FUT2 Genes and Your Health, HMO’s (2′-FL) Prebiotic Review

There is a prebiotic that might be more effective than my recommended prebiotic GOS (galactooligosaccharide) to help improve the probiotic diversity of your microbiome and your digestive issues. I coach many people that have FUT2 (galactoside 2-alpha-L-fucosyltransferase two) polymorphisms; therefore, they may have microbiome dysbiosis that is difficult to remedy. If you do not have FUT2 polymorphisms, you produce the prebiotic human milk oligosaccharide 2′-FL (2′-fucosyllactose) in your breast milk and histo-blood group antigens in your saliva, tears, gastric, intestinal fluids, and mucosa which enriches your microbiome diversity and helps you maintain proper digestive health. The company Glycom has finally released their prebiotic supplement Holigos for sale in the United States (they are currently reformulating it), so is it worth supplementing with 2’FL and will it improve your digestion?

All about 2′-FL

2′-FL is a prebiotic human milk oligosaccharide meaning it is a carbohydrate found in most human breast milk that feeds our microbiome. 2′-FL was isolated from breast milk by the researchers Kuhn and Montreuil, in the 1950s. I have written in the past about how certain bacteria including Bifidobacteria might have evolved preferences for the oligosaccharides in human breast milk so they can maintain a long-term symbiotic relationship with us. “Earlier, in 1926, Schönfeld had reported that the whey fraction of human milk contains a growth-promoting factor for Lactobacillus bifidus (later reclassified as Bifidobacterium bifidus). The chemical nature of the “bifidus factor” in human milk was unknown, but Kuhn and György hypothesized a connection between Moro’s and Tissier’s work on bacteria and Polonowski’s and Lespagnol’s work on “gynolactose”. In the end, they were able to confirm that the “bifidus factor” indeed consists of oligosaccharides” Human breast milk mainly contains the carbohydrate lactose like most milk, which is easily digested and metabolized into glucose to fuel the infant’s growing energy demand. Lactose is synthesized in human mammary glands within the Golgi apparatus of mammary epithelial cells. Our duodenum contains the enzyme lactase (it is embedded in the lining) which metabolizes the lactose we ingest. People with lactose intolerance produce less if any lactase and the lactose instead of being metabolized correctly in the duodenum passes through into the colon where it is fermented by bacteria and creates digestive discomfort including excessive gas, bloating, and diarrhea.^{1 2}

Human breast milk also contains indigestible soluble glycans like 2′-FL which act as fiber and feed the microbiome and keep it healthy. 2′-FL is the second abundant saccharide in breast milk, lactose being the first. However, 2′-FL is not present in the breast milk produced by all mothers, and differing concentration amounts vary during lactation periods and among mothers. “Although the expression of lactose requires the presence of an enzyme that is necessary for proper embryogenesis, growth, and development, that is not the case for the synthesis of fucosylated oligosaccharides such as 2′‐FL. The enzymes necessary for the synthesis of these structures are primary gene products that are not uniformly distributed amongst humans; therefore, milk glycans are secondary gene products that may or may not be present in milk depending on the genotype of the mother.” Synthesis of 2′-FL within the milk requires the fucosyltransferase 2 enzyme to metabolize some of the lactose in the mammary glands, which is encoded by the FUT2 gene. Some mothers have heterozygous or homozygous FUT2 polymorphisms which would cause a lack of production of the fucosyltransferase 2 enzyme needed to produce 2′-FL.^{3 4}

What is Fucosyltransferase 2 and What are the Implications of Having or Not Having a FUT2 Polymorphism?

Fucosyltransferase is an enzyme that transfers an L-fucose saccharide from GDP-fucose (guanosine diphosphate) to an acceptor substrate. So, for the production of 2′-FL, lactose combined with GDP-fucose metabolized by FUT2 (galactoside 2-alpha-L-fucosyltransferase two) produces 2′-FL. Like I mentioned above synthesis of 2′-FL depends on the number of enzymes that are encoded by the FUT2 gene and polymorphisms can lead to a reduction or absence of 2′-FL in breast milk. FUT2 is also responsible for the synthesis of the A, B, O, and H antigens found in tears, saliva, gastric, intestinal fluids, and on mucosal surfaces. The antigens act as an adherent site for microorganisms. However, having polymorphisms of FUT2 means more then if you produce 2′-FL in your breast milk. If you have a homozygous polymorphism in FUT2 you are in the histo-blood group “Lewis (non-secretor)” if you have heterozygous FUT2 polymorphisms you secrete but in lower amounts, and if you have no polymorphisms of the FUT2 gene you are in the histo-blood group “secretor.” Seventy to eighty percent of the population are secretors, and the rest have FUT2 polymorphisms and range from being partial secretors to non-secretor’s (Lewis). Jason Hooper wrote about secretors and non-secretors and their potential differences in his review of the Blood Type Diet. Secretors will test positive for the presences of α1‐2 fucosylated epitopes, such as 2′-FL in their breast milk if they are female. “Secretor” and “Lewis” histo‐blood groups are highly polymorphic, and their inheritance is believed to play an evolutionary role in increasing our chances of survival during differing epidemics (H. pylori dysbiosis, Norovirus, and Rotavirus to name a few).^{5 6 7 8}

There are positives and negatives associated with being either a secretor, partial secretor, and a non-secretor. However, based on the research it is better to be a secretor in most instances instead of being a non-secretor. First off, if you are a secretor, the proposed health benefits are numerous. Secretors are less likely to develop urinary tract infections caused by E. coli because of histo-blood group metabolites being eliminated through the body in urine reducing E. coli urinary tract virulence and colonization. Secretors are less likely to develop vaginal candidiasis (yeast infection) because of the secretion of histo-blood group antigens within the vaginal mucosa. Secretors are less likely to suffer from infections caused by the bacteria Haemophilus influenzae, Neisseria meningitidis, Pseudomonas aeruginosa, Vibrio cholerae, and Streptococcus pneumoniae. Secretors also have a lesser chance of developing opportunistic Campylobacter and enterotoxigenic E. coli dysbiosis and associated diarrhea. Secretors are also less likely to suffer from Mycobacterium avium paratuberculosis dysbiosis which I believe is the cause of ulcerative colitis and Crohn’s disease. Finally, secretors seem to have a protection against Mumps rubulavirus the virus that causes the mumps, because the binding of Mumps rubulavirus to host cell sialic acid receptors is reduced when the cell contains FUT2-dependent antigens.^{9 10 11
12 13}

Secretors have higher amounts of probiotic Bifidobacteria colonies within their colon, possibly from swallowing the histo-blood group antigens in their saliva and tears and the antigens being produced on the mucosal surface of the intestines which are Bifidobacterial growth factors. Furthermore, if your mother was a secretor, and you ingested an ample amount of 2′-FL during breastfeeding (being breastfed for months or years), you probably have abundant Bifidobacteria colonies comprising your colonic microbiome from both being able to express histo-blood group antigens in fluids and mucosal surfaces and ingesting 2′-FL in your mother’s breast milk. If you are a secretor, even if your child is a partial or non-secretor, breastfeeding still increases Bifidobacteria colonic colonies and is highly beneficial. Breastfeeding is still essential for your child’s physical and microbiome development even if you are a non-secretor. Your breast milk would contain greater concentrations of other important human milk oligosacharides, including, LNFP III, 3′-FL, and nonfucosylated human milk oligosaccharides such as lacto-N-tetraose (LNT), which still grow Bifidobacterial colonies and protect the infant from protozoan parasite colonization. I would talk to your child’s pediatrician about adding a little 2′-FL prebiotic to your child’s breast milk daily if you are a non-secretor. Finally, I would recommend talking to your child’s pediatrician about adding 2′-FL to your homemade infant formula to improve the microbiome of your children if you are unable to breastfeed.^{14 15}

Secretors have a less diverse microbiome at the phylum, class, and order level, but had a more structured diverse microbiome at the family and genus level having more particular organisms (hopefully probiotic organisms) making up their microbiome. If you are a secretor and you have an A blood type, you might have the most diverse microbiome of all the possible combinations. Secretors were found to have a greater concentration of the probiotic bacterial genuses Barnesiella, Lactobacillus, Robinsoniella, Ruminococcus (strain-specific), and the opportunistic bacterial genuses Odoribacter, Bacteroides, and Helicobacter. Partial secretors might have a reduced chance of developing arthritic conditions. Finally, the following is a relevant analysis from a recent FUT2 study that breaks down the importance of 2′-FL ingestion and being a secretor. “Host-associated microbial communities can be viewed as a complex and plastic phenotype influenced by numerous factors including host genetics, initial community initiation (mode of delivery), community disturbances (antibiotics) and diet. Glycans (including 2′-FL) represent a major part of the mucosa acting as attachment sites for the microbial community and also as essential nutrient sources. Furthermore, genes responsible for glycan synthesis appear essential for host-bacteria homeostasis as their expression is directly triggered by the resident microbial communities. Glycan liberation through the microbial community is a highly collaborative process that can influence the colonization success of commensals and pathogens. Liberated fucose seems to represent a danger response of intestinal epithelial cells to buffer disturbances in microbial communities during infection, through a modulation of quorum sensing and virulence mechanisms, and thus appears to represent a direct link between the host and its resident communities.“^{16 17}

Early studies showed there was a link between FUT2 polymorphisms (mainly rs601338), H. pylori dysbiosis, and vitamin B-12 altered metabolism. However, newer studies have demonstrated the alteration of vitamin B-12 altered metabolism is independent of H. pylori colonization. Haptocorrin (transcobalamin-I), is a glycoprotein produced by our salivary glands when we consume food. Haptocorrin binds strongly to vitamin B-12 we ingest to protect it from the low pH environment of the stomach. Once the complex has traveled to the higher pH duodenum, pancreatic proteases degrade haptocorrin, releasing free cobalamin, which binds to intrinsic factor for absorption by ileal enterocytes. Transcobalamin-II (is not glycolated like haptocorrin, therefore is not dependent on FUT2) binds free cobalamin once it has been taken up by enterocytes of the terminal ileum and enters circulation to become cellularly available. Haptocorrin binds to approximately 80% of serum B-12, rendering it unavailable for cellular delivery by transcobalamin-II. These carrier proteins carry significantly different quantities of vitamin B-12 in blood and have different biological properties. Transcobalamin-II delivers vitamin B-12 to all of our cells, while vitamin B-12 carried by haptocorrin is ultimately returned to the liver to be recycled and available when needed. The connection between secretor and B-12 levels are consistent with FUT2 and its fucosylation function on B-12 carriers. Therefore, FUT2 polymorphisms affect the recycling of B-12 and non-secretors may have falsely elevated B-12 serum tests. Non-secretors might be deficient in vitamin B-12 if they show symptoms of pernicious anemia or are suffering from H. pylori dysbiosis, even if they have standard B-12 serum test results.^{18 19}

Non-secretors might also have a lower amount of specific amino acid biosynthesis within the gut. “A broad-based decrease in amino-acid biosynthesis was observed, including lower abundances of lysine, valine, leucine, isoleucine, phenylalanine, tyrosine, and tryptophan biosynthesis pathways. These data suggest that FUT2 gene polymorphism acted in a haploinsufficient manner to perturb metabolic pathways such as amino-acid biosynthesis encoded by the gut microbiome at the mucosal interface.” If you are a non-secretor, you might want to make sure that your diet is rich in foods that contain these amino acids, depending on your need. Ingestion of a 2′-FL might improve the microbiome to facilitate proper amino acid biosynthesis. A reduction in the absorption of lysine, for example, might cause a lysine deficiency and may lead to chronic Herpesviridae reactivation or worsen it and reduce the utilization of the active form of vitamin B6, pyridoxal phosphate. A reduction in the amino acid L-tyrosine might reduce catecholamine production (dopamine, epinephrine, norepinephrine), leading to depression, and thyroid function (thyroid hormones require tyrosine) leading to the development or worsening of hypothyroidism. Finally, a reduction of tryptophan might reduce serotonin and melatonin production, lead to mood destabilization, constipation, and poor sleep.^{20 21 22 23}

However, there are increased risk of some health issues and chances of developing specific dysbiosis associated with being a secretor, being a secretor is not all positive. Secretors are more likely to develop upper gut H. pylori dysbiosis because to colonize H. pylori uses histo-blood group antigen secretions to be able to adhere and colonize the digestive tract. 2-FL ingested or in supplemental form could be a growth factor for H. pylori dysbiosis, especially if a person is suffering from gastroparesis and the H. pylori has enough time to process it. Norovirus and Rotavirus (being a non-secretor has a lower risk associated with getting ill from Rotavirus infection than being vaccinated) caused gastrointestinal illness. Histo-blood group antigen secretions are binding ligands and receptors for the Norovirus, and other viruses in its family, Caliciviruses, and Rotavirus to attach themselves and proliferate. Secretors are more likely to suffer from partial secretors, may have an increased susceptibility to Neisseria gonorrhoeae dysbiosis (gonorrhea) as well. Partial secretors were also found to have an increased risk of biliary Candida, E. coli, and Streptococcus, dysbiosis causing them more prone to developing primary sclerosing cholangitis. Finally, people with FUT2 polymorphisms (especially those of the histo-blood group Lewis, non-secretor) and if they are blood type B are more likely to suffer from pancreatitis, have an increased risk of pancreatic cancer, and have elevated serum lipase levels when suffering from those health issues.^{24 25 26 27 28}

What Can You Do to Improve and Protect Your Health If You Have FUT2 Polymorphisms?

Well, good news for you there is a way to improve your microbiome if you have FUT2 polymorphisms, 2′-FL HMO products are available for purchase to improve your digestive health. I have known quite a few people on Facebook groups with FUT2 polymorphisms to react positively to the supplement even those who are suffering from chronic digestive issues. No prebiotic is perfect, for example, if you are suffering from severe H. pylori, Odoribacter, or Bacteroides dysbiosis you might not want to use 2′-FL or start with a minimal amount, 1/4 of a satchel mixed with a glass of filtered water at breakfast daily. In addition, if you believe you are suffering from acute Norovirus or Rotavirus gastrointestinal illnesses, you would also not want to supplement with the prebiotic for a few weeks after your recovery. All that being said, consuming 2′-FL if you have FUT2 polymorphisms might reduce colonies of Haemophilus influenzae, Pseudomonas aeruginosa, Vibrio cholerae, Mycobacterium avium paratuberculosis, Campylobacter, enterotoxigenic E. coli, and Streptococcus pneumoniae, so anyone dealing with these as the cause of your dysbiosis might find relief from taking the prebiotic.

Recommended 2′-FL Prebiotic

Layer Origin HMO

Supplement Recommendations: For most people, I recommend you start with one half of a satchel or one satchel mixed well in a glass of filtered water at breakfast daily to test how you react to the prebiotic. Many people reported that taking it with a meal helps prevent nausea that some people got from taking the prebiotic on an empty stomach. You can increase the dosage as needed daily as long as the prebiotic does not worsen your symptoms, like increased bloating and flatulence. I would recommend that you probably do not ingest more than two satchel’s daily because taking too much prebiotics can sometimes worsen or cause digestive issues as well by overfeeding the microbiome.