Modelling the emergent dynamics and major metabolites of the human colonic microbiota

We present here a first attempt at modelling microbial dynamics in the human colon incorporating both uncertainty and adaptation. This is based on the development of a Monod‐equation based, differential equation model, which produces computer simulations of the population dynamics and major metabolites of microbial communities from the human colon. To reduce the complexity of the system, we divide the bacterial community into 10 bacterial functional groups (BFGs) each distinguished by its substrate preferences, metabolic pathways and its preferred pH range. The model simulates the growth of a large number of bacterial strains and incorporates variation in microbiota composition between people, while also allowing succession and enabling adaptation to environmental changes. The model is shown to reproduce many of the observed changes in major phylogenetic groups and key metabolites such as butyrate, acetate and propionate in response to a one unit pH shift in experimental continuous flow fermentors inoculated with human faecal microbiota. Nevertheless, it should be regarded as a learning tool to be updated as our knowledge of bacterial groups and their interactions expands. Given the difficulty of accessing the colon, modelling can play an extremely important role in interpreting experimental data and predicting the consequences of dietary modulation.     

Iron in infectious diseases friend or foe?: The role of gut microbiota

Iron is a trace element involved in metabolic functions for all organisms, from microorganisms to mammalians. Iron deficiency is a prevalent health problem that affects billions of people worldwide, and iron overload could have some hazardous effect. The complex microbial community in the human body, also called microbiota, influences the host immune defence against infections. An imbalance in gut microbiota, dysbiosis, changes the host's susceptibility to infections by regulating the immune system. In recent years, the number of studies on the relationship between infectious diseases and microbiota has increased. Gut microbiota is affected by different parameters, including mode of delivery, hygiene habits, diet, drugs, and plasma iron levels during the lifetime. Gut microbiota may influence iron levels in the body, and iron overload and deficiency can also affect gut microbiota composition. Novel researches on microbiota shed light on the fact that the bidirectional interactions between gut microbiota and iron play a role in the pathogenesis of many diseases, especially infections. A better understanding of these interactions may help us to comprehend the pathogenesis of many infectious and metabolic diseases affecting people worldwide and following the development of more effective preventive and/or therapeutic strategies. In this review, we aimed to present the iron-mediated host-gut microbiota interactions, susceptibility to bacterial infections, and iron-targeted therapy approaches for infections.     

Bacterial microbiota similarity between predators and prey in a blue tit trophic network

Trophic networks are composed of many organisms hosting microbiota that interact with their hosts and with each other. Yet, our knowledge of the factors driving variation in microbiota and their interactions in wild communities is limited. To investigate the relation among host microbiota across a trophic network, we studied the bacterial microbiota of two species of primary producers (downy and holm oaks), a primary consumer (caterpillars), and a secondary consumer (blue tits) at nine sites in Corsica. To quantify bacterial microbiota, we amplified 16S rRNA gene sequences in blue tit feces, caterpillars, and leaf samples. Our results showed that hosts from adjacent trophic levels had a more similar bacterial microbiota than hosts separated by two trophic levels. Our results also revealed a difference between bacterial microbiota present on the two oak species, and among leaves from different sites. The main drivers of bacterial microbiota variation within each trophic level differed across spatial scales, and sharing the same tree or nest box increased similarity in bacterial microbiota for caterpillars and blue tits. This study quantifies host microbiota interactions across a three-level trophic network and illustrates how the factors shaping bacterial microbiota composition vary among different hosts.Subject terms: Food webs, Microbial ecology     

Aquacultured Rainbow Trout (Oncorhynchus mykiss) Possess a Large Core Intestinal Microbiota That Is Resistant to Variation in Diet and Rearing Density

As global aquaculture fish production continues to expand, an improved understanding of how environmental factors interact in fish health and production is needed. Significant advances have been made toward economical alternatives to costly fishmeal-based diets, such as grain-based formulations, and toward defining the effect of rearing density on fish health and production. Little research, however, has examined the effects of fishmeal- and grain-based diets in combination with alterations in rearing density. Moreover, it is unknown whether interactions between rearing density and diet impact the composition of the fish intestinal microbiota, which might in turn impact fish health and production. We fed aquacultured adult rainbow trout (Oncorhynchus mykiss) fishmeal- or grain-based diets, reared them under high- or low-density conditions for 10 months in a single aquaculture facility, and evaluated individual fish growth, production, fin indices, and intestinal microbiota composition using 16S rRNA gene sequencing. We found that the intestinal microbiotas were dominated by a shared core microbiota consisting of 52 bacterial lineages observed across all individuals, diets, and rearing densities. Variations in diet and rearing density resulted in only minor changes in intestinal microbiota composition despite significant effects of these variables on fish growth, performance, fillet quality, and welfare. Significant interactions between diet and rearing density were observed only in evaluations of fin indices and the relative abundance of the bacterial genus Staphylococcus. These results demonstrate that aquacultured rainbow trout can achieve remarkable consistency in intestinal microbiota composition and suggest the possibility of developing novel aquaculture strategies without overtly altering intestinal microbiota composition.     

The role of the commensal microbiota in adaptive and maladaptive stressor-induced immunomodulation

Over the past decade, it has become increasingly evident that there are extensive bidirectional interactions between the body and its microbiota. These interactions are evident during stressful periods, where it is recognized that commensal microbiota community structure is significantly changed. Many different stressors, ranging from early life stressors to stressors administered during adulthood, lead to significant, community-wide differences in the microbiota. The mechanisms through which this occurs are not yet known, but it is known that commensal microbes can recognize, and respond to, mammalian hormones and neurotransmitters, including those that are involved with the physiological response to stressful stimuli. In addition, the physiological stress response also changes many aspects of gastrointestinal physiology that can impact microbial community composition. Thus, there are many routes through which microbial community composition might be disrupted during stressful periods. The implications of these disruptions in commensal microbial communities for host health are still not well understood, but the commensal microbiota have been linked to stressor-induced immunopotentiation. The role of the microbiota in stressor-induced immunopotentiation can be adaptive, such as when these microbes stimulate innate defenses against bacterial infection. However, the commensal microbiota can also lead to maladaptive immune responses during stressor-exposure. This is evident in animal models of colonic inflammation where stressor exposure increases the inflammation through mechanisms involving the microbiota. It is likely that during stressor exposure, immune cell functioning is regulated by combined effects of both neurotransmitters/hormones and commensal microbes. Defining this regulation should be a focus of future studies.     

The Molecular Basis of Bacterial–Insect Symbiosis

Insects provide experimentally tractable and cost-effective model systems to investigate the molecular basis of animal–bacterial interactions. Recent research is revealing the central role of the insect innate immune system, especially anti-microbial peptides and reactive oxygen species, in regulating the abundance and composition of the microbiota in various insects, including Drosophila and the mosquitoes Aedes and Anopheles. Interactions between the immune system and microbiota are, however, bidirectional with evidence that members of the resident microbiota can promote immune function, conferring resistance to pathogens and parasites by both activation of immune effectors and production of toxins. Antagonistic and mutualistic interactions among bacteria have also been implicated as determinants of the microbiota composition, including exclusion of pathogens, but the molecular mechanisms are largely unknown. Some bacteria are crucial for insect nutrition, through provisioning of specific nutrients (e.g., B vitamins, essential amino acids) and modulation of the insect nutritional sensing and signaling pathways (e.g., insulin signaling) that regulate nutrient allocation, especially to lipid and other energy reserves. A key challenge for future research is to identify the molecular interaction between specific bacterial effectors and animal receptors, as well as to determine how these interactions translate into microbiota-dependent signaling, metabolism, and immune function in the host.     

Next‐generation sequencing sheds light on intricate regulation of insect gut microbiota

Next‐generation sequencing (NGS) technologies are getting cheaper and easier and hence becoming readily accessible for many researchers in biological disciplines including ecology. In this issue of Molecular Ecology, Sudakaran et al. (2012) show how the NGS revolution contributes to our better and more comprehensive understanding of ecological interactions between gut symbiotic microbiota and the host organism. Using the European red firebug Pyrrhocoris apterus as a model system, they demonstrated that the gut microbiota consists of a small number of major bacterial phylotypes plus other minor bacterial associates. The major bacteria are localized in a specific anoxic section of the midgut and quantitatively account for most of the gut microbiota irrespective of host's geographic populations. The specific gut microbiota is established through early nymphal development of the host insect. Interestingly, the host feeding on different food, namely linden seeds, sunflower seeds or wasp larvae, scarcely affected the symbiont composition, suggesting homoeostatic control over the major symbiotic microbiota in the anoxic section of the midgut. Some of the minor components of the gut microbiota, which conventional PCR/cloning/sequencing approaches would have failed to detect, were convincingly shown to be food‐derived. These findings rest on the robust basis of high‐throughput sequencing data, and some of them could not be practically obtained by conventional molecular techniques, highlighting the significant impact of NGS approaches on ecological aspects of host–symbiont interactions in a nonmodel organism.     

Ecological Modeling from Time-Series Inference: Insight into Dynamics and Stability of Intestinal Microbiota

The intestinal microbiota is a microbial ecosystem of crucial importance to human health. Understanding how the microbiota confers resistance against enteric pathogens and how antibiotics disrupt that resistance is key to the prevention and cure of intestinal infections. We present a novel method to infer microbial community ecology directly from time-resolved metagenomics. This method extends generalized Lotka–Volterra dynamics to account for external perturbations. Data from recent experiments on antibiotic-mediated Clostridium difficile infection is analyzed to quantify microbial interactions, commensal-pathogen interactions, and the effect of the antibiotic on the community. Stability analysis reveals that the microbiota is intrinsically stable, explaining how antibiotic perturbations and C. difficile inoculation can produce catastrophic shifts that persist even after removal of the perturbations. Importantly, the analysis suggests a subnetwork of bacterial groups implicated in protection against C. difficile. Due to its generality, our method can be applied to any high-resolution ecological time-series data to infer community structure and response to external stimuli.     

Daily follow-up of bacterial communities in the human gut reveals stable composition and host-specific patterns of interaction

In the last decade, an extensive effort has been made to characterize the human intestinal microbiota by means of SSU rRNA gene sequence and metagenomic analysis. Relatively few studies have followed intestinal bacterial communities over time to assess their stability in the absence of perturbation. In this study, we have monitored the faecal bacteria of three healthy subjects during 15 consecutive days. The global community structure was analysed through SSU rRNA gene sequencing. In agreement with previous studies, we found that the between-subject variation in community structure was larger than within. The composition was fairly stable throughout, although daily fluctuations were detected for all genera and phylotypes at 97% of sequence identity. While the core shared between subjects was very small, each subject harboured a stable high-abundance core composed of a small number of bacterial groups (9% of the phylotypes accounted for between 74% and 93% of the sequences). This may suggest that studies aimed at linking the microbiota composition with disease risk should be limited to the numerically most dominant phylotypes, as the rest appears transient. Networks of potential interactions between co-occurring genera were also subject-specific, even for the same bacterial genus, which might be reflecting host-specific selective pressures and historic events.     

Interspecies bacterial competition regulates community assembly in the C. elegans intestine

From insects to mammals, a large variety of animals hold in their intestines complex bacterial communities that play an important role in health and disease. To further our understanding of how intestinal bacterial communities assemble and function, we study the C. elegans microbiota with a bottom-up approach by feeding this nematode with bacterial monocultures as well as mixtures of two to eight bacterial species. We find that bacteria colonizing well in monoculture do not always do well in co-cultures due to interspecies bacterial interactions. Moreover, as community diversity increases, the ability to colonize the worm gut in monoculture becomes less important than interspecies interactions for determining community assembly. To explore the role of host–microbe adaptation, we compare bacteria isolated from C. elegans intestines and non-native isolates, and we find that the success of colonization is determined more by a species’ taxonomy than by the isolation source. Lastly, by comparing the assembled microbiotas in two C. elegans mutants, we find that innate immunity via the p38 MAPK pathway decreases bacterial abundances yet has little influence on microbiota composition. These results highlight that bacterial interspecies interactions, more so than host–microbe adaptation or gut environmental filtering, play a dominant role in the assembly of the C. elegans microbiota.Subject terms: Microbiome, Microbial ecology     

A Feeding Induced Switch from a Variable to a Homogenous State of the Earthworm Gut Microbiota within a Host Population

Background

The distribution pattern of the earthworm gut microbiota at the host population level is of fundamental importance to understand host-microbiota interactions. Our current understanding of these interactions is very limited. Since feeding represents a main perturbation of the gut microbiota, we determined the effect of a single dose of feed on the microbiota associated with an earthworm population in a simulated microenvironment.

Methodology

Earthworms were sampled 0, 1 and 7 days after feeding. We determined the overall composition of the earthworm-associated microbiota by 16S rRNA gene cloning and sequencing. Based on the 16S rRNA gene data we constructed quantitative PCR''s (Q-PCR) for the seven most dominating bacterial groups.

Principal Findings

Q-PCR revealed low density and highly variable microbiota among the earthworms before feeding, while a high-density homologous microbiota resulted from feeding. We found that the microbiota 1 day after feeding was more equal to the microbiota after 7 days than before feeding. Furthermore, we found that the gut microbiota was very distinct from that of the bedding and the feed.

Significance

The homogenous population response represents fundamental new knowledge about earthworm gut associated bacteria.     

Gut microbiome in cancer immunotherapy: Current trends,translational challenges and future possibilities

Gut microbiota is regarded as a crucial regulator of the immune system. Healthy gut microbiota plays a specialized role in host xenobiotics, nutrition, drug metabolism, regulation of the structural integrity of the gut mucosal barrier, defense against infections, and immunomodulation. It is now understood that any imbalance in gut microbiota composition from that present in a healthy state is linked to genetic susceptibility to a number of metabolic disorders, including diabetes, autoimmunity, and cancer. Recent research has suggested that immunotherapy can treat many different cancer types with fewer side effects and better ability to eradicate tumors than conventional chemotherapy or radiotherapy. However, a significant number of patients eventually develop immunotherapy resistance. A strong correlation was observed between the composition of the gut microbiome and the effectiveness of treatment by examining the variations between populations that responded to immunotherapy and those that did not. Therefore, we suggest that modulating the microbiome could be a potential adjuvant therapy for cancer immunotherapy and that the architecture of the gut microbiota may be helpful in explaining the variation in treatment response. Herein, we focus on recent research on the interactions among the gut microbiome, host immunity, and cancer immunotherapy. In addition, we highlighted the clinical manifestations, future opportunities, and limitations of microbiome manipulation in cancer immunotherapy.     

Unraveling negative biotic interactions determining soil microbial community assembly and functioning

Microbial communities play important roles in all ecosystems and yet a comprehensive understanding of the ecological processes governing the assembly of these communities is missing. To address the role of biotic interactions between microorganisms in assembly and for functioning of the soil microbiota, we used a top-down manipulation approach based on the removal of various populations in a natural soil microbial community. We hypothesized that removal of certain microbial groups will strongly affect the relative fitness of many others, therefore unraveling the contribution of biotic interactions in shaping the soil microbiome. Here we show that 39% of the dominant bacterial taxa across treatments were subjected to competitive interactions during soil recolonization, highlighting the importance of biotic interactions in the assembly of microbial communities in soil. Moreover, our approach allowed the identification of microbial community assembly rule as exemplified by the competitive exclusion between members of Bacillales and Proteobacteriales. Modified biotic interactions resulted in greater changes in activities related to N- than to C-cycling. Our approach can provide a new and promising avenue to study microbial interactions in complex ecosystems as well as the links between microbial community composition and ecosystem function.Subject terms: Soil microbiology, Ecology     

Chemical regulation of body feather microbiota in a wild bird

The microbiota has a broad range of impacts on host physiology and behaviour, pointing out the need to improve our comprehension of the drivers of host–microbiota composition. Of particular interest is whether the microbiota is acquired passively, or whether and to what extent hosts themselves shape the acquisition and maintenance of their microbiota. In birds, the uropygial gland produces oily secretions used to coat feathers that have been suggested to act as an antimicrobial defence mechanism regulating body feather microbiota. However, our comprehension of this process is still limited. In this study, we for the first time coupled high‐throughput sequencing of the microbiota of both body feathers and the direct environment (i.e., the nest) in great tits with chemical analyses of the composition of uropygial gland secretions to examine whether host chemicals have either specific effects on some bacteria or nonspecific broad‐spectrum effects on the body feather microbiota. Using a network approach investigating the patterns of co‐occurrence or co‐exclusions between chemicals and bacteria within the body feather microbiota, we found no evidence for specific promicrobial or antimicrobial effects of uropygial gland chemicals. However, we found that one group of chemicals was negatively correlated to bacterial richness on body feathers, and a higher production of these chemicals was associated with a poorer body feather bacterial richness compared to the nest microbiota. Our study provides evidence that chemicals produced by the host might function as a nonspecific broad‐spectrum antimicrobial defence mechanism limiting colonization and/or maintenance of bacteria on body feathers, providing new insight about the drivers of the host's microbiota composition in wild organisms.     

Deterministic Assembly of Complex Bacterial Communities in Guts of Germ-Free Cockroaches

The gut microbiota of termites plays important roles in the symbiotic digestion of lignocellulose. However, the factors shaping the microbial community structure remain poorly understood. Because termites cannot be raised under axenic conditions, we established the closely related cockroach Shelfordella lateralis as a germ-free model to study microbial community assembly and host-microbe interactions. In this study, we determined the composition of the bacterial assemblages in cockroaches inoculated with the gut microbiota of termites and mice using pyrosequencing analysis of their 16S rRNA genes. Although the composition of the xenobiotic communities was influenced by the lineages present in the foreign inocula, their structure resembled that of conventional cockroaches. Bacterial taxa abundant in conventional cockroaches but rare in the foreign inocula, such as Dysgonomonas and Parabacteroides spp., were selectively enriched in the xenobiotic communities. Donor-specific taxa, such as endomicrobia or spirochete lineages restricted to the gut microbiota of termites, however, either were unable to colonize germ-free cockroaches or formed only small populations. The exposure of xenobiotic cockroaches to conventional adults restored their normal microbiota, which indicated that autochthonous lineages outcompete foreign ones. Our results provide experimental proof that the assembly of a complex gut microbiota in insects is deterministic.     

Gut microbiota instead of host genotype drive the specificity in the interaction of a natural host-parasite system

Specific interactions between parasite genotypes and host genotypes (G_p × G_h) are commonly found in invertebrate systems, but are largely lacking a mechanistic explanation. The genotype of invertebrate hosts can be complemented by the genomes of microorganisms living on or within the host (‘microbiota’). We investigated whether the bacterial gut microbiota of bumble bees (Bombus terrestris) can account for the specificity of interactions between individuals from different colonies (previously taken as host genotype proxy) and genotypes of the parasite Crithidia bombi. For this, we transplanted the microbiota between individuals of six colonies. Both the general infection load and the specific success of different C. bombi genotypes were mostly driven by the microbiota, rather than by worker genotype. Variation in gut microbiota can therefore be responsible for specific immune phenotypes and the evolution of gut parasites may be driven by interactions with ‘microbiota types’ as well as with host genotypes.     

The intestinal microbiota plays a role in Salmonella-induced colitis independent of pathogen colonization

The intestinal microbiota is composed of hundreds of species of bacteria, fungi and protozoa and is critical for numerous biological processes, such as nutrient acquisition, vitamin production, and colonization resistance against bacterial pathogens. We studied the role of the intestinal microbiota on host resistance to Salmonella enterica serovar Typhimurium-induced colitis. Using multiple antibiotic treatments in 129S1/SvImJ mice, we showed that disruption of the intestinal microbiota alters host susceptibility to infection. Although all antibiotic treatments caused similar increases in pathogen colonization, the development of enterocolitis was seen only when streptomycin or vancomycin was used; no significant pathology was observed with the use of metronidazole. Interestingly, metronidazole-treated and infected C57BL/6 mice developed severe pathology. We hypothesized that the intestinal microbiota confers resistance to infectious colitis without affecting the ability of S. Typhimurium to colonize the intestine. Indeed, different antibiotic treatments caused distinct shifts in the intestinal microbiota prior to infection. Through fluorescence in situ hybridization, terminal restriction fragment length polymorphism, and real-time PCR, we showed that there is a strong correlation between the intestinal microbiota composition before infection and susceptibility to Salmonella-induced colitis. Members of the Bacteroidetes phylum were present at significantly higher levels in mice resistant to colitis. Further analysis revealed that Porphyromonadaceae levels were also increased in these mice. Conversely, there was a positive correlation between the abundance of Lactobacillus sp. and predisposition to colitis. Our data suggests that different members of the microbiota might be associated with S. Typhimurium colonization and colitis. Dissecting the mechanisms involved in resistance to infection and inflammation will be critical for the development of therapeutic and preventative measures against enteric pathogens.