Gut microbiome are heritable

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Our gut microbiome – the ever-changing “rainforest” of bacteria living in our intestines – is primarily affected by our lifestyle, including what we eat or the medications we take, most studies show.

But a University of Notre Dame study has found a much greater genetic component at play than was once known.

In the study, published recently in Science, researchers discovered that most bacteria in the gut microbiome are heritable after looking at more than 16,000 gut microbiome profiles collected over 14 years from a long-studied population of baboons in Kenya’s Amboseli National Park.

However, this heritability changes over time, across seasons and with age. The team also found that several of the microbiome traits heritable in baboons are also heritable in humans.

“The environment plays a bigger role in shaping the microbiome than your genes, but what this study does is move us away from the idea that genes play very little role in the microbiome to the idea that genes play a pervasive, if small, role,” said Elizabeth Archie, professor in the Department of Biological Sciences and a principal investigator on the study who is also affiliated with the Eck Institute for Global Health and the Environmental Change Initiative.

The gut microbiome performs several jobs. In addition to helping with food digestion, it creates essential vitamins and assists with training the immune system. This new research is the first to show a definitive connection with heritability.

Previous studies on the gut microbiome in humans showed only 5 to 13 percent of microbes were heritable, but Archie and the research team hypothesized the low number resulted from a “snapshot” approach to studying the gut microbiome: All prior studies only measured microbiomes at one point in time.

In their study, the researchers used fecal samples from 585 wild Amboseli baboons, typically with more than 20 samples per animal. Microbiome profiles from the samples showed variations in the baboons’ diets between wet and dry seasons. Collected samples included detailed information about the host, including known descendants, data on environmental conditions, social behavior, demography and group-level diet at the time of collection.

The research team found that 97 percent of microbiome traits, including overall diversity and the abundance of individual microbes, were significantly heritable. However, the percentage of heritability appears much lower – down to only 5 percent -when samples are tested from only a single point in time, as is done in humans. This emphasizes the significance of studying samples from the same host over time.

“This really suggests that in human work, part of the reason researchers haven’t found that heritability is because in humans they don’t have a decade and half of fecal samples in the freezer, and they don’t have all the initial host (individual) information they need to tease these details out,” said Archie.

The team did find evidence that environmental factors influence trait heritability in the gut microbiome. Microbiome heritability was typically 48 percent higher in the dry season than in the wet, which may be explained by the baboons’ more diverse diet during the rainy season. Heritability also increased with age, according to the study.

Because the research also showed the significant impact of environment on the gut microbiomes in baboons, their findings agreed with previous studies showing that environmental effects on the variation in the gut microbiome play a larger role than additive genetic effects. Combined with their discovery of the genetic component, the team plans to refine its understanding of the environmental factors involved.

But knowing that genes in the gut microbiome are heritable opens the door to identifying microbes in the future that are shaped by genetics. In the future, therapies could be tailored for people based on the genetic makeup of their gut microbiome.

The Amboseli Baboon Project, started in 1971, is one of the longest-running studies of wild primates in the world. Focused on the savannah baboon, the project is located in the Amboseli ecosystem of East Africa, north of Mount Kilimanjaro. Research teams have tracked hundreds of baboons in several social groups over the course of their entire lives. Researchers currently monitor around 300 animals, but have accumulated life history information on more than 1,500 animals.


HUMAN GUT MICROBIOME

The human body is constantly interacting with various microorganisms that cover its external surfaces and are collectively called the microbiome. The gut microbiome, which contains more than 1000 species of bacteria, is considered the largest and most studied in the field to date. 1 , 2 Although it was previously thought that the gut microbiome formation begins at birth, recent studies suggest that this initial development occurs at prenatal stages. 3

After birth, especially during the first 3 years of life, the development of this microbiome is accelerated mainly due to environmental exposure. It has been demonstrated that factors, such as nutrition, 4 antibiotics, 5 mode of delivery, and cessation of breast‐feeding, 6 have a major impact on its shape in adults. 7 In addition to the dynamics and variability of the microbial communities within the individual, the composition of the microbiome varies significantly between individuals; for example, the species that inhabit the gut, the relative ratios among different bacteria, and the identity of the dominant species. 8 , 9 , 10

In the past decade, especially after the establishment of the Human Microbiome Project, 10 great progress has been made in understanding the importance of the gut microbiome in maintaining our health. 11 , 12 It has been discovered that changes in the gut microbiome are associated with various diseases and health conditions. 13 Increasing evidence of intestinal microbiota involvement in pathogenesis and disease development reveals its potential as a promising therapeutic target for disease management, prevention, and cure. 14

Thus, considerable effort is focused on understanding the factors that shape microbial composition. The gut microbiome is a complex trait affected by multiple factors, including genetics and environment. 15 The typical methods for characterizing the microbiome are either with 16S ribosomal RNA (rRNA) gene sequencing, shotgun, or high‐throughput metagenome sequencing techniques. 8 These techniques allow quantification of taxa or gene functions, which can be used as a database for different ecological metrics that characterize diversity in a sample or within a population. 15

The early studies focused on 16S rRNA sequences which are relatively short, often conserved within a species, and generally different between species. Many 16S rRNA sequences have been found, which do not belong to any known cultured species, indicating that there are numerous non‐isolated organisms. 16S rRNA sequencing has been developed in response to the need for more rapid and accurate identification of complex microbiome. 16 The 16S rRNA gene “Marker gene” 17 codes for a ribosomal subunit that is widely conserved among bacteria and contains hypervariable regions V1‐V9 interspersed among conserved regions of its sequence.

These hypervariable regions are unique to each bacterial species, allowing for classification or taxonomy. The conserved regions, on the other hand, allow for the development of universal primers that bind to known sequences shared among most bacteria. The 16S rRNA gene is amplified from total extracted DNA using universal primers to target the conserved regions of the gene, and the resulting PCR products are sequenced to identify the bacterial species present. 18

For the nine hypervariable regions, some regions better characterize bacteria and the choice of which region, and therefore, the appropriate primers to use are an important step in study design. 19 Regardless of the sequencing method, final results are represented in operational taxonomic units (OTUs), which is a sequence identifying an organism usually at the genus or species level.

OTUs are based on similarity, in which, the similarity between a pair of sequences is computed as the percentage of sites that agree in a pairwise sequence alignment. A common similarity threshold used is 97%, which was derived from an empirical study that showed most strains had 97% 16S rRNA sequence similarity. 20

While with the advancement in refinements of DNA amplification, the proliferation of computational power and bioinformatics tools have greatly aided the analysis of DNA sequences recovered from environmental samples, allowing the adaptation of shotgun sequencing to metagenomic samples (known also as whole metagenome shotgun or WMGS sequencing). Shotgun sequencing is a method used for sequencing random DNA strands. 21 , 22

The approach, used to sequence many cultured microorganisms and the human genome, randomly shears DNA, sequences many short sequences (reads), overlapping ends of different reads to assemble them into a continuous sequence and subsequently reconstruct them into a publically consensus sequence, using sophisticated computer programs. Shotgun metagenomics provides information both about, which organisms are present and what metabolic processes are possible in the community. 23

Because the collection of DNA from an environment is largely uncontrolled, the most abundant organisms in an environmental sample are most highly represented in the resulting sequence data. To achieve the high coverage needed to fully resolve the genomes of under‐represented community members, large samples, often prohibitively so, are needed. In contrast, the random nature of shotgun sequencing ensures that many of these organisms, which would otherwise go unnoticed using traditional culturing techniques, will be represented by at least some small sequence segments. 24

Finally, recently a high‐throughput sequencing technique, which does not require cloning the DNA before sequencing, removing one of the main biases and bottlenecks in environmental sampling was developed. The first metagenomic studies conducted using high‐throughput sequencing used massively parallel 454 pyrosequencing. 25

Three other technologies commonly applied to environmental sampling are the Ilumina MiSeq and HiSeq, and the Applied Biosystems SOLid systems. 26 These techniques for sequencing DNA generate shorter fragments than Sanger sequencing; 454 pyrosequencing typically produces ~400 bp reads, Illumina MiSeq produces 400‐700 bp reads (depending on whether paired‐end options are used), and SOLiD produce 25‐75 bp reads. 27 Using this technique, it is possible to comprehensively sequence the entire microbiota in a given biological sample and subsequently compare it to a publically consensus sequence.

Using these molecular genetic sequence methods, it will be possible to identify and quantify the different microbiome species and families in a given biological sample. Figure 1 shows a diagram that describes the procedures the assessment of microbial populations in a given biological sample using the three methods including shotgun and high‐throughput metagenomics, and 16S‐based sequence approaches.

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FIGURE 1
Shotgun and high‐throughput metagenomics, and 16S‐based sequence approaches for assessing microbial populations in a given biological sample

While environmental factors such as diet and lifestyle have been shown to influence the microbiome composition, the role of the host genetics remains unclear. 28 The microbiome structural complexity, the challenge of multiple comparisons, and the large effect of the environment, probably result in variability and inconsistency between the results of recent studies. 28

Therefore, the question of the extent to which human genetics shapes the microbiome composition remains open. In this review, we will present the recent studies and discuss their results in order to provide a current assessment of the role of host genetics in shaping the gut microbiome composition. Additionally, we will review the major insights from mouse studies and discuss how this model can contribute to future human microbiome research.

ASSESSMENT OF THE MICROBIOME HERITABILITY FROM TWIN STUDIES

The term “heritability” describes the inheritance extent of quantitative traits (eg, the abundance of gut bacteria), or in other words, the proportion of variation in a trait that can be explained by the host genetic. 29 In order to investigate and assess the role of genetic background that determines the characteristics of the microbiome, environmental effects should be minimized as much as possible.

One of the effective approaches is to compare the differences between groups of monozygotic (MZ) and dizygotic (DZ) twins. 28 , 30 Assuming that each type of twin experiences the same environmental conditions and that there is a difference in genetic similarity between MZ (100%) and DZ (~50%) twins, the heritability of traits can be estimated. Figure 2 represents a diagram shows the microbial similarity in monozygotic twins, while genetic diversity is observed in dizygotic twins.

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FIGURE 2
Microbial similarity in monozygotic twins, while genetic diversity is observed in dizygotic twins

Although twin studies are the basic method to investigate whether genetic variation in the host is related to genetic variation in the microbiome, they have not provided the same answers over the years. 8 , 9 Earlier studies reported that there was no significant difference in gut microbiome composition between MZ and DZ twins. 31 , 32

In contrast, recent studies have shown opposite results suggesting that the abundances of specific members of the intestinal microbiota are slightly influenced by host genetics. 8 , 33 While the first two studies 31 , 32 were based on relatively small cohorts (54 and 87 twin pairs, respectively), the current studies 8 , 9 significantly increased the sample size (416 and 1,126 twin pairs, respectively) and therefore were able to reveal the associations.

By using 16S rRNA gene‐based analysis, they identified many heritable taxa. 34 , 35 The most heritable was the family Christensenellaceae (phylum Firmicutes), which was also the hub of a co‐occurrence network that includes other taxa with high heritability. Furthermore, this heritable taxon was enriched in individuals with low BMI, and adding it to an obese‐associated microbiome reduced weight gain in transplanted germ‐free mice.

These observations indicate that heritable microbes can directly contribute to the host phenotype and that the microbial phenotype is additionally influenced by host genetics. 35 In 2016, a follow‐up study that included both previous and new data were published. 9 The expanded dataset resulted in heritability estimates with narrower confidence intervals and revealed additional heritable taxa.

They discovered that heritable taxa are temporally stable over long periods, suggesting that their relative abundances are less affected by environmental factors. To further investigate the involvement of host genetics, another study on a subset of Twins‐UK participants (250 twins) was performed, using metagenomics shotgun sequencing for the analysis. 36

They showed heritability not only for many microbial taxa but also for functional modules in the gut microbiome that can relate to the risk of complex diseases. When comparing to previous results that used 16S profiles, most of the microbiome heritability in this study were higher, suggesting that metagenomics analyses can provide greater resolution and power. 36

However, as the twins began to live apart, the microbial similarity between them declined, indicating that the environment overshadows genetics in the gut microbiome design. 36 , 37 A recent twin study found associations between high heredity microbial taxa and visceral fat accumulation, indicating host genetics as a potential mediator between obese complex phenotype and gut microbiome composition. 38

Contrary to the findings presented above, several non‐twin studies showed a significant bacterial similarity among genetically unrelated individuals who shared a household, but such similarity was not observed across family members that did not share a household. 39 , 40 , 41 These results indicate that the gut microbiome is primarily shaped by environmental factors and that the effect of host genetics is apparently quite modest.

ASSOCIATIONS BETWEEN HOST GENETICS AND GUT MICROBIOME

One of the main approaches to investigate microbiome‐host genome associations is microbial genome‐wide association studies (mGWAS), which are cohort studies that combine human genotyping or whole‐genome sequencing with microbiome analysis (16S rRNA or metagenomics sequencing) from the same individual. 42

Newer and cheaper technologies in recent years have enabled the discovery of several gut microbiomes associated with SNPs. These are related to the innate immune system or metabolism and are located near host genes associated with complex diseases. 9 , 33 , 43 , 44 , 45 , 46 , 47 , 48 , 49 However, most of the associations were not statistically significant after multiple testing corrections and the reported variants were not repeated in different studies. 28 , 40 Therefore, these results are limited.

The great complexity of the microbiome structure and the strong environmental effects probably result in variability and inconsistency between the results of recent studies. 28 , 37 Furthermore, an analysis of 5 previous studies, which included 225 SNPs significantly associated with microbiome parameters, showed almost no overlap between the loci reported in different studies. 40 However, the lactase gene (LCT) is an exception. In fact, the association between LCT locus and the relative abundance of the Bifidobacterium (phylum Actinobacteria) is the only consistent finding that has been validated in subsequent cohorts. 40 , 42 , 45

The lactase enzyme is responsible for the breakdown of lactose and encoded by the LCT gene, whose variants are associated with lactase persistence and lactose tolerance in adults. 9 Bifidobacterium is part of the gut microbiome composition that can utilize lactose, the milk sugar, as an energy source. Thus, its association with the LCT gene may be mediated through environmental factors like diet and lactose consumption that are also influenced by culture and geography. 9 , 50 The different genotypes of this SNP showed associations with different levels of the Bifidobacterium.

To be more specific, the SNP that is typically associated with lactase nonpersistence was also associated with the elevated abundance of Bifidobacterium. 34 When combining the dietary information of the subjects, the association was only in lactase non‐persistence individuals that consumed lactose. 45 This finding can explain why the phenotype predicted by the genotype (lactose tolerance or intolerance) is not always accurate. 51 In some cases, the microbiome has more influence than the genotype on the observed phenotype. 15

Studies that used another approach, which defines the entire microbiome composition as one feature (β‐diversity) rather than treating taxa separately, managed to find several genetic associations for the overall microbial variation, 52 for example, in VDR gene (vitamin D receptor). 37 , 49

In addition, it was argued that 42 SNPs can explain over 10% of the β‐diversity variance, 49 but since further studies failed to replicate this, the association of any individual SNP with microbiome β‐diversity is very limited. 40 , 53 In contrast, when the associations with environmental factors related to diet and lifestyle were examined, they explain over 20% of the variance in microbiome β‐diversity and thereby indicate greater environmental influence than genetic influence. 34 , 40 , 53 , 54

MICROBIOME HERITABILITY

The heritability of the trait in the study population tells us the correlation between the observed phenotype of an individual in that population and the true genetic value of the individual. Since the heritability is usually less than 1.0, this means that an individual with a given observed phenotype can have a true genetic value that varies more or less widely about that phenotype.

Calculating and estimating the hereditability rate of the gut microbiome profiles are important in determining the level of the host genetic effect on the microbiome patterns. It is known that as the sample size is increased, the estimated heritability becomes more powerful and accurate. 9

Nevertheless, in previous studies, the estimated heritability of gut microbiome profiles was found to be relatively low compared to other various complex traits tested in the same research populations. 69 , 70 , 71 While the estimated heritability of the microbial taxa in some of the reported studies was ranged between 0.10 and 0.30, the estimated heritability of other assessed phenotypic traits was much higher. These findings supported the previous statements, that several gut bacteria are heritable; however, the overall heritability tends to be smaller than it was initially estimated and expected. 37 , 40

reference link :https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529332/


More information: “Gut microbiome heritability is nearly universal but environmentally contingent” Science (2021). science.sciencemag.org/cgi/doi … 1126/science.aba5483

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