August 2018 Issue
Shaping the Gut Microbiota
By Carrie Dennett, MPH, RDN, CD
Vol. 20, No. 8, P. 16
Do genes or the environment matter more in influencing one's internal ecosystem?
The human gut microbiota—which includes about 10 times more cells than are in the entire human body—is an important factor in human health, playing critical roles in metabolism, immunity, development, and even human behavior.1 One reason is that the gut microbiome, the collective DNA of our gut microbes, is in effect our second genome, significantly expanding our physiological potential.2
The composition of the gut microbiota—which includes thousands of species of bacteria, viruses, fungi, and protozoa—varies from person to person and shifts to some degree over time. Diversity and abundance of various species in gut microbial communities can vary widely across populations, with dramatic contrasts observed in people living on different continents.3 Many differences appear to be driven by varying diets, lifestyles, and other environmental exposure, but genetic ancestry also may shape the microbiota.
In theory, the human genome could evolve to promote a microbiome that contributes to host health—it would certainly be in its best interest.2,4 The original hypothesis was that our genes drive our microbiota, in part because the microbiota exhibits some stability over time,4-6 but newer research suggests that diet and environment may play the larger roles in shaping our gut microbiome across the lifespan. So which is ultimately more important, nature or nurture?
The Heritability Question
One open question is how much of our gut microbiota is "heritable." Heritability is the proportion of variance in phenotype—a set of observable traits—explained by host genetics rather than environmental factors. For example, height is highly heritable, so variation in height across a population has a strong genetic basis.2-7 Researchers have identified several bacterial taxa (classifications based on genus, family, class, order, phylum, etc) that appear heritable, as well as some associations of varying strengths between single nucleotide polymorphisms (SNPs)—the most common type of genetic variation—in the human host and individual bacterial taxa. The lingering question was what proportion of our microbiota these heritable taxa make up.
As recently as a decade ago, the heritability of a phenotype was assessed by studying families and making assumptions about the genetic similarities. In the wake of the mapping of the human genome, researchers can now measure heritability with genomewide association studies (GWAS), but they're finding there's a "heritability gap." In other words, the genetic variants identified through GWAS don't completely explain the heritability of complex traits.7 And the gut microbiota is certainly complex. Recent GWAS suggest that environmental factors explain 10% to 20% of microbiome variance, with genetics explaining 10%.8 It's unclear what factors explain the microbiome variance that can't be accounted for by genes or environment.7,8
Family members tend to have more similar microbiotas than unrelated individuals. When family members share a household, these similarities are often attributed to shared environmental influences, such as dietary preference.9,10 However, related individuals also share DNA.
Genetics aside, we acquire microbes via two types of transmission. Vertical transmission, when microbes pass directly from parents to offspring, tends to happen early in life, and these primary colonizers easily establish themselves. Our microbiota is largely shaped during infancy, starting with birth, and it may be that the microbial species that establish themselves during this pivotal time are the ones that persist.2,11 Horizontal transmission, the spread of microbes via environmental exposure and social interaction, including cohabitation, happens later in life. These microbes have a harder time integrating themselves permanently into the already-stable gut microbial community.12
From Genome to Microbiome
A number of twin studies have looked at whether monozygotic (identical) twins have microbiotas that are more similar than those of dizygotic (fraternal) twins. Identical twins share 100% of their DNA, and fraternal twins share 50%, on average, yet they share the same mother and environment.2
Early twin studies did find that identical twin pairs had more similar microbiomes than fraternal twins, strongly suggesting a genetic component, but these studies had some major limitations, including very small population sizes—20 to 30 twin pairs—and less-advanced techniques than are currently available.2 Later studies, from six to 10 years ago, had small sample sizes but better techniques. They also found a genetic effect on the overall gut microbiome, albeit not enough to reach statistical significance, seeing few differences between identical and fraternal twins.2,13
Then, a 2014 twin study looked at samples from 416 twin pairs from the UK Twin Registry, focusing on dominant bacterial families.14 It confirmed previous studies, finding that identical twin microbiomes were more similar overall than those of fraternal twins, but with the increased sample size the difference reached statistical significance and allowed for heritability for many specific taxa to be calculated.2 The same authors followed up with a 2016 study of 1,126 twin pairs.5
This was shaken up a bit when a study published in March in Nature found that host genetics have only a minor role in determining the makeup of our gut microbiota.13 The study looked at more than 1,000 healthy Israeli individuals from several distinct ancestral origins—primarily Ashkenazi but also including North African, Middle Eastern, Shephardi, and Yemenite—but with similar lifestyles. Blood samples provided information on genotypes and phenotypes, while stool samples provided information on the metagenome—the collective genome of microbes from an environmental sample, in this case the stool.13
The researchers found no significant associations between the gut microbiota and genetic ancestry or SNPs. What they did find was significant microbial similarity among genetically unrelated individuals who share a household. As for relatives who have never shared a household? No significant similarities. Whether individuals in the study were genetically related or not, it was past or present household sharing that partly determined composition of the gut microbiota.13 The authors also reanalyzed the most recent UK Twins data, finding that the percentage of the microbiome that's heritable is between 1.9% and 8.1%, significantly lower than other estimates.8,13
"Previous research has shown that some gut bacterial species are heritable," says Omer Weissbrod, PhD, one of the Nature study's lead authors and a postdoctoral fellow at Harvard University. "However, our analysis showed that such species form a small minority of the overall microbiome composition. We believe that research like ours will shift the focus back to the role of diet/lifestyle."
He says the most important take-home message is that we can potentially reshape our gut microbiome by changing our lifestyle and dietary habits. "In other words, our gut microbiome is not necessarily tied to our biological parents," he says. "Another important conclusion is that we can likely carry out microbiome transplant (a very effective treatment for C difficile infections) without worrying about genetic compatibility between a donor and a host."
A recent study of 127 participants from the Hutterite community found a genetic effect on specific bacterial taxa, but the environmental influence was much larger. The Hutterites are a religious group that has reduced genetic diversity because they're descended from a small number of colonizing ancestors. They also live on communal farms and prepare and eat meals together, limiting the dietary and environmental differences that could mask genetic effects on the microbiota.15
Likely Gene-Microbe Pairings
No matter what total number, it appears that heritability is lower in the microbiome than in other traits—such as height—and may not be distributed equally among taxa. Specifically, more heritability has been found among bacteria in the phylum Firmicutes than among Bacteroidetes.16
The UK twin study found the highest heritability within the Christensenellaceae family, which has greater abundance in lean twins and is associated with low serum triglyceride levels. It co-occurs with other heritable taxa, including the dominant methane-producing species, Methanobrevibacter smithii, also associated with leanness.2,14 The second most heritable taxon identified was the genus Turicibacter, an active member of the small intestinal microbiome. It appears to be a pathobiont,5 an organism that can activate the immune system and amplify any imbalances in the microbota (dysbiosis), promoting inflammation.7,17
There's a particularly strong link between the LCT gene and Bifidobacterium. The LCT gene codes for the enzyme lactase, which humans need to metabolize the disaccharide lactose in dairy foods. Genetic variants of LCT are directly related to an individual's "lactase persistence"—the ability to digest lactose after weaning and into adulthood. However, members of the genus Bifidobacterium also can metabolize lactose, and it's the preferred food for some strains.18 The abundance of bifidobacteria appears to be dependent on the interaction between genotype and intake of dairy products, which serves as evidence of interaction between diet and host genetics in regulating the composition of the microbiome19:
- Lactase persisters digest the lactose directly, so they have few bifidobacteria; there's no leftover lactose to feed them.
- Nonpersisters who still consume dairy products have more bifidobacteria because they have an ample food source.
- Individuals who don't consume dairy have low bifidobacteria levels regardless of whether they still produce lactase.2,5
Explanations of how the genome might shape the microbiome are scarce. The most commonly proposed mechanisms are genetically driven biochemical and physical factors such as levels of immunoglobulin A antibodies, gut pH, metabolism, concentrations of metabolites, and gut motility, all of which could affect the gut microbiota.7,12,20 For example, hormones in the brain influence bacteria in the gut,15 and some SNPs associated with Crohn's disease—including variants of the NOD2 gene—have been shown to affect both the immune system response and the gut microbiota.8,20 Simply being a carrier of the NOD2 variation is associated with higher abundance of Enterobacteriaceae, a bacterial family that includes a number of pathogens including E coli, Klebsiella, and Shigella.8
Should researchers be focusing less on matching diet to genotype and more on matching diet—and other environmental interventions—to microbial-driven phenotype? Weissbrod says yes, for two reasons. "First, we showed that our microbiome can reflect many clinically relevant phenotypes, like waist-hip ratio or fasting glucose, much better than our own genotypes. Second, the microbiome can reflect lifestyle-related factors like fitness, whereas our genome is determined from birth." The following are some of the most notable environmental factors affecting the gut microbiota.
Vaginal vs C-section Delivery
When comparing vaginally delivered infants and infants delivered via C-section, the gut microbiota of C-section infants had significantly less resemblance to their mothers' gut microbiotas, with a 41% match to species found in the mother's stool, compared with a 72% match for vaginally born infants. This difference starts to diminish between 4 and 12 months of age,1 although the initial microbiota will influence the microbiota composition later in life.21
Changes in diet can affect both the composition and function of the gut microbiota community.22
The microbiota of the breast-fed infant is rich in species found in the breast milk, including Bifidobacterium. The infant's gut microbiota starts to mature into a more complex, adultlike composition once breast-feeding is stopped.1,11 Breast milk is high in microbiota-accessible carbohydrates (MACs)—complex polysaccharides that are resistant to our digestive enzymes but are digestible by enzymes produced by gut microbes—and a postweaning diet that supports a healthy, diverse, gut microbial population will also be high in MACs while being low in saturated fat, which pathobionts thrive on.17,23,24
That said, a one-size-fits-all approach to dietary interventions for the microbiota is unlikely to be beneficial, says Genelle Healey, PhD, who researches the gut microbiota at the University of British Columbia. "Presently, it is very difficult to predict how a dietary intervention may affect an individual's gut microbiota and subsequent health, as it appears there is profound interindividual variability in dietary responsiveness," she says, adding that baseline gut microbiota and habitual dietary intake may influence how both microbiota and host respond to dietary changes.25
Antibiotic use in children, especially in early childhood, has become more widespread in the United States. It's estimated that children in the United States receive an average of three courses of antibiotic treatment before 2 years of age, roughly twice the amount prescribed to children in northern European countries.21
The effect on the gut microbiota depends on the antibiotic class, dose, and length of exposure, as well as the mode of action and the target bacteria.21
A very small 2015 study of three dichorionic triplet sets—one pair of monozygotic twins plus a fraternal sibling—found that host genetics appeared to play a role in the composition of an individual's gut microbiome at 1 month of age, unless antibiotics were administered, as was the case with two of the triplet sets. By 12 months of age, environmental factors had a larger role in gut microbiome composition for all three sets of infants, and the early antibiotic exposure appeared to no longer have a strong influence.26
A study of 48 wild baboons from two different social groups in Kenya found that an individual's social group and social network predicted the species found in its gut microbiota, even when other factors—such as diet, kinship, and shared environments—were taken into account.27
Interaction With the Environment
The hygiene hypothesis—that proper hygiene and cleanliness were associated with a lower risk of immune-mediated conditions and protection from infection—was recently reframed as "the old friends hypothesis," which emphasizes the benefit of exposure to nonpathogenic microorganisms in order to help develop the microbiome while still practicing basic hygiene. This may reduce the risk of immune-mediated diseases, such as asthma and allergies, while preventing spread of pathogens and the rise of antimicrobial resistance.28
In their book, The Good Gut: Taking Control of Your Weight, Your Mood, and Your Long-Term Health, Stanford researchers Justin and Erica Sonnenburg, PhDs, recommend being vigilant about handwashing during flu season, but not as much the rest of the year. Other tips? Get your hands dirty in an herbicide- and pesticide-free garden—and get (or at least pet) a dog.24 Pets collect beneficial microbes from outside, increasing our exposure.24,29
One reason that studying the impact of host genes on the gut microbiome is complicated is that the microbiome is strongly influenced by diet, environment, medications, and overall health status, which could mask any effects of the host's genetics.6,8,20 Discovering clinically relevant associations may be possible only in study populations with specific diseases, such as inflammatory bowel disease or rheumatoid arthritis, which have complex genetic features and are associated with a disrupted gut microbiota.6 That said, association isn't causation, and the microbiota's natural fluctuations due to diet and environment mean one individual's microbiota could look very different depending on when you look at it.30
"There is still a lot of research to be done to understand exactly how and why our lifestyle and diet affects our microbiome, and how our microbiome affects our health," Weissbrod says. "We are actively working on trying to figure this out."
Healey says these will be key factors in harnessing the gut microbiota as a target for personalized medicine and personalized nutrition, which has great potential in clinical practice. "Additional research that focuses on the factors involved in interindividual variability in gut microbiota and host response is needed before this can become a reality." In the future, she says, algorithms that can predict successful dietary interventions—which currently are being developed—may better help dietitians provide personalized advice that ultimately improves health.31-33
— Carrie Dennett, MPH, RDN, CD, is the nutrition columnist for The Seattle Times and speaks frequently on nutrition-related topics. She also provides nutrition counseling via the Menu for Change program in Seattle.
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