The gut microbiome in bullous pemphigoid: implications of the gut-skin axis for disease susceptibility.

Bullous pemphigoid (BP) is an autoimmune blistering disease that primarily affects the elderly. An altered skin microbiota in BP was recently revealed. Accumulating evidence points toward a link between the gut microbiota and skin diseases; however, the gut microbiota composition of BP patients remains largely underexplored, with only one pilot study to date, with a very limited sample size and no functional profiling of gut microbiota. To thoroughly investigate the composition and function of the gut microbiota in BP patients, and explore possible links between skin conditions and gut microbiota, we here investigated the gut microbiota of 66 patients (81.8% firstly diagnosed) suffering from BP and 66 age-, sex-, and study center-matched controls (CL) with non-inflammatory skin diseases (132 total participants), using 16S rRNA gene and shotgun sequencing data. Decreased alpha-diversity and an overall altered gut microbial community is observed in BP patients. Similar trends are observed in subclassifications of BP patients, including first diagnoses and relapsed cases. Furthermore, we observe a set of BP disease-associated gut microbial features, including reduced Faecalibacterium prausnitzii and greater abundance of pathways related to gamma-aminobutyric acid (GABA) metabolism in BP patients. Interestingly, F. prausnitzii is a well-known microbiomarker of inflammatory diseases, which has been reported to be reduced in the gut microbiome of atopic dermatitis and psoriasis patients. Moreover, GABA plays multiple roles in maintaining skin health, including the inhibition of itching by acting as a neurotransmitter, attenuating skin lesions by balancing Th1 and Th2 levels, and maintaining skin elasticity by increasing the expression of type I collagen. These findings thus suggest that gut microbiota alterations present in BP may play a role in the disease, and certain key microbes and functions may contribute to the link between gut dysbiosis and BP disease activity. Further studies to investigate the underlying mechanisms of the gut-skin interaction are thus clearly warranted, which could aid in the development of potential therapeutic interventions.

Key features of the genetic architecture and evolution of host-microbe interactions revealed by high-resolution genetic mapping of the mucosa-associated gut microbiome in hybrid mice.

Determining the forces that shape diversity in host-associated bacterial communities is critical to understanding the evolution and maintenance of metaorganisms. To gain deeper understanding of the role of host genetics in shaping gut microbial traits, we employed a powerful genetic mapping approach using inbred lines derived from the hybrid zone of two incipient house mouse species. Furthermore, we uniquely performed our analysis on microbial traits measured at the gut mucosal interface, which is in more direct contact with host cells and the immune system. Several mucosa-associated bacterial taxa have high heritability estimates, and interestingly, 16S rRNA transcript-based heritability estimates are positively correlated with cospeciation rate estimates. Genome-wide association mapping identifies 428 loci influencing 120 taxa, with narrow genomic intervals pinpointing promising candidate genes and pathways. Importantly, we identified an enrichment of candidate genes associated with several human diseases, including inflammatory bowel disease, and functional categories including innate immunity and G-protein-coupled receptors. These results highlight key features of the genetic architecture of mammalian host-microbe interactions and how they diverge as new species form.

The digestive system, particularly the large intestine, hosts many types of bacteria which together form the gut microbiome. The exact makeup of different bacterial species is specific to an individual, but microbiomes are often more similar between related individuals, and more generally, across related species. Whether this is because individuals share similar environments or similar genetic backgrounds remains unclear. These two factors can be disentangled by breeding different animal lineages ­ which have different genetic backgrounds while belonging to the same species ­ and then raising the progeny in the same environment. To investigate this question, Doms et al. studied the genes and microbiomes of mice resulting from breeding strains from multiple locations in a natural hybrid zone between different subspecies. The experiments showed that 428 genetic regions affected the makeup of the microbiome, many of which were known to be associated with human diseases. Further analysis revealed 79 genes that were particularly interesting, as they were involved in recognition and communication with bacteria. These results show how the influence of the host genome on microbiome composition becomes more specialized as animals evolve. Overall, the work by Doms et al. helps to pinpoint the genes that impact the microbiome; this knowledge could be helpful to examine how these interactions contribute to the emergence of conditions such as diabetes or inflammatory bowel disease, which are linked to perturbations in gut bacteria.

Assessing similarities and disparities in the skin microbiota between wild and laboratory populations of house mice.

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.

Inhibition of ERK-MAP kinase signaling by RSK during Drosophila development.

Although p90 ribosomal S6 kinase (RSK) is known as an important downstream effector of the ribosomal protein S6 kinase/extracellular signal-regulated kinase (Ras/ERK) pathway, its endogenous role, and precise molecular function remain unclear. Using gain-of-function and null mutants of RSK, its physiological role was successfully characterized in Drosophila. Surprisingly, RSK-null mutants were viable, but exhibited developmental abnormalities related to an enhanced ERK-dependent cellular differentiation such as ectopic photoreceptor- and vein-cell formation. Conversely, overexpression of RSK dramatically suppressed the ERK-dependent differentiation, which was further augmented by mutations in the Ras/ERK pathway. Consistent with these physiological phenotypes, RSK negatively regulated ERK-mediated developmental processes and gene expressions by blocking the nuclear localization of ERK in a kinase activity-independent manner. In addition, we further demonstrated that the RSK-dependent inhibition of ERK nuclear migration is mediated by the physical association between ERK and RSK. Collectively, our study reveals a novel regulatory mechanism of the Ras/ERK pathway by RSK, which negatively regulates ERK activity by acting as a cytoplasmic anchor in Drosophila.