Recent evidence suggests that natural selection operating on hosts to maintain their microbiome contributes to the emergence of new species, that is, the ‘hologenomic basis of speciation’. Here we analyse the gut microbiota of two house mice subspecies, Mus musculus musculus and M. m. domesticus, across their Central European hybrid zone, in addition to hybrids generated in the lab. Hybrid mice display widespread transgressive phenotypes (that is, exceed or fall short of parental values) in a variety of measures of bacterial community structure, which reveals the importance of stabilizing selection operating on the intestinal microbiome within species. Further genetic and immunological analyses reveal genetic incompatibilities, aberrant immune gene expression and increased intestinal pathology associated with altered community structure among hybrids. These results provide unique insight into the consequences of evolutionary divergence in a vertebrate ‘hologenome’, which may be an unrecognized contributing factor to reproductive isolation in this taxonomic group.

The rise of antimicrobial resistance (AMR) in bacterial pathogens is acknowledged by the WHO as a major global health crisis. It is estimated that in 2050 annually up to 10 million people will die from infections with drug resistant pathogens if no efficient countermeasures are implemented. Evolution of pathogens lies at the core of this crisis, which enables rapid adaptation to the selective pressures imposed by antimicrobial usage in both medical treatment and agriculture, consequently promoting the spread of resistance genes or alleles in bacterial populations. Approaches developed in the field of Evolutionary Medicine attempt to exploit evolutionary insight into these adaptive processes, with the aim to improve diagnostics and the sustainability of antimicrobial therapy. Here, we review the concept of evolutionary trade-offs in the development of AMR as well as new therapeutic approaches and their impact on host-microbiome-pathogen interactions. We further discuss the possible translation of evolution-informed treatments into clinical practice, considering both the rapid cure of the individual patients and the prevention of AMR.

Mutations in mitochondrial DNA (mtDNA) lead to heteroplasmy, i.e., the intracellular coexistence of wild-type and mutant mtDNA strands, which impact a wide spectrum of diseases but also physiological processes, including endurance exercise performance in athletes. However, the phenotypic consequences of limited levels of naturally arising heteroplasmy have not been experimentally studied to date. We hence generated a conplastic mouse strain carrying the mitochondrial genome of an AKR/J mouse strain (B6-mtAKR) in a C57BL/6 J nuclear genomic background, leading to >20% heteroplasmy in the origin of light-strand DNA replication (OriL). These conplastic mice demonstrate a shorter lifespan as well as dysregulation of multiple metabolic pathways, culminating in impaired glucose metabolism, compared to that of wild-type C57BL/6 J mice carrying lower levels of heteroplasmy. Our results indicate that physiologically relevant differences in mtDNA heteroplasmy levels at a single, functionally important site impair the metabolic health and lifespan in mice.

We read with great interest the recent communication by Simrén et al,1 reporting a correlation between visceral hypersensitivity and GI symptom severity in functional GI disorders (FGID). Previously, it has been shown that visceral hypersensitivity can be modulated or even induced in animal models, by altering the composition of their gut microbiota with antibiotics or faecal transplantation from IBS donors.2 3 Hence, while a direct link between gut microbiota composition and visceral pain may need to be conclusively established, this holds great potential for translational exploitation in the treatment of IBS and other FGID. Thus far, the potential association between microbiota and abdominal pain in humans has only been investigated in one study that included 15 individuals.4 For this purpose, we studied 159 individuals (average age 59.1, 39.6% men) from the Swedish Population-based Colonoscopy (PopCol) cohort, previously described and with faecal microbiota 16S sequencing data and daily recordings of abdominal pain (number of episodes, duration and intensity) collected over the same period (7.41±7.91 days).5–7 Among these, 52 individuals (assigned to the case group) reported at least one episode

The house mouse is a key model organism in skin research including host–microbiota interactions, yet little is known about the skin microbiota of free-living mice. It is similarly unclear how closely laboratory mice, which typically live under exceptionally hygienic conditions, resemble the ancestral state of microbial variation in the wild. In this study, we sampled an area spanning 270 km2 in south-west France and collected 203 wild Mus musculus domesticus. We profiled the ear skin microbiota on standing and active communities (DNA-based and RNA-based 16 rRNA gene sequencing, respectively), and compared multiple community aspects between wild-caught and laboratory-reared mice kept in distinct facilities. Compared to lab mice, we reveal the skin microbiota of wild mice on the one hand to be unique in their composition within the Staphylococcus genus, with a majority of sequences most closely matching known novobiocin-resistant species, and display evidence of a rare biosphere. On the other hand, despite drastic disparities between natural and laboratory environments, we find that shared taxa nonetheless make up the majority of the core skin microbiota of both wild- and laboratory skin communities, suggesting that mammalian skin is a highly specialized habitat capable of strong selection from available species pools. Finally, the influence of environmental factors suggests RNA-based profiling as a preferred method to reduce environmental noise.

Nutrition appears to be an important environmental factor involved in the onset of inflammatory bowel diseases (IBD) through yet poorly understood biological mechanisms. Most studies focused on fat content in high caloric diets, while refined sugars represent up to 40% of caloric intake within industrialized countries and contribute to the growing epidemics of inflammatory diseases. Herein we aim to better understand the impact of a high-fat-high-sucrose diet on intestinal homeostasis in healthy conditions and the subsequent colitis risk. We investigated the early events and the potential reversibility of high caloric diet-induced damage in mice before experimental colitis. C57BL/6 mice were fed with a high-fat or high-fat high-sucrose or control diet before experimental colitis. In healthy mice, a high-fat high-sucrose diet induces a pre-IBD state characterized by gut microbiota dysbiosis with a total depletion of bacteria belonging to Barnesiella that is associated with subclinical endoscopic lesions. An overall down-regulation of the colonic transcriptome converged with broadly decreased immune cell populations in the mesenteric lymph nodes leading to the inability to respond to tissue injury. Such in-vivo effects on microbiome and transcriptome were partially restored when returning to normal chow. Long-term consumption of diet enriched in sucrose and fat predisposes mice to colitis. This enhanced risk is preceded by gut microbiota dysbiosis and transcriptional reprogramming of colonic genes related to IBD. Importantly, diet-induced transcriptome and microbiome disturbances are partially reversible after switching back to normal chow with persistent sequelae that may contribute to IBD predisposition in the general population.

Background B4galnt2 is a blood group-related glycosyltransferase that displays cis-regulatory variation for its tissue-specific expression patterns in house mice. The wild type allele, found e.g. in the C57BL/6 J strain, directs intestinal expression of B4galnt2, which is the pattern observed among vertebrates, including humans. An alternative allele class found in the RIIIS/J strain and other mice instead drives expression in blood vessels, which leads to a phenotype similar to type 1 von Willebrand disease (VWD), a common human bleeding disorder. We previously showed that alternative B4galnt2 alleles are subject to long-term balancing selection in mice and that variation in B4galnt2 expression influences host-microbe interactions in the intestine. This suggests that the costs of prolonged bleeding in RIIIS/J allele-bearing mice might be outweighed by benefits associated with resistance against gastrointestinal pathogens. However, the conditions under which such trade-offs could lead to the long-term maintenance of disease-associated variation at B4galnt2 are unclear.ResultsTo explore the persistence of B4galnt2 alleles in wild populations of house mice, we combined B4galnt2 haplotype frequency data together with a mathematical model based on an evolutionary game framework with a modified Wright-Fisher process. In particular, given the potential for a heterozygote advantage as a possible explanation for balancing selection, we focused on heterozygous mice, which express B4galnt2 in both blood vessels and the gastrointestinal tract. We show that B4galnt2 displays an interesting spatial allelic distribution in Western Europe, likely due to the recent action of natural selection. Moreover, we found that the genotype frequencies observed in nature can be produced by pathogen-driven selection when both heterozygotes and RIIIS/J homozygotes are protected against infection and the fitness cost of bleeding is roughly half that of infection.ConclusionBy comparing the results of our models to the patterns of polymorphism at B4galnt2 in natural populations, we are able to recognize the long-term maintenance of the RIIIS/J allele through host-pathogen interactions as a viable hypothesis. Further, our models identify that a putative dominant-, yet unknown protective function of the RIIIS/J allele appears to be more likely than a protective loss of intestinal B4galnt2 expression in RIIIS/J homozygotes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12862-017-1035-7) contains supplementary material, which is available to authorized users.

BackgroundThe MHC class I and II loci mediate the adaptive immune response and belong to the most polymorphic loci in vertebrate genomes. In fact, the number of different alleles in a given species is often so large that it remains a challenge to provide an evolutionary model that can fully account for this.ResultsWe provide here a general survey of MHC allele numbers in house mouse populations and two sub-species (M. m. domesticus and M. m. musculus) for H2 class I D and K, as well as class II A and E loci. Between 50 and 90% of the detected different sequences constitute new alleles, confirming that the discovery of new alleles is indeed far from complete. House mice live in separate demes with small effective population sizes, factors that were proposed to reduce, rather than enhance the possibility for the maintenance of many different alleles. To specifically investigate the occurrence of alleles within demes, we focused on the class II H2-Aa and H2-Eb exon 2 alleles in nine demes of M. m. domesticus from two different geographic regions. We find on the one hand a group of alleles that occur in different sampling regions and three quarters of these are also found in both sub-species. On the other hand, the larger group of different alleles (56%) occurs only in one of the regions and most of these (89%) only in single demes. We show that most of these region-specific alleles have apparently arisen through recombination and/or partial gene conversion from already existing alleles.ConclusionsDemes can act as sources of alleles that outnumber the set of alleles that are shared across the species range. These findings support the reservoir model proposed for human MHC diversity, which states that large pools of rare MHC allele variants are continuously generated by neutral mutational mechanisms. Given that these can become important in the defense against newly emerging pathogens, the reservoir model complements the selection based models for MHC diversity and explains why the exceptional diversity exists.Electronic supplementary materialThe online version of this article (10.1186/s12983-018-0266-9) contains supplementary material, which is available to authorized users.