Social environment and genetics underlie body site‐specific microbiomes of Yellowstone National Park gray wolves (Canis lupus)

The host‐associated microbiome is an important player in the ecology and evolution of species. Despite growing interest in the medical, veterinary, and conservation communities, there remain numerous questions about the primary factors underlying microbiota, particularly in wildlife. We bridged this knowledge gap by leveraging microbial, genetic, and observational data collected in a wild, pedigreed population of gray wolves (Canis lupus) inhabiting Yellowstone National Park. We characterized body site‐specific microbes across six haired and mucosal body sites (and two fecal samples) using 16S rRNA amplicon sequencing. At the phylum level, we found that the microbiome of gray wolves primarily consists of Actinobacteria, Bacteroidetes, Firmicutes, Fusobacteria, and Proteobacteria, consistent with previous studies within Mammalia and Canidae. At the genus level, we documented body site‐specific microbiota with functions relevant to microenvironment and local physiological processes. We additionally employed observational and RAD sequencing data to examine genetic, demographic, and environmental correlates of skin and gut microbiota. We surveyed individuals across several levels of pedigree relationships, generations, and social groups, and found that social environment (i.e., pack) and genetic relatedness were two primary factors associated with microbial community composition to differing degrees between body sites. We additionally reported body condition and coat color as secondary factors underlying gut and skin microbiomes, respectively. We concluded that gray wolf microbiota resemble similar host species, differ between body sites, and are shaped by numerous endogenous and exogenous factors. These results provide baseline information for this long‐term study population and yield important insights into the evolutionary history, ecology, and conservation of wild wolves and their associated microbes.     

Micro-coevolution of host genetics with gut microbiome in three Chinese ethnic groups

Understanding the micro-coevolution of the human gut microbiome with host genetics is challenging but essential in both evolutionary and medical studies. To gain insight into the interactions between host genetic variation and the gut microbiome, we analyzed both the human genome and gut microbiome collected from a cohort of 190 students in the same boarding college and representing 3 ethnic groups, Uyghur, Kazakh, and Han Chinese. We found that differences in gut microbiome were greater between genetically distinct ethnic groups than those genetically closely related ones in taxonomic composition, functional composition, enterotype stratification, and microbiome genetic differentiation. We also observed considerable correlations between host genetic variants and the abundance of a subset of gut microbial species. Notably, interactions between gut microbiome species and host genetic variants might have coordinated effects on specific human phenotypes. Bacteroides ovatus, previously reported to modulate intestinal immunity, is significantly correlated with the host genetic variant rs12899811 (meta-P = 5.55 × 10⁻⁵), which regulates the VPS33B expression in the colon, acting as a tumor suppressor of colorectal cancer. These results advance our understanding of the micro-coevolution of the human gut microbiome and their interactive effects with host genetic variation on phenotypic diversity.     

Geography,Host Genetics,and Cross‐Domain Microbial Networks Structure the Skin Microbiota of Fragmented Brazilian Atlantic Forest Frog Populations

The host‐associated microbiome plays a significant role in health. However, the roles of factors such as host genetics and microbial interactions in determining microbiome diversity remain unclear. We examined these factors using amplicon‐based sequencing of 175 Thoropa taophora frog skin swabs collected from a naturally fragmented landscape in southeastern Brazil. Specifically, we examined (1) the effects of geography and host genetics on microbiome diversity and structure; (2) the structure of microbial eukaryotic and bacterial co‐occurrence networks; and (3) co‐occurrence between microeukaryotes with bacterial OTUs known to affect growth of the fungal pathogen Batrachochytrium dendrobatidis (Bd). While bacterial alpha diversity varied by both site type and host MHC IIB genotype, microeukaryotic alpha diversity varied only by site type. However, bacteria and microeukaryote composition showed variation according to both site type and host MHC IIB genotype. Our network analysis showed the highest connectivity when both eukaryotes and bacteria were included, implying that ecological interactions may occur among domains. Lastly, anti‐Bd bacteria were not broadly negatively co‐associated with the fungal microbiome and were positively associated with potential amphibian parasites. Our findings emphasize the importance of considering both domains in microbiome research and suggest that for effective probiotic strategies for amphibian disease management, considering potential interactions among all members of the microbiome is crucial.     

Gut microbial diversity across a contact zone for California voles: Implications for lineage divergence of hosts and mitonuclear mismatch in the assembly of the mammalian gut microbiome

Gut microbial diversity is thought to reflect the co‐evolution of microbes and their hosts as well as current host‐specific attributes such as genetic background and environmental setting. To explore interactions among these parameters, we characterized variation in gut microbiome composition of California voles (Microtus californicus) across a contact zone between two recently diverged lineages of this species. Because this contact zone contains individuals with mismatched mitochondrial‐nuclear genomes (cybrids), it provides an important opportunity to explore how different components of the genotype contribute to gut microbial diversity. Analyses of bacterial 16S rRNA sequences and joint species distribution modelling revealed that host genotypes and genetic differentiation among host populations together explained more than 50% of microbial community variation across our sampling transect. The ranked importance (most to least) of factors contributing to gut microbial diversity in our study populations were: genome‐wide population differentiation, local environmental conditions, and host genotypes. However, differences in microbial communities among vole populations (β‐diversity) did not follow patterns of lineage divergence (i.e., phylosymbiosis). Instead, among‐population variation was best explained by the spatial distribution of hosts, as expected if the environment is a primary source of gut microbial diversity (i.e., dispersal limitation hypothesis). Across the contact zone, several bacterial taxa differed in relative abundance between the two parental lineages as well as among individuals with mismatched mitochondrial and nuclear genomes. Thus, genetic divergence among host lineages and mitonuclear genomic mismatches may also contribute to microbial diversity by altering interactions between host genomes and gut microbiota (i.e., hologenome speciation hypothesis).     

Male‐biased dispersal in a fungus‐gardening ant symbiosis

For nearly all organisms, dispersal is a fundamental life‐history trait that can shape their ecology and evolution. Variation in dispersal capabilities within a species exists and can influence population genetic structure and ecological interactions. In fungus‐gardening (attine) ants, co‐dispersal of ants and mutualistic fungi is crucial to the success of this obligate symbiosis. Female‐biased dispersal (and gene flow) may be favored in attines because virgin queens carry the responsibility of dispersing the fungi, but a paucity of research has made this conclusion difficult. Here, we investigate dispersal of the fungus‐gardening ant Trachymyrmex septentrionalis using a combination of maternally (mitochondrial DNA) and biparentally inherited (microsatellites) markers. We found three distinct, spatially isolated mitochondrial DNA haplotypes; two were found in the Florida panhandle and the other in the Florida peninsula. In contrast, biparental markers illustrated significant gene flow across this region and minimal spatial structure. The differential patterns uncovered from mitochondrial DNA and microsatellite markers suggest that most long‐distance ant dispersal is male‐biased and that females (and concomitantly the fungus) have more limited dispersal capabilities. Consequently, the limited female dispersal is likely an important bottleneck for the fungal symbiont. This bottleneck could slow fungal genetic diversification, which has significant implications for both ant hosts and fungal symbionts regarding population genetics, species distributions, adaptive responses to environmental change, and coevolutionary patterns.     

Non‐invasive monitoring of multiple wildlife health factors by fecal microbiome analysis

Fecal microbial biomarkers represent a less invasive alternative for acquiring information on wildlife populations than many traditional sampling methodologies. Our goal was to evaluate linkages between fecal microbiome communities in Rocky Mountain elk (Cervus canadensis) and four host factors including sex, age, population, and physical condition (body‐fat). We paired a feature‐selection algorithm with an LDA‐classifier trained on elk differential bacterial abundance (16S‐rRNA amplicon survey) to predict host health factors from 104 elk microbiomes across four elk populations. We validated the accuracy of the various classifier predictions with leave‐one‐out cross‐validation using known measurements. We demonstrate that the elk fecal microbiome can predict the four host factors tested. Our results show that elk microbiomes respond to both the strong extrinsic factor of biogeography and simultaneously occurring, but more subtle, intrinsic forces of individual body‐fat, sex, and age‐class. Thus, we have developed and described herein a generalizable approach to disentangle microbiome responses attributed to multiple host factors of varying strength from the same bacterial sequence data set. Wildlife conservation and management presents many challenges, but we demonstrate that non‐invasive microbiome surveys from scat samples can provide alternative options for wildlife population monitoring. We believe that, with further validation, this method could be broadly applicable in other species and potentially predict other measurements. Our study can help guide the future development of microbiome‐based monitoring of wildlife populations and supports hypothetical expectations found in host‐microbiome theory.     

Gut microbiome of migratory shorebirds: Current status and future perspectives

Migratory shorebirds have many unique life history characteristics, such as long‐distance travel between breeding sites, stopover sites, and wintering sites. The physiological challenges for migrant energy requirement and immunity may affect their gut microbiome community. Here, we reviewed the specific features (e.g., relatively high proportion of Corynebacterium and Fusobacterium) in the gut microbiome of 18 migratory shorebirds, and the factors (e.g., diet, migration, environment, and phylogeny) affecting the gut microbiome. We discussed possible future studies of the gut microbiome in migratory shorebirds, including the composition and function of the spatial‐temporal gut microbiome, and the potential contributions made by the gut microbiome to energy requirement during migration.     

Unravelling the effects of the environment and host genotype on the gut microbiome

To what extent do host genetics control the composition of the gut microbiome? Studies comparing the gut microbiota in human twins and across inbred mouse lines have yielded inconsistent answers to this question. However, candidate gene approaches, in which one gene is deleted or added to a model host organism, show that a single host gene can have a tremendous effect on the diversity and population structure of the gut microbiota. Now, quantitative genetics is emerging as a highly promising approach that can be used to better understand the overall architecture of host genetic influence on the microbiota, and to discover additional host genes controlling microbial diversity in the gut. In this Review, we describe how host genetics and the environment shape the microbiota, and how these three factors may interact in the context of chronic disease.     

Geographic pattern of antibiotic resistance genes in the metagenomes of the giant panda

The rise in infections by antibiotic-resistant bacteria poses a serious public health problem worldwide. The gut microbiome of animals is a reservoir for antibiotic resistance genes (ARGs). However, the correlation between the gut microbiome of wild animals and ARGs remains controversial. Here, based on the metagenomes of giant pandas (including three wild populations from the Qinling, Qionglai and Xiaoxiangling Mountains, and two major captive populations from Yaan and Chengdu), we investigated the potential correlation between the constitution of the gut microbiome and the composition of ARGs across the different geographic locations and living environments. We found that the types of ARGs were correlated with gut microbiome composition. The NMDS cluster analysis using Jaccard distance of the ARGs composition of the gut microbiome of wild giant pandas displayed a difference based on geographic location. Captivity also had an effect on the differences in ARGs composition. Furthermore, we found that the Qinling population exhibited profound dissimilarities of both gut microbiome composition and ARGs (the highest proportion of Clostridium and vancomycin resistance genes) when compared to the other wild and captive populations studies, which was supported by previous giant panda whole-genome sequencing analysis. In this study, we provide an example of a potential consensus pattern regarding host population genetics, symbiotic gut microbiome and ARGs. We revealed that habitat isolation impacts the ARG structure in the gut microbiome of mammals. Therefore, the difference in ARG composition between giant panda populations will provide some basic information for their conservation and management, especially for captive populations.     

Assessing age,breeding stage,and mating activity as drivers of variation in the reproductive microbiome of female tree swallows

Sexually transmitted microbes are hypothesized to influence the evolution of reproductive strategies. Though frequently discussed in this context, our understanding of the reproductive microbiome is quite nascent. Indeed, testing this hypothesis first requires establishing a baseline understanding of the temporal dynamics of the reproductive microbiome and of how individual variation in reproductive behavior and age influence the assembly and maintenance of the reproductive microbiome as a whole. Here, we ask how mating activity, breeding stage, and age influence the reproductive microbiome. We use observational and experimental approaches to explain variation in the cloacal microbiome of free‐living, female tree swallows (Tachycineta bicolor). Using microsatellite‐based parentage analyses, we determined the number of sires per brood (a proxy for female mating activity). We experimentally increased female sexual activity by administering exogenous 17ß‐estradiol. Lastly, we used bacterial 16S rRNA amplicon sequencing to characterize the cloacal microbiome. Neither the number of sires per brood nor the increased sexual activity of females significantly influenced female cloacal microbiome richness or community structure. Female age, however, was positively correlated with cloacal microbiome richness and influenced overall community structure. A hypothesis to explain these patterns is that the effect of sexual activity and the number of mates on variation in the cloacal microbiome manifests over an individual''s lifetime. Additionally, we found that cloacal microbiome alpha diversity (Shannon Index, Faith''s phylogenetic distance) decreased and community structure shifted between breeding stages. This is one of few studies to document within‐individual changes and age‐related differences in the cloacal microbiome across successive breeding stages. More broadly, our results contribute to our understanding of the role that host life history and behavior play in shaping the cloacal microbiomes of wild birds.     

Decomposing Spatial β‐Diversity in the temperate forests of Northeastern China

β‐Diversity, which describes the extent of change in species composition in a given region, has become a core issue in ecology in recent years. However, it is hard to understand the underlying mechanisms of β‐diversity by using indices that yield identical values under species replacement and nestedness pattern. Partitioning β‐diversity into turnover (caused by species replacement among plots) and nestedness components (caused by species loss or gain among plots) may provide improved understanding of the variation in species composition. Here, we collected presence–absence data of 456 one‐tenth ha circular plots in the temperate forests of Northeastern China spanning a latitudinal range of 12° (41–53°N). We decomposed β‐diversity to assess the relative contribution of the turnover and nestedness components across latitudinal gradients. We used regression analysis to assess the relationship between spatial distance and β‐diversity. We applied variation partitioning to evaluate the importance of the measured environmental and spatial variables in explaining β‐diversity. We used the Tukey honest significant difference test to test the differences of β‐diversity along latitudinal gradients. Pearson correlations (r) and significance (p‐value) were computed using the Mantel tests to verify the relationship between distance and β‐diversity. The ANOVA test was used to verify whether the variation of β‐diversity explained by the environment and distance was significant. Our results showed that (1) β‐diversity and the turnover component were higher at low latitudes (zones A and B) than at high latitudes (zones C and D), while there was no relationship between the nestedness component and latitude. (2) The turnover component was dominant. (3) The spatial distance explained more variation of β‐diversity than the measured environmental factors. Therefore, we conclude that β‐diversity is mainly a product of species turnover in our temperate forests, suggesting that different localities harbor different species. We find that decomposing β‐diversity into the turnover and nestedness components is a useful approach to explore the variation of community composition and their causes.     

Population genetic structure of the predatory,social wasp Vespula pensylvanica in its native and invasive range

Invasive species cause extensive damage to their introduced ranges. Ocean archipelagos are particularly vulnerable to invasive taxa. In this study, we used polymorphic microsatellite markers to investigate the genetic structure of the social wasp Vespula pensylvanica in its native range of North America and its introduced range in the archipelago of Hawaii. Our goal was to gain a better understanding of the invasion dynamics of social species and the processes affecting biological invasions. We found that V. pensylvanica showed no significant genetic isolation by distance and little genetic structure over a span of 2000 km in its native range. This result suggests that V. pensylvanica can successfully disperse across large distances either through natural‐ or human‐mediated mechanisms. In contrast to the genetic patterns observed in the native range, we found substantial genetic structure in the invasive V. pensylvanica range in Hawaii. The strong patterns of genetic differentiation within and between the Hawaiian Islands may reflect the effects of geographic barriers and invasion history on gene flow. We also found some evidence for gene flow between the different islands of Hawaii which was likely mediated through human activity. Overall, this study provides insight on how geographic barriers, invasion history, and human activity can shape population genetic structure of invasive species.     

The gut microbiome reflects ancestry despite dietary shifts across a hybrid zone

The microbiome is critical to an organism's phenotype, and its composition is shaped by, and a driver of, eco-evolutionary interactions. We investigated how host ancestry, habitat and diet shape gut microbial composition in a mammalian hybrid zone between Neotoma lepida and N. bryanti that occurs across an ecotone between distinct vegetation communities. We found that habitat is the primary determinant of diet, while host genotype is the primary determinant of the gut microbiome—a finding further supported by intermediate microbiome composition in first-generation hybrids. Despite these distinct primary drivers, microbial richness was correlated with diet richness, and individuals that maintained higher dietary richness had greater gut microbial community stability. Both relationships were stronger in the relative dietary generalist of the two parental species. Our findings show that host ancestry interacts with dietary habits to shape the microbiome, ultimately resulting in the phenotypic plasticity that host–microbial interactions allow.     

Gut microbiomes of free‐ranging and captive Namibian cheetahs: Diversity,putative functions and occurrence of potential pathogens

Although the significance of the gut microbiome for host health is well acknowledged, the impact of host traits and environmental factors on the interindividual variation of gut microbiomes of wildlife species is not well understood. Such information is essential; however, as changes in the composition of these microbial communities beyond the natural range might cause dysbiosis leading to increased susceptibility to infections. We examined the potential influence of sex, age, genetic relatedness, spatial tactics and the environment on the natural range of the gut microbiome diversity in free‐ranging Namibian cheetahs (Acinonyx jubatus). We further explored the impact of an altered diet and frequent contact with roaming dogs and cats on the occurrence of potential bacterial pathogens by comparing free‐ranging and captive individuals living under the same climatic conditions. Abundance patterns of particular bacterial genera differed between the sexes, and bacterial diversity and richness were higher in older (>3.5 years) than in younger individuals. In contrast, male spatial tactics, which probably influence host exposure to environmental bacteria, had no discernible effect on the gut microbiome. The profound resemblance of the gut microbiome of kin in contrast to nonkin suggests a predominant role of genetics in shaping bacterial community characteristics and functional similarities. We also detected various Operational Taxonomic Units (OTUs) assigned to potential pathogenic bacteria known to cause diseases in humans and wildlife species, such as Helicobacter spp., and Clostridium perfringens. Captive individuals did not differ in their microbial alpha diversity but exhibited higher abundances of OTUs related to potential pathogenic bacteria and shifts in disease‐associated functional pathways. Our study emphasizes the need to integrate ecological, genetic and pathogenic aspects to improve our comprehension of the main drivers of natural variation and shifts in gut microbial communities possibly affecting host health. This knowledge is essential for in situ and ex situ conservation management.     

Comparative metagenomics analysis reveals how the diet shapes the gut microbiota in several small mammals

The gut microbiomes of the host are large and complex communities, which helps to maintain homeostasis, improves digestive efficiency, and promotes the development of the immune system. The small mammals distributed in Sichuan Province are the most popular species for biodiversity research in Southwest China. However, the effects of different diets on the structure and function of the gut microbial community of these small mammals are poorly understood. In this study, whole‐metagenome shotgun sequencing has been used to analyze the composition and functional structures of the gut microbiota of seven small mammals in Laojunshan National Nature Reserve, Sichuan Province, China. Taxonomic classification revealed that the most abundant phyla in the gut of seven small mammals were Bacteroides, Proteobacteria, and Firmicutes. Moreover, Hafnia, Lactobacillus, and Yersinia were the most abundant genus in the gut microbiomes of these seven species. At the functional level, we annotated a series of KEGG functional pathways, six Cazy categories, and 46,163 AROs in the gut microbiomes of the seven species. Comparative analysis found that the difference in the gut microbiomes between the Soricidea and Muridae concentrated on the increase in the F/B (Firmicutes/Bacteroides) ratio in the Soricidea group, probably driven by the high‐fat and ‐calorie digestive requirements due to their insectivorous diet. The comparative functional profiling revealed that functions related to metabolism and carbohydrates were significantly more abundant in Muridae group, which may be attributed to their high carbohydrate digestion requirements caused by their herbivorous diet. These data suggested that different diets in the host may play an important role in shaping the gut microbiota, and lay the foundation for teasing apart the influences of heritable and environmental factors on the evolution of gut microbial communities.     

The role of anthropogenic dispersal in shaping the distribution and genetic composition of a widespread North American tree species

Dispersal and colonization are among the most important ecological processes for species persistence as they allow species to track changing environmental conditions. During the last glacial maximum (LGM), many cold‐intolerant Northern Hemisphere plants retreated to southern glacial refugia. During subsequent warming periods, these species expanded their ranges northward. Interestingly, some tree species with limited seed dispersal migrated considerable distances after the LGM ~19,000 years before present (YBP). It has been hypothesized that indigenous peoples may have dispersed valued species, in some cases beyond the southern limits of the Laurentide Ice Sheet. To investigate this question, we employed a molecular genetics approach on a widespread North American understory tree species whose fruit was valued by indigenous peoples. Twenty putative anthropogenic (near pre‐Columbian habitations) and 62 wild populations of Asimina triloba (pawpaw), which produces the largest edible fruit of any North American tree, were genetically assayed with nine microsatellite loci. Putative anthropogenic populations were characterized by reduced genetic diversity and greater excess heterozygosity relative to wild populations. Anthropogenic populations in regions that were glaciated during the LGM had profiles consistent with founder effects and reduced gene flow, and shared rare alleles with wild populations hundreds of kilometers away (mean = 723 km). Some of the most compelling evidence for human‐mediated dispersal is that putative anthropogenic and wild populations sharing rare alleles were separated by significantly greater distances (mean = 695 km) than wild populations sharing rare alleles (mean = 607 km; p = .014). Collectively, the genetic data suggest that long‐distance dispersal played an important role in the distribution of pawpaw and is consistent with the hypothesized role of indigenous peoples.     

Lack of Spatial Immunogenetic Structure among Wolverine (Gulo gulo) Populations Suggestive of Broad Scale Balancing Selection

Elucidating the adaptive genetic potential of wildlife populations to environmental selective pressures is fundamental for species conservation. Genes of the major histocompatibility complex (MHC) are highly polymorphic, and play a key role in the adaptive immune response against pathogens. MHC polymorphism has been linked to balancing selection or heterogeneous selection promoting local adaptation. However, spatial patterns of MHC polymorphism are also influenced by gene flow and drift. Wolverines are highly vagile, inhabiting varied ecoregions that include boreal forest, taiga, tundra, and high alpine ecosystems. Here, we investigated the immunogenetic variation of wolverines in Canada as a surrogate for identifying local adaptation by contrasting the genetic structure at MHC relative to the structure at 11 neutral microsatellites to account for gene flow and drift. Evidence of historical positive selection was detected at MHC using maximum likelihood codon-based methods. Bayesian and multivariate cluster analyses revealed weaker population genetic differentiation at MHC relative to the increasing microsatellite genetic structure towards the eastern wolverine distribution. Mantel correlations of MHC against geographical distances showed no pattern of isolation by distance (IBD: r = -0.03, p = 0.9), whereas for microsatellites we found a relatively strong and significant IBD (r = 0.54, p = 0.01). Moreover, we found a significant correlation between microsatellite allelic richness and the mean number of MHC alleles, but we did not observe low MHC diversity in small populations. Overall these results suggest that MHC polymorphism has been influenced primarily by balancing selection and to a lesser extent by neutral processes such as genetic drift, with no clear evidence for local adaptation. This study contributes to our understanding of how vulnerable populations of wolverines may respond to selective pressures across their range.     

Molecular approaches reveal weak sibship aggregation and a high dispersal propensity in a non‐native fish parasite

Inferring parameters related to the aggregation pattern of parasites and to their dispersal propensity are important for predicting their ecological consequences and evolutionary potential. Nonetheless, it is notoriously difficult to infer these parameters from wildlife parasites given the difficulty in tracking these organisms. Molecular‐based inferences constitute a promising approach that has yet rarely been applied in the wild. Here, we combined several population genetic analyses including sibship reconstruction to document the genetic structure, patterns of sibship aggregation, and the dispersal dynamics of a non‐native parasite of fish, the freshwater copepod ectoparasite Tracheliastes polycolpus. We collected parasites according to a hierarchical sampling design, with the sampling of all parasites from all host individuals captured in eight sites spread along an upstream–downstream river gradient. Individual multilocus genotypes were obtained from 14 microsatellite markers, and used to assign parasites to full‐sib families and to investigate the genetic structure of T. polycolpus among both hosts and sampling sites. The distribution of full‐sibs obtained among the sampling sites was used to estimate individual dispersal distances within families. Our results showed that T. polycolpus sibs tend to be aggregated within sites but not within host individuals. We detected important upstream‐to‐downstream dispersal events of T. polycolpus between sites (modal distance: 25.4 km; 95% CI [22.9, 27.7]), becoming scarcer as the geographic distance from their family core location increases. Such a dispersal pattern likely contributes to the strong isolation‐by‐distance observed at the river scale. We also detected some downstream‐to‐upstream dispersal events (modal distance: 2.6 km; 95% CI [2.2–23.3]) that likely result from movements of infected hosts. Within each site, the dispersal of free‐living infective larvae among hosts likely contributes to increasing genetic diversity on hosts, possibly fostering the evolutionary potential of T. polycolpus.     

Towards a mechanistic understanding of reciprocal drug–microbiome interactions

Broad‐spectrum antibiotics target multiple gram‐positive and gram‐negative bacteria, and can collaterally damage the gut microbiota. Yet, our knowledge of the extent of damage, the antibiotic activity spectra, and the resistance mechanisms of gut microbes is sparse. This limits our ability to mitigate microbiome‐facilitated spread of antibiotic resistance. In addition to antibiotics, non‐antibiotic drugs affect the human microbiome, as shown by metagenomics as well as in vitro studies. Microbiome–drug interactions are bidirectional, as microbes can also modulate drugs. Chemical modifications of antibiotics mostly function as antimicrobial resistance mechanisms, while metabolism of non‐antibiotics can also change the drugs’ pharmacodynamic, pharmacokinetic, and toxic properties. Recent studies have started to unravel the extensive capacity of gut microbes to metabolize drugs, the mechanisms, and the relevance of such events for drug treatment. These findings raise the question whether and to which degree these reciprocal drug–microbiome interactions will differ across individuals, and how to take them into account in drug discovery and precision medicine. This review describes recent developments in the field and discusses future study areas that will benefit from systems biology approaches to better understand the mechanistic role of the human gut microbiota in drug actions.