for intestinal transcription have also been found in the -13910 region, which further shows how this mutation is crucial to the regulation of lactase expression. In addition to this mutation, more recent studies have found that epigenetics have found a role in the regulation of lactase through DNA methylation. LNP haplotypes containing -13910*C alleles are found to store methylated cytosines with age. Overtime, this eventually silences the regulatory factors of LCT. This evidence explains that one’s genetic background allows for epigenetic changes that influence lactase production and expression overtime.

Lactose intolerance is heavily determined by genetic variations within the region of LCT. These variations ultimately control the production of lactase and whether or not the individual will develop LP or LNP into their adulthood.

Bacteria in the Small Intestine

Within the human gut microbiome, there was found to be a significant difference between those with LP and LNP. One of the main differences was the presence of the bacterial families of lactobacillaceae and lachnospiraceae. These two bacterial families contain species that are able to metabolize lactose; one ferments lactose into lactic acid, while the other is known to metabolize carbohydrates to produce acetate (respectively). Although found in all healthy gut microbiomes, it was observed that those without the LP gene who continued to consume lactose ended up with a higher proportion of this bacteria compared to those who consumed less. This has led to the conclusion that the increase of undigested lactose resulted in an increase of bacteria that are able to utilize this now abundant resource within the body. It was found that the species of bacteria within the lachnospiraceae that seemed the most abundant were the species: Blautia, Roseburia, and Coprococcus. The increase of these bacteria, especially blautia appeared to help regulate the effects of lactose intolerance (ie. reducing gas production and abdominal discomfort).

For individuals with LP, lactose is digested in the small intestine. However, for those with LNP, the small intestine lacks the proper lactase enzymes to complete this task, therefore, the undigested lactose then travels to the colon and meets the primary habitat for gut bacteria. Once reaching the colon, the undigested lactose is then fermented by bacteria. The fermentation process generates short-chain fatty acids (SCFAs): acetate, lactic acid, hydrogen. With an increase in lactic acid, the microbial environment may become more acidic which would lead to changes within the microbiome. This process is what primarily causes negative gastrointestinal symptoms.

Studies have shown a lack of very significant differences regarding the small intestine microbiome of those with and without LP. By analyzing the mucosal lining of the small intestine, the microbial composition of this lining is observed to be different from the composition of the luminal microbiome. The main difference between the two is that the luminal microbiota come in direct contact with what is entering the intestine. The luminal microbiota is what is more crucial to digesting foods. Bacterial overgrowth within parts of the small intestine is noted as a result of improper digestion due to gastrointestinal disorders like LNP.

It has been difficult to distinctly categorize the microbiome of the small intestine. From what scientists have been able to uncover it is seen the small intestine typically contains a lower concentration of bacteria compared to the colon while it is important to nutrient absorption.

Epigenetics and Context

Figure 1. Map of distribution of LP within the old world. (data from , image from )

For infant humans along with other mammals, lactase is essential for nutrition, growth, and development as it is a key component within a mother’s breast milk. After weaning, most mammals’ lactase activity will naturally decline, which eventually leads to LNP. However, some humans have grown to retain the ability to properly digest lactose into their adulthood. The development of this trait has more of an epigenetic background, compared to random mutation.

Due to certain cultures and practices, some populations have developed a habit or even reliance on consuming milk and dairy products. For example, a large population of Europeans, especially northern Europeans have shown to be LP due to their long history of pastoralism. We also have seen dairy very often used in their cuisines. It has also been revealed that regions with lower sunlight exposure have populations that may be more dependent on lactose to aid in calcium absorption. Additionally, due to arid climates, milk served as a highly beneficial source of hydration. Overall, the dependencies on lactose have come together as an example of convergent evolution due to the many different populations in different regions developing this common genetic trait.

If you look at modern cuisine amongst different cultures, there are some clear points that demonstrate an epigenetic cause for LP. Asians also often lack LP, however their cuisine does not often contain much dairy, nor were they historically dairy farmers (there are specific regions in Asia that appear to have a higher frequency of LP, however the statistics still remain low across the region). In Africa, the majority of the population has not grown to develop LP, however in Beni Amir (a region in Sudan) over 50% of the population was noted to develop the trait, compared to much less frequencies in surrounding regions. It is also known that this specific region has a history of pastoralism.

Conclusion

Drawing from research and historical context, we can better understand the development of lactose intolerance (lactase non-persistence; LNP) and lactase persistance (LP).

References

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Edited by Bettirose Epstein, student of Joan Slonczewski for BIOL 116, 2024, Kenyon College.