Intestinal microflora does not depend much on the genotype of the host, but is closely related to its phenotype.

A comparison of the composition of the intestinal microbiota with the genotype, lifestyle, and phenotypic traits of 1,046 Israelis and 836 Dutch showed that the microbial population of the intestine is weakly dependent on the host genotype and is determined mainly by environmental factors. At the same time, the composition of the microbiota significantly correlates with many phenotypic traits that are important from a medical point of view. As it turned out, the composition of the intestinal microbiota can predict the state of certain traits with about the same accuracy as the genotype, and if you take into account both genes and the microbiota, the accuracy of predictions doubles. The results highlight the importance of studying intestinal bacteria, including for the development of personalized medicine.

Intestinal microflora does not depend much on the genotype of the host, but is closely related to its phenotype.
The idea that most multicellular organisms are actually “symbiotic superorganisms”, many of whose properties are determined by microscopic symbionts, is increasingly becoming commonplace. The “Elements” have repeatedly addressed this topic (see the links at the end of the news). The human gut microbiota and its multifaceted connections with important phenotypic traits (including the risks of various diseases) have been actively studied in recent years, but some fundamental issues still remain unresolved. One of them is the degree of heritability of the microbiota, that is, to what extent the composition of the microbial population of the intestine depends on the individual’s genes, and to what extent it depends on the “environment” in a broad sense, that is, on diet, lifestyle, medications taken, and everything else. Previously, attempts have been made to assess the heritability of the microbiota and find specific genes that affect its composition (including using a genome-wide association search, see GWAS). These studies have yielded contradictory results. On the one hand, dozens of polymorphic loci have been found in the human genome that seem to correlate with certain characteristics of the intestinal microbiota. On the other hand, the statistical reliability of the correlations found was usually low, and the sets of genes found in different studies turned out to be suspiciously different from each other. A large team of biologists from several scientific institutions in Israel, in collaboration with colleagues from the Netherlands, conducted, apparently, the largest study to date, designed to clarify the controversial issue of the influence of genes and environment on the microbial population of our intestines. The main study was conducted on a sample of 1,046 Israelis, and the results were then compared with previously obtained data on 836 residents of the Netherlands. For each individual, using metagenomic analysis (see Metagenomics), the qualitative and quantitative composition of the intestinal microbiota was determined with great accuracy. All subjects were genotyped according to 712,540 polymorphic loci (see: Single nucleotide polymorphism), which in the context of this task differs little in meaning from reading complete genomes. For each individual, information was collected on a number of phenotypic traits (such as height, weight, waist size, glycemic index, cholesterol level, etc.), as well as on diet (subjects had to talk about their eating habits, which, however, can also be considered as phenotypic traits). In addition, the subjects had to tell where all their grandparents came from. This made it possible to divide the Israeli sample into six parts by origin (Ashkenazi, Sephardi, people from Yemen, North Africa, the Middle East, and the last, the “others” group, which included people of mixed origin). To begin with, the authors compared the background data with the genotypes. Groups of different origins formed distinct clusters of allele sets, as would be expected (Fig. 1, left). This is consistent with the idea that there are genetic differences between Ashkenazim, Sephardim, etc., and that people have given truthful information about their ancestry. In addition, people with mixed ancestry showed a strong positive correlation between similarity in origin and similarity in genotype. At the same time, no connection could be found between the origin of a person and the composition of his intestinal microbiota (Fig. 1, right). In particular, there is no correlation between similarity in origin and similarity in microbiota. This is true both for the integral characteristics of the microbiota, such as its general taxonomic diversity, and for the abundance of individual groups of microorganisms. It follows from this that the heritability of microbiota characteristics (that is, their dependence on the individual’s genes), if it exists, is not too great. However, a recent study performed on 1,126 pairs of twins from the UK (see Twin study) identified 33 taxa of intestinal microorganisms with significant heritability. (J. K. Goodrich et al., 2016. Genetic Determinants of the Gut Microbiome in UK Twins). Do these results contradict each other? The authors re-processed the data from the 2016 work and found that all identified groups of “inherited” microbes together make up only 5.6% of the microbial population of the intestine. Taking this into account, it turns out that the host genotype explains only from 1.9 to 8.1% of the variability in the composition of the intestinal microbiota. Such a large variation is explained by the fact that there is no complete clarity on the issue of the required level of rigor of the applied statistical criteria in this case. But in any case, it turns out that the heritability of the intestinal microbiota is small compared to the influence of environmental factors. The authors then tried to identify specific single-nucleotide polymorphisms correlating with any characteristics of the intestinal microbiota. Previous studies have found several dozen polymorphisms that seem to affect differences between individuals in the taxonomic composition of the microbiota. However, the new data did not confirm this connection. Moreover, the authors managed to obtain arguments in favor of the fact that the previously obtained results are most likely an artifact of the statistical methods used and do not prove the existence of real relationships. Although the influence of the genotype on the microbiota is not detectable at the level of the entire microbial community as a whole, some loci seem to have a significant, albeit weak, effect on the abundance of certain bacterial genera and species. It is possible to speak with the greatest confidence about the influence of several polymorphisms related to the metabolism of lactose on the abundance of bacteria of the genus Bifidobacterium. This conclusion, as well as other research results, was first obtained on an Israeli sample, and then confirmed on a Dutch one. Additional arguments in favor of the fact that the intestinal microbiota depends mainly on the environment, and not on human genes, were provided by the analysis of data on people related but living separately, as well as on unrelated individuals living together. It turned out that in the first case, the similarity of the intestinal microbiota was not increased compared to the average level, and in the second case, it was significantly increased. The conclusion about the weak dependence of the intestinal microbial population on the host genes poses new questions for scientists related to clarifying the reasons for the relative stability of the composition of the intestinal microbiota. It is known that the microbial community living in the human intestine has a certain resistance, changes relatively little over time, and is even able to withstand, within certain limits, the perturbations associated with infections and taking antibiotics. (C. A. Lozupone et al., 2012. Diversity, stability and resilience of the human gut microbiota). If the composition of a community depends so little on human genes (and, therefore, should depend mainly on the environment), then the question arises what ensures its stability. Future research should provide an answer to this question, but for now it remains open. The next task that the researchers set themselves was to find a link between the composition of the microbiota and the phenotypic traits of humans. For this purpose, a quantitative indicator was developed, which the authors designated as b2 (by analogy with heritability, which is traditionally designated h2). If h2 is, simply put, the proportion of variation by trait, explained by the genetic variability of the studied population (or the accuracy with which the phenotype can be predicted by genotype), then b2 is a value indicating the accuracy with which the phenotype can be predicted by the intestinal microbiome. The calculations were performed separately for the Israeli and Dutch samples. The results are shown in the table.

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Published

July, 2024

Duration of reading

About 3-4 minutes

Category

Genetics

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