How a Milk-Digesting Gene Alters Probiotic & Protein Needs (MCM6)

MCM6 Gene: The Basics

About 70% of adults worldwide have lactose intolerance, with huge differences among different ethnicities [R].

MCM6 gene variants are the main cause. MCM6 works as a proxy for the lactase (LCT) gene, controlling its activity [R, R].

Several MCM6 SNPs have been associated with lactose intolerance, but the best-researched one is rs4988235. This SNP has also been linked to obesity, gut microbiome diversity, and weight loss on different diets. 

A Good Side to Lactose Intolerance?

Nobody wants to be lactose intolerant. Given the choice, most people would prefer to be able to digest dairy without discomfort. And lactase persistence–this uniquely human ability to keep making the lactase enzyme into old age–is typically seen as an evolutionary advantage. 

Since rare MCM6 variations help people digest large amounts of lactose, they’re the “good” type… right? 

Science tells a different story, hinting at the dark side of lactase persistence. It turns out that the same variations that help people digest milk might make them more prone to obesity. Meanwhile, lactose intolerance seems to be the genetic trade-off for being slimmer.

In a study of 940 people at risk of heart disease, those with the lactose-intolerant genotype (rs4988235 GG) had lower BMI and less belly fat. Their lactose-digesting counterparts (AG and AA genotypes) were at a higher risk of obesity–but only if they consumed over 8g of lactose per day [R].

Further studies replicated the link between rare MCM6 rs4988235 variations and increased belly fat, total fat, and weight [R, R, R]. 

Rare variants of rs4988235 that help people digest lactose might also make them more prone to obesity, especially if their lactose intake is moderately high. 

Focus on the Gut Microbiome

Researchers recently revealed an association between the more common rs4988235 genotype (GG) and an abundance of Bifidobacteria in the gut microbiome. Bifidobacterium strains are commonly used as probiotics [R]. 

A large analysis confirmed this link. They didn’t find any difference in dairy intake among the groups. But, they came to a new discovery: people with the lactose-intolerant genotype (GG) had more gut Bifidobacteria if they consumed larger amounts of milk (a couple of cups per day) [R].  

Another small study of 51 people gives us similar clues. The participants first went through a 2-week dairy-avoidance phase, followed by 2 weeks of lactose reintroduction. During the second phase, they had to ingest 25 g of lactose twice a day. At the end of the trial, only lactose-intolerant individuals had increased Bifidobacteria counts [R].

Prebiotics feed our good bacteria and most fall under the category of fiber and complex carbohydrates. Lactose seems an unlikely candidate. 

Yet scientists think that lactose can act as a prebiotic, but only in people who are lactose intolerant. This might be because lactose-digesters break down most of the lactose they consume before it reaches the colon where probiotic bacteria reside [R].  

People with the lactose-intolerant rs4988235 genotype who drink milk every day seem to have more gut Bifidobacteria.

Gut Bacteria May Determine Weight Loss on a High-Protein Diet

One study of 583 people investigated weight loss diets using the intolerance-linked ‘G’ allele of rs4988235 as a genetic marker for gut Bifidobacterium abundance [R].

According to them, overweight and obese G-allele carriers may lose more weight by eating a low-calorie, high-protein diet [R]

Protein intake may change how gut bacteria affect weight. Earlier studies reported that weight loss with high-protein diets improved gut microbial gene richness, colonic health, and gut microbiota composition in obese people [R].

Once again, it’s not just about one probiotic strain, it’s more about the gut microbiome as a whole. 

Gut microbial gene richness looks at the total number of genetically distinct probiotics in a person’s gut, which is emerging as a true measure of microbiome diversity. People with low gut microbial gene richness appear to be more prone to poor metabolism and low-grade inflammation, according to limited human data [R]. 

In animals, boosting gut Bifidobacteria helps reduce belly fat and normalize inflammation and insulin resistance, two conditions that are often connected to type 2 diabetes and obesity  [R, R, R]. 

Bifidobacteria probiotics may specifically help people lose dangerous belly fat. In a small clinical trial of obese people, a Bifidobacterium strain (animalis ssp. lactis GCL2505) reduced belly fat but not total body weight [R]. 

Researchers believe that increased protein intake may boost the fat-loss action of Bifidobacteria in rs4988235 G-allele carriers while supporting overall gut health. However, we are still lacking a clear mechanistic explanation.  

Overweight and obese people with high-Bifidobacteria, lactose-intolerant variants may lose more weight on a low-calorie, high-protein diet.

You can see your genotypes for MCM6 in the table below. However, keep in mind that these associations are based on studies from certain ethnic populations—so you should interpret your results with caution if you are not descended from one of these specific groups!

SNP Summary and Table

MCM6 rs4988235 

• ‘AA’ = Can digest milk, but more prone to obesity with higher lactose intake. Less diverse microbiome. Low-protein diets may be better for weight loss.
• ‘GA’ = Slight lactose intolerance is possible; may be more prone to obesity with higher lactose intake. High-protein diets enhance weight loss.  
• ‘GG’ = Probably lactose intolerant but less likely to be obese. High-protein diets enhance weight loss. 
• The ‘A’ allele is more common in people of European descent  
• ‘GG’ is more common in people of Asian and African descent

MCM6 & Milk 

To learn more about other MCM6 SNPs that play a role in lactose intolerance, check out this article.