Lactose Intolerance
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INTRODUCTION
Ever wondered why many of us are lactose intolerant? In this article, we will look into the several reasons why our body may not be able to produce enough lactase, i.e. the different types of lactose intolerance, why the inability of digesting lactose can lead to many symptoms such as bloating, diarrhea and cramps, and the prevalence of lactose intolerance around the world.
LACTOSE INTOLERANCE
Lactose intolerance is a common digestive problem where the body is unable to break down lactose, the main carbohydrate found in milk and dairy products. When lactose enters the digestive tract, it is broken down into galactose and glucose in the small intestine by lactase (See Fig. 1) [1] [2].
Fig. 1 Structure of Lactose, a disaccharide made of Galactose and Glucose
Image taken from Chikode, Prashant, et al. “Determination of Diffusion Coefficient of Lactose Solution.” Journal of Holography and Speckle, vol. 4, no. 1-7, June 2007, www.researchgate.net/publication/257734427_Determination_of_Diffusion_Coefficient_of_Lactose_Solution.
Without sufficient lactase, lactose will move through your gut undigested which can cause several digestive symptoms (in detail later on in Symptoms) [3].
Note that lactase is an enzyme that is naturally produced by the body from birth (lactose intolerance usually emerges after early childhood). The lactase is encoded by the gene LCT, located on chromosome 2 and encodes an mRNA transcript of 6274nt (See Fig. 2). It has two active sites: Glu1273 and Glu1749, which help break down the lactose [wiki].
Fig. 2 LCT gene
Image taken from Mulcare C. Natural selection, maths and milk. Plus Magazine. 2008
Looking into the prevalence of lactose intolerance in recent populations around the world, we
can see that this condition is most predominant amongst populations of countries in Asia, South America, Africa, the Middle East and Greenland (See Fig. 3). There are many research studies have looked into why Northern Europeans typically have a higher lactose tolerance. One study (that argued against in situ milk consumption as a factor that causes lactose tolerance) concluded that it was the result of the immigration of people representing the so-called Corded Ware Culture, an early culture representing agricultural development in Europe - it is believed that they introduced the gene variant that codes for lactase that is able to break down lactose during adulthood [4]. There are many studies out there that argue the association of lactose tolerance (lactase persistence) with milk consumption after the suckling period [5]; however, it is not necessarily the case. In the next section, we will look into Lactase Persistence.
In total, approximately 75% of the world’s population is lactose intolerant [3].
Fig. 3 Worldwide prevalence of lactose intolerance in recent populations
Image credit: Food Intolerance Network
LACTASE PERSISTENCE
There are two distinct phenotypes - ‘lactase persistent’ (derived phenotype) and ‘lactase non persistent’ (hypolactasia, lactose intolerance), which are genetically programmed. In many studies, the lactase persistant phenotype is found to involve high mRNA expression and high lactase activity, which leading to the ability to digest lactose. On the other hand, lactase nonpersistent phenotype involves low mRNA expression and low lactase activity [6]. Additionally to note, there are two distinct phenotypes of hypolactasia: Phenotype I (reduced synthesis of precursor LPH) and phenotype II (ample precursor synthesis, but reduced conversion of the protein to its mature molecular form) [7].
Lactose intolerance (Hypolactasia) is an autosomal recessive condition, which means that for a person to be affected, they must inherit two copies of a low lactase-activity allele from their parents [5]. If an individual inherits one allele that is high activity, then they will not be affected - this is due to the fact that half levels of lactase activity are higher than the threshold level, showing significant digestion of lactose [8]. There are studies looking into cis-acting transcriptional silence of the lactase gene which can lead to a hypolactasia phenotype (cis regulatory elements are regions of non-coding DNA that can regulate transcription of the genes close to it) [5]. Moreover, It was found that only eight cases were found where the parents of a child with lactase persistence were both hypolactasic. Following the previous section Lactose Intolerance, there have been no evidence discovered for adaptive alteration of lactase expression within an individual in response to changes in lactose consumption levels [8].
So far, scientists have discovered approximately six mutations (SNPs, single-nucleotide polymorphisms) associated with lactase expression [9]. They are all located in the region of the gene MCM6 upstream of LCT - which is in the enhancer region for the transcription of LCT [10]. The first SNP identified to be associated with lactase persistence is C/T*-13910 [11]. C means ancestral allele and T is the derived allele (associated with lactase persistence). The other identified alleles or gene variants associated with lactase persistence are G*/A-22018, G/C*-14010, C/G*-13907, and T/G*-13915 [12] [13]; the rarer ones are G/A*14107 in the Xhosa and the Fulani (from Mali) [14] [9]; the C/T* 13906 in the Fulani (from Mali) [9]. All these variants are spread throughout the world.
Why is lactase persistence so common within European populations? This is due to the high frequency of the mutation C/T*13910 [7]; on the other hand, the mutation is low frequency in other populations of the world. The T*13910 is a more powerful enhancer than C-13910, hence this mutation is believed to cause these differences in lactase expression, but there is not enough evidence to prove a causal link yet between T*13910 and lactase persistence [5]. Moreover, in one study, it was found that the lactase gene is highly expressed when G-22018 is combined with T-13910 [5].
In one study, an association between a certain single nucleotide polymorphism (C>T-13910 and G>A-22018) with lactose intolerance in a northeastern Brazilian population was discovered. In Indo-Europe, it was found that the rs4982235 SNP (or -13910C>T) is also associated with lactase deficiency, which may lead to the condition becoming more susceptible to lactose intolerance [15]. Scientists still don’t have a detailed picture of how these variants can regulate LCT expression - all the studies show correlations, rather than casuations. In the future, more variants may be discovered.
PATHOPHYSIOLOGY OF LACTOSE INTOLERANCE
As we have mentioned before, lactose must be hydrolysed into its monosaccharides galactose and lactose in order to be absorbed by the small intestinal mucosa. Therefore, if there is a deficiency of intestinal lactase, then many of the lactose will remain undigested. The osmotic load of the unabsorbed lactose causes secretion of fluid and electrolytes until the osmotic equilibrium is reached. The intestine will in turn dilate due to osmosis, and this will cause an acceleration of small intestinal transit (speed at which the food is pushed through) - increasing the degree of maldigestion. The free lactose in the large intestine is fermented by colonic bacteria, which produces short-chain fatty acids and hydrogen gas. This overall increase in fecal water, intestinal transit and generated hydrogen gas are the factors that cause a variety of gastrointestinal symptoms associated with lactose intolerance (See Fig. 3) [15].
Fig. 3 Lactose Intolerance
Image taken from https://ib.bioninja.com.au/standard-level/topic-2-molecular-biology/25-enzymes/lactose-intolerance.html
Therefore, lactose intolerance causes symptoms such as diarrhea, dehydration, bloating, abdominal pain, nausea and vomiting [2].
DIFFERENT TYPES OF LACTOSE INTOLERANCE
Cross & Terril identified that there are three kinds of lactose intolerance; primary, secondary and congenital. Primary intolerance is due to being weaned off dairy from a child into adulthood - it is an inherited genetic fault that runs in families which causes your lactase production to decrease as your diet becomes less reliant on milk and dairy products [16]; Secondary intolerance is due to an illness that damages the intestinal brush border (the damage reduces lactase secretion) - examples include Diabetic Gastropathy, Carcinoid syndrome, Gastrinoma and Kwashiorkor; Congenital Lactose Intolerance is a rare autosomal recessive disorder, so the affected individual is unable to produce lactase.
DIAGNOSIS
Disclaimer: This information is only for educational purposes. If seeking medical advice, please go to your physician or local health provider.
There are two common ways to confirm a diagnosis of lactose intolerance, they are the Hydrogen Breath Test and the Lactose Tolerance Test [17].
Hydrogen breath Test
After drinking a liquid that contains high levels of lactose, the doctor measures the amount of hydrogen in your breath at regular intervals. If there is a large amount of hydrogen, then it means that not all of the lactose is digested (See Fig. 5) [17].
Fig. 5 Hydrogen Breath Test
Image taken from https://www.uofmhealth.org/conditions-treatments/digestive-and-liver-health/hydrogen-breath-test
Lactose tolerance Test
Two hours after drinking a liquid that contains high levels of lactose, undergo a blood test and measure blood glucose levels. If the glucose level doesn’t rise (or doesn’t rise as much as expected), then it means that not all of the lactose has been digested [17].
TREATMENT
If you are lactose intolerant, the best way to treat it is to simply avoid dairy products or any food containing lactose. There are also probiotics that you can take which can help you digest lactose. These probiotics contain living organisms that can help maintain a healthy digestive tract - they are usually either found in yoghurts or taken as supplements in capsule form (See Fig. 6) [17].
Fig. 6 Probiotic supplements that aid digestion of lactose
Image taken from Foodtown
https://www.foodtown.com/shopping/health_and_personal_care/medicine_cabinet/digestion_and_nausea/probiotics/schiff_lactose_intolerance_therapy_32_caplets/p/544082
BIBLIOGRAPHY
[1] NHS Choices, NHS, www.nhs.uk/conditions/lactose-intolerance/.
[2] Today, Med. LACTOSE INTOLERANCE : Pathophysiology,Causes,Signs and Symptoms,Treatment. YouTube, Med Today, 24 Feb. 2020, www.youtube.com/watch?v=vjTRAuKbcq0.
[3] West, Helen. “Lactose Intolerance 101 - Causes, Symptoms and Treatment.” Healthline, Healthline Media, 24 June 2017, www.healthline.com/nutrition/lactose-intolerance-101#TOC_TITLE_HDR_2.
[4] Arjamaa, Olli, et al. High Lactose Tolerance in North Europeans: A Result of Migration, Not In Situ Milk Consumption, vol. 55, no. 2, 2012. Spring 2012, www.researchgate.net/publication/225073065_High_Lactose_Tolerance_in_North_Europeans_A_Result_of_Migration_Not_In_Situ_Milk_Consumption.
[5] Troelsen, Jesper T. “Adult-type hypolactasia and regulation of lactase expression.” Biochimica et biophysica acta vol. 1723,1-3 (2005): 19-32. doi:10.1016/j.bbagen.2005.02.003
Swallow D M. annual Review of Genetics. Genetics of Lactase Persistence and Lactose Intolerance: Annual Reviews [internet] 2003
[6] Harvey CB, Wang Y, Hughes LA, Swallow DM, Thurrell WP, Sams VR, Barton R, Lanzon-Miller S, Sarner M. Studies on the expression of intestinal lactase in different individuals. Gut. 1995 Jan;36(1):28-33. doi: 10.1136/gut.36.1.28. PMID: 7890232; PMCID: PMC1382348.
[7] Lloyd, M et al. “Regulation of intestinal lactase in adult hypolactasia.” The Journal of clinical investigation vol. 89,2 (1992): 524-9. doi:10.1172/JCI115616
[8] Swallow, Dallas M. “Genetics of lactase persistence and lactose intolerance.” Annual review of genetics vol. 37 (2003): 197-219. doi:10.1146/annurev.genet.37.110801.143820
[9] Lokki, A Inkeri et al. “Lactase persistence genotypes and malaria susceptibility in Fulani of Mali.” Malaria journal vol. 10 9. 14 Jan. 2011, doi:10.1186/1475-2875-10-9
[10] Jensen, Tine G K et al. “The -14010*C variant associated with lactase persistence is located between an Oct-1 and HNF1α binding site and increases lactase promoter activity.” Human genetics vol. 130,4 (2011): 483-93. doi:10.1007/s00439-011-0966-0
[11] Enattah, Nabil Sabri et al. “Identification of a variant associated with adult-type hypolactasia.” Nature genetics vol. 30,2 (2002): 233-7. doi:10.1038/ng826
[12] Tishkoff, Sarah A et al. “Convergent adaptation of human lactase persistence in Africa and Europe.” Nature genetics vol. 39,1 (2007): 31-40. doi:10.1038/ng1946
[13] Imtiaz, F et al. “The T/G 13915 variant upstream of the lactase gene (LCT) is the founder allele of lactase persistence in an urban Saudi population.” Journal of medical genetics vol. 44,10 (2007): e89. doi:10.1136/jmg.2007.051631
[14] Torniainen, Suvi et al. “Screening of variants for lactase persistence/non-persistence in populations from South Africa and Ghana.” BMC genetics vol. 10 31. 5 Jul. 2009, doi:10.1186/1471-2156-10-31
[15] Roy, Praveen K, et al. “What Is the Pathophysiology of Lactose Intolerance?” Edited by Burt Cagir, Latest Medical News, Clinical Trials, Guidelines - Today on Medscape, 4 Dec. 2019, www.medscape.com/answers/187249-159227/what-is-the-pathophysiology-of-lactose-intolerance.
[16] NHS Choices, NHS, www.nhs.uk/conditions/lactose-intolerance/causes/#:~:text=Primary%20lactase%20deficiency%20is%20the,on%20milk%20and%20dairy%20products.
[17] “Lactose Intolerance.” Mayo Clinic, Mayo Foundation for Medical Education and Research, 7 Apr. 2020, www.mayoclinic.org/diseases-conditions/lactose-intolerance/diagnosis-treatment/drc-20374238.
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