Christoph A. Thaiss

Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms.

Inflammation is a fundamental innate immune response to perturbed tissue homeostasis. Chronic inflammatory processes affect all stages of tumour development as well as therapy. In this Review, we outline the principal cellular and molecular pathways that coordinate the tumour-promoting and tumour-antagonizing effects of inflammation and we discuss the crosstalk between cancer development and inflammatory processes. In addition, we discuss the recently suggested role of commensal microorganisms in inflammation-induced cancer and we propose that understanding this microbial influence will be crucial for targeted therapy in modern cancer treatment.

Artificial sweeteners induce glucose intolerance by altering the gut microbiota

Non-caloric artificial sweeteners (NAS) are among the most widely used food additives worldwide, regularly consumed by lean and obese individuals alike. NAS consumption is considered safe and beneficial owing to their low caloric content, yet supporting scientific data remain sparse and controversial. Here we demonstrate that consumption of commonly used NAS formulations drives the development of glucose intolerance through induction of compositional and functional alterations to the intestinal microbiota. These NAS-mediated deleterious metabolic effects are abrogated by antibiotic treatment, and are fully transferrable to germ-free mice upon faecal transplantation of microbiota configurations from NAS-consuming mice, or of microbiota anaerobically incubated in the presence of NAS. We identify NAS-altered microbial metabolic pathways that are linked to host susceptibility to metabolic disease, and demonstrate similar NAS-induced dysbiosis and glucose intolerance in healthy human subjects. Collectively, our results link NAS consumption, dysbiosis and metabolic abnormalities, thereby calling for a reassessment of massive NAS usage.

The microbiome and innate immunity

The intestinal microbiome is a signalling hub that integrates environmental inputs, such as diet, with genetic and immune signals to affect the hosts metabolism, immunity and response to infection. The haematopoietic and non-haematopoietic cells of the innate immune system are located strategically at the host–microbiome interface. These cells have the ability to sense microorganisms or their metabolic products and to translate the signals into host physiological responses and the regulation of microbial ecology. Aberrations in the communication between the innate immune system and the gut microbiota might contribute to complex diseases.

Microglia development follows a stepwise program to regulate brain homeostasis.

Microglia development follows a stepwise program Microglia are cells that defend the central nervous system. However, because they migrate into the brain during development, the changes that they undergo, including those that affect gene expression, have been difficult to document. Matcovitch-Natan et al. transcriptionally profiled gene expression and analyzed epigenetic signatures of microglia at the single-cell level in the early postnatal life of mice. They identified three stages of microglia development, which are characterized by gene expression and linked with chromatin changes, occurring in sync with the developing brain. Furthermore, they showed that the proper development of microglia is affected by the microbiome. Science, this issue p. 789 The microbiota help regulate the development of active immune defense in the central nervous system of mice. INTRODUCTION Microglia, as the resident myeloid cells of the central nervous system, play an important role in life-long brain maintenance and in pathology. Microglia are derived from erythromyeloid progenitors that migrate to the brain starting at embryonic day 8.5 and continuing until the blood-brain barrier is formed; after this, self-renewal is the only source of new microglia in the healthy brain. As the brain develops, microglia must perform different functions to accommodate temporally changing needs: first, actively engaging in synapse pruning and neurogenesis, and later, maintaining homeostasis. Although the interactions of microglia with the brain environment at steady state and in response to immune challenges have been well studied, their dynamics during development have not been fully elucidated. RATIONALE We systematically studied the transcriptional and epigenomic regulation of microglia throughout brain development to decipher the dynamics of the chromatin state and gene networks governing the transformation from yolk sac progenitor to adult microglia. We used environmental and genetic perturbation models to investigate how timed disruptions to microglia impact their natural development. RESULTS Global profiles of transcriptional states indicated that microglia development proceeds through three distinct temporal stages, which we define as early microglia (until embryonic day 14), pre-microglia (from embryonic day 14 to a few weeks after birth), and adult microglia (from a few weeks after birth onward). ATAC-seq (assay for transposase-accessible chromatin followed by sequencing) for chromatin accessibility and ChIP-seq (chromatin immunoprecipitation followed by sequencing) for histone modifications further characterized the differential regulatory elements in each developmental phase. Single-cell transcriptome analysis revealed minor mixing of the gene expression programs across phases, suggesting that individual cells shift their regulatory networks during development in a coordinated manner. Specific markers and regulatory factors distinguish each phase: For example, we identified MAFB as an important transcription factor of the adult microglia program. Microglia-specific knockout of MafB led to disruption of homeostasis in adulthood and increased expression of interferon and inflammation pathways. We found that microglia from germ-free mice exhibited dysregulation of dozens of genes associated with the adult phase and immune response. In addition, maternal immune activation, which has been linked to behavioral disorders in adult offspring, had the greatest impact on pre-microglia, resulting in a transcriptional shift toward the more advanced developmental stage. CONCLUSION Our work identifies a stepwise developmental program of microglia in synchrony with the developing brain. Each stage of microglia development has evolved distinct pathways for processing the relevant signals from the environment to balance their time-dependent role in neurogenesis with regulation of immune responses that may cause collateral damage. Genetic or environmental perturbations of these pathways can disrupt stage-specific functions of microglia and lead to loss of brain homeostasis, which may be associated with neurodevelopmental disorders. Microglia development proceeds in a stepwise manner. Microglia were isolated from mice throughout development from embryo to adult. Data from population-level RNA-seq, ChIP-seq, and ATAC-seq, as well as single-cell RNA-seq, show that microglia development proceeds through three distinct stages—early, pre-, and adult— with characteristic gene expression and functional states. Perturbations of this developmental process, such as from MafB knockout, lead to disrupted brain homeostasis by the dysregulation of adult and inflammatory genes. Tn5, transposase 5. Microglia, the resident myeloid cells of the central nervous system, play important roles in life-long brain maintenance and in pathology. Despite their importance, their regulatory dynamics during brain development have not been fully elucidated. Using genome-wide chromatin and expression profiling coupled with single-cell transcriptomic analysis throughout development, we found that microglia undergo three temporal stages of development in synchrony with the brain—early, pre-, and adult microglia—which are under distinct regulatory circuits. Knockout of the gene encoding the adult microglia transcription factor MAFB and environmental perturbations, such as those affecting the microbiome or prenatal immune activation, led to disruption of developmental genes and immune response pathways. Together, our work identifies a stepwise microglia developmental program integrating immune response pathways that may be associated with several neurodevelopmental disorders.

Microbiota Diurnal Rhythmicity Programs Host Transcriptome Oscillations

The intestinal microbiota undergoes diurnal compositional and functional oscillations that affect metabolic homeostasis, but the mechanisms by which the rhythmic microbiota influences host circadian activity remain elusive. Using integrated multi-omics and imaging approaches, we demonstrate that the gut microbiota features oscillating biogeographical localization and metabolome patterns that determine the rhythmic exposure of the intestinal epithelium to different bacterial species and their metabolites over the course of a day. This diurnal microbial behavior drives, in turn, the global programming of the host circadian transcriptional, epigenetic, and metabolite oscillations. Surprisingly, disruption of homeostatic microbiome rhythmicity not only abrogates normal chromatin and transcriptional oscillations of the host, but also incites genome-wide de novo oscillations in both intestine and liver, thereby impacting diurnal fluctuations of host physiology and disease susceptibility. As such, the rhythmic biogeography and metabolome of the intestinal microbiota regulates the temporal organization and functional outcome of host transcriptional and epigenetic programs.

Growth dynamics of gut microbiota in health and disease inferred from single metagenomic samples

Estimating bacterial growth dynamics The pattern of sequencing read coverage of bacteria in metagenomic samples reflects the growth rate. This pattern is predictive of growth because bacterial genomes are circular, with a single origin of replication. So during growth, copies of the genome accumulate at the origin. Korem et al. use the ratio of copy number at the origin to the copy number at the terminus to detect the actively growing species in a microbiome (see the Perspective by Segre). They could spot the difference between virulent and avirulent strains, population diurnal oscillations, species that are growing in irritable bowel disease, and what happens when a hosts diet changes. Results were consistent in chemostats, in mice, and in human fecal samples. Science, this issue p. 1101; see also p. 1058 A new method provides a quantitative measure of the growth rate of multiple gut microbes in one go. [Also see Perspective by Segre] Metagenomic sequencing increased our understanding of the role of the microbiome in health and disease, yet it only provides a snapshot of a highly dynamic ecosystem. Here, we show that the pattern of metagenomic sequencing read coverage for different microbial genomes contains a single trough and a single peak, the latter coinciding with the bacterial origin of replication. Furthermore, the ratio of sequencing coverage between the peak and trough provides a quantitative measure of a species’ growth rate. We demonstrate this in vitro and in vivo, under different growth conditions, and in complex bacterial communities. For several bacterial species, peak-to-trough coverage ratios, but not relative abundances, correlated with the manifestation of inflammatory bowel disease and type II diabetes.

Persistent microbiome alterations modulate the rate of post-dieting weight regain

In tackling the obesity pandemic, considerable efforts are devoted to the development of effective weight reduction strategies, yet many dieting individuals fail to maintain a long-term weight reduction, and instead undergo excessive weight regain cycles. The mechanisms driving recurrent post-dieting obesity remain largely elusive. Here we identify an intestinal microbiome signature that persists after successful dieting of obese mice and contributes to faster weight regain and metabolic aberrations upon re-exposure to obesity-promoting conditions. Faecal transfer experiments show that the accelerated weight regain phenotype can be transmitted to germ-free mice. We develop a machine-learning algorithm that enables personalized microbiome-based prediction of the extent of post-dieting weight regain. Additionally, we find that the microbiome contributes to diminished post-dieting flavonoid levels and reduced energy expenditure, and demonstrate that flavonoid-based ‘post-biotic’ intervention ameliorates excessive secondary weight gain. Together, our data highlight a possible microbiome contribution to accelerated post-dieting weight regain, and suggest that microbiome-targeting approaches may help to diagnose and treat this common disorder.

Dysbiosis and the immune system

Throughout the past century, we have seen the emergence of a large number of multifactorial diseases, including inflammatory, autoimmune, metabolic, neoplastic and neurodegenerative diseases, many of which have been recently associated with intestinal dysbiosis — that is, compositional and functional alterations of the gut microbiome. In linking the pathogenesis of common diseases to dysbiosis, the microbiome field is challenged to decipher the mechanisms involved in the de novo generation and the persistence of dysbiotic microbiome configurations, and to differentiate causal host–microbiome associations from secondary microbial changes that accompany disease course. In this Review, we categorize dysbiosis in conceptual terms and provide an overview of immunological associations; the causes and consequences of bacterial dysbiosis, and their involvement in the molecular aetiology of common diseases; and implications for the rational design of new therapeutic approaches. A molecular- level understanding of the origins of dysbiosis, its endogenous and environmental regulatory processes, and its downstream effects may enable us to develop microbiome-targeting therapies for a multitude of common immune-mediated diseases.

Role of the intestinal microbiome in liver disease.

The liver integrates metabolic outcomes with nutrient intake while preventing harmful signals derived from the gut to spread throughout the body. Direct blood influx from the gastrointestinal tract through the portal vein makes the liver a critical firewall equipped with a broad array of immune cells and innate immune receptors that recognize microbial-derived products, microorganisms, toxins and food antigens that have breached the intestinal barrier. An overwhelming amount of evidence obtained in the last decade indicates that the intestinal microbiota is a key component of a wide variety of physiological processes, and alterations in the delicate balance that represents the intestinal bacterial communities are now considered important determinants of metabolic syndrome and immunopathologies. Moreover, it is now evident that the interaction between the innate immune system and the intestinal microbiota during obesity or autoimmunity promotes chronic liver disease progression and therefore it might lead to novel and individualized therapeutic approaches. In this review, we discuss a growing body of evidence that highlights the central relationship between the immune system, the microbiome, and chronic liver disease initiation and progression.

The interplay between the innate immune system and the microbiota

The human gastrointestinal tract harbors one of the highest densities of microorganisms on earth, called the microbiota. In fact, the number of microbial cells in the intestine outnumbers the amount of human cells of the entire organism by a factor of 10. As such, a human being is more and more perceived as a super-organism consisting of a eukaryotic and a prokaryotic part. The compartment mediating the communication between both parts is the innate immune system and its various microbe-sensing pattern-recognition receptors. Co-evolution of the microbiota with the innate immune system has resulted in elaborate interdependency and feedback mechanisms by which both systems control mutual homeostasis. Here, we review the most important innate immune-microbiota interdependencies known to date. While microbial sensing by pattern-recognition receptors is required for stable microbial composition, the presence of the microbiota, in turn, is necessary for proper development and function of the immune system.