How modern nutrition drives the rapid development of intestinal bacteria

How modern nutrition drives the rapid development of intestinal bacteria

By tracking how adaptive genes move through gut bacteria across continents, researchers are uncovering a hidden evolutionary response to modern diets and lifestyles and a powerful new way to study microbiome evolution.

Study: Gene-specific selective sweeps are ubiquitous in the human gut microbiome. Photo credit: Danijela Maksimovic/Shutterstock.com

A recent study inNaturedeveloped an integrated linkage disequilibrium score (iLDS), a novel selection scan statistic, to identify adaptive alleles that spread across the host microbiome through recombination-mediated processes, including migration and horizontal gene transfer (HGT). This underlines Common selection pressures and their role in shaping microbiome diversity and function.

Genetic adaptations in the intestinal microbiome

The different species in the human gut microbiome change and develop over the course of a person's life and even across multiple generations. Studies show that gut bacteria often evolve quickly, with new mutations appearing within days or months in healthy adults, even without antibiotic treatment. Further research is needed to understand how these changes spread to individuals over time.

When a new adaptation occurs in a person's gut microbiome, it can spread to others through horizontal gene transfer (HGT). The human gut is a known hotspot for HGT and facilitates the incorporation of useful genes into new strains of bacteria. HGT is important for the spread of certain genes, such as antibiotic resistance, particularly between different species. To date, it is unclear to what extent HGT facilitates the movement of adaptive genes between strains of the same species, particularly through homologous recombination.

When an adaptive gene spreads through a population via a process called “gene-specific” selective sweep, neighboring genetic variants that may be harmless or potentially harmful can be swept along. This means that the same stretch of DNA, including the adaptive gene and these “hitchhikers,” can occur in unrelated strains of bacteria that live in the gut microbiomes of different people. This sharing of DNA creates a striking pattern called increased linkage disequilibrium (LD). This means that certain combinations of genes appear together near the adaptive gene more often than expected.

LD-based scans for selection in bacteria have been limited, possibly due to the prevalence and dynamics of recombination in many bacterial species, particularly intestinal commensals. Furthermore, LD-based statistics can be confounded by other non-selective evolutionary forces, including demographic contractions, which can increase LD20.

Uncovering selection forces in gut bacterial populations through linkage disequilibrium patterns

Researchers used simulations to test whether positive selection and hitchhiking increase LD between nonsynonymous variants compared to synonymous variants and whether this pattern only occurs under selection or can occur by chance. They found that this genetic pattern does not arise without positive selection, even under different evolutionary scenarios. The signature appeared only when purifying selection was stronger than drift and positive selection was stronger than purifying selection. In such cases, weakly deleterious variants could hitchhike during a sweep, leading to increased LD for common nonsynonymous variants.

After simulations showed that selective sweeps can increase LD in common variants, researchers measured LD in human gut bacteria to determine whether this pattern occurs in natural populations. They analyzed metagenomic data from 693 people on three continents. By matching sequencing reads and identifying samples with a dominant strain, they were able to reliably determine haplotypes. This allowed calculation of the LD between pairs of alleles. A total of 3,316 haplotypes from 32 species were analyzed. Additional evidence was collected using metagenome assembled genomes (MAGs) and isolates from 24 global populations. Because LD can be influenced by population structure, only haplotypes from the largest group of each species were considered.

In most species analyzed, LD was significantly higher for common nonsynonymous variants, suggesting positive selection. For rare variants, the LD was lower, indicating purifying selection. These patterns suggest widespread purification and positive selection at nonsynonymous sites in gut bacteria.

Application of iLDS to study microbial gene adaptations in the intestine

The iLDS statistic was developed to identify candidate genomic regions under current positive selection by measuring overall LD and non-synonymous LD. It was calculated in sliding windows across the genome and highlighted outliers after standardization. The current study tested iLDS on simulated and real Clostridioides difficile data and demonstrated sensitivity to current and ongoing sweeps while maintaining a low false positive rate. In 135 C. difficile isolates, iLDS located known sweep regions such as tcdB and the S-layer cassette, with most regions showing no signal while some indicating selection.

Six sweeps were identified, including tcdB and S-layer. iLDS outperformed other statistics because it frequently matched known virulence genes and revealed sweeps consistent with recombination-mediated spread of adaptive alleles. Its effectiveness has also been confirmed on Helicobacter pylori and Drosophila melanogaster.

iLDS applied to 32 gut microbiome species identified 155 sweeps affecting 447 genes, with some classes of genes, such as the starch utilization genes susC/susD and glycoside hydrolases, subjected to repeated selection. This suggested that carbohydrate metabolism and transport genes were often targeted by selection.

The mdxE and mdxF genes involved in maltodextrin transport were selected in starch-metabolizing intestinal bacteria and showed signs of recent recombination and horizontal transfer. Previous studies have shown that industrialization is associated with reduced microbiome diversity and increased gene transfer rates. iLDS scans revealed 309 sweeps in 24 populations and 16 species, most of which affected only one population, suggesting local adaptation.

Thirty-five percent of the searches were conducted between different populations, some of which were global. Industrialized groups shared results more often than non-industrialized groups, suggesting common ecological and nutritional selection pressures.

Only three runs were shared between the two groups, while 32 were for the industrialized or non-industrialized population only. The R. bromii mdxEF locus was selected in all industrialized but not in non-industrialized groups, suggesting adaptation to modern lifestyles. Sweep numbers per population were similar between groups, indicating comparable rates of adaptation.

Conclusions

The development and application of iLDS showed how selective pressure shapes the gut microbiome and how gut bacteria adapt. Although hundreds of selective sweeps were detected, the conservative calibration of iLDS likely missed some truly positive results, suggesting that positive selection in gut commensals may be more widespread than observed. Further studies of loci identified by iLDS are needed to clarify how microbiome genetics impact host phenotypes, aid in the diagnosis and treatment of diseases, and aid in the development of targeted probiotics.

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