Gut Microbiome Research Research Articles

Application of zebrafish in the study of the gut microbiome.

Zebrafish (Danio rerio) have attracted much attention over the past decade as a reliable model for gut microbiome research. Owing to their low cost, strong genetic and development coherence, efficient preparation of germ‐free (GF) larvae, availability in high‐throughput chemical screening, and fitness for intravital imaging in vivo, zebrafish have been extensively used to investigate microbiome‐host interactions and evaluate the toxicity of environmental pollutants. In this review, the advantages and disadvantages of zebrafish for studying the role of the gut microbiome compared with warm‐blooded animal models are first summarized. Then, the roles of zebrafish gut microbiome on host development, metabolic pathways, gut‐brain axis, and immune disorders and responses are addressed. Furthermore, their applications for the toxicological assessment of aquatic environmental pollutants and exploration of the molecular mechanism of pathogen infections are reviewed. We highlight the great potential of the zebrafish model for developing probiotics for xenobiotic detoxification, resistance against bacterial infection, and disease prevention and cure. Overall, the zebrafish model promises a brighter future for gut microbiome research.

Microbial metabolites: cause or consequence in gastrointestinal disease?

Systems biology studies have established that changes in gastrointestinal microbiome composition and function can adversely impact host physiology. Notable diseases synonymously associated with dysbiosis include inflammatory bowel diseases, cancer, metabolic disorders, and opportunistic and recurrent pathogen infections. However, there is a scarcity of mechanistic data that advances our understanding of taxonomic correlations with pathophysiological host-microbiome interactions. Generally, to survive a hostile gut environment, microbes are highly metabolically active and produce trans-kingdom signaling molecules to interact with competing microorganisms and the host. These specialized metabolites likely play important homeostatic roles, and identifying disease-specific taxa and their effector pathways can provide better strategies for diagnosis, treatment, and prevention, as well as the discovery of innovative therapeutics. The signaling role of microbial biotransformation products such as bile acids, short-chain fatty acids, polysaccharides, and dietary tryptophan is increasingly recognized, but little is known about the identity and function of metabolites that are synthesized by microbial biosynthetic gene clusters, including ribosomally synthesized and posttranslationally modified peptides (RiPPs), nonribosomal peptides (NRPs), polyketides (PKs), PK-NRP hybrids, and terpenes. Here we consider how bioactive natural products directly encoded by the human microbiome can contribute to the pathophysiology of gastrointestinal disease, cancer, autoimmune, antimicrobial-resistant bacterial and viral infections (including COVID-19). We also present strategies used to discover these compounds and the biological activities they exhibit, with consideration of therapeutic interventions that could emerge from understanding molecular causation in gut microbiome research.

Short- and long-read metagenomics of urban and rural South African gut microbiomes reveal a transitional composition and undescribed taxa

Human gut microbiome research focuses on populations living in high-income countries and to a lesser extent, non-urban agriculturalist and hunter-gatherer societies. The scarcity of research between these extremes limits our understanding of how the gut microbiota relates to health and disease in the majority of the world’s population. Here, we evaluate gut microbiome composition in transitioning South African populations using short- and long-read sequencing. We analyze stool from adult females living in rural Bushbuckridge (n = 118) or urban Soweto (n = 51) and find that these microbiomes are taxonomically intermediate between those of individuals living in high-income countries and traditional communities. We demonstrate that reference collections are incomplete for characterizing microbiomes of individuals living outside high-income countries, yielding artificially low beta diversity measurements, and generate complete genomes of undescribed taxa, including Treponema, Lentisphaerae, and Succinatimonas. Our results suggest that the gut microbiome of South Africans does not conform to a simple “western-nonwestern” axis and contains undescribed microbial diversity.

Global research trends on the links between the gut microbiome and cancer: a visualization analysis

BackgroundSignificant links between the microbiota and human health have emerged in the last 20 years. A correlation has recently been demonstrated between changes in the gut microbiota and the development of cancer. This study aimed to use bibliometric analysis of the published gut microbiome and cancer literature to present the research status and summarize the hotspots for frontier studies.MethodsA literature search for research on the gut microbiome and cancer research from 2001 to 2020 was conducted using the Scopus database on 20 March 2021. VOSviewer software (version 1.6.16) was used to perform the visualization analysis.ResultsFrom 2001 to 2020, a total of 2061 publications were retrieved. Annual publication output grew from 10 in 2001 to 486 in 2020. The USA had the largest number of publications, making the largest contribution to the field (n = 566, 27.46%). Before 2016, most studies focused on the ‘effect of probiotics on cancer’. The latest trends showed that ‘microbiota composition and gene expression’ and ‘host-microbiome interaction in cancer immunotherapy’ would be more concerned more widely in the future.ConclusionsResearch on ‘microbiota composition and gene expression’ and ‘host-microbiome interaction in cancer immunotherapy’ will continue to be the hotspot. Therefore, this study provides the trend and characteristics of the literature on the gut microbiota and cancer literature, which provided a useful bibliometric analysis for researchers to conduct further research.

16S rRNA gene sequencing analysis of gut microbiome in a mini‐pig diabetes model

BackgroundCurrently, increasing attention is being paid to the important role of intestinal microbiome in diabetes. However, few studies have evaluated the characteristics of gut microbiome in diabetic miniature pigs, despite it being a good model animal for assessing diabetes.MethodsIn this study, a mini‐pig diabetes model (DM) was established by 9‐month high‐fat diet (HFD) combined with low‐dose streptozotocin, while the animals fed standard chow diet constituted the control group. 16S ribosomal RNA (rRNA) gene sequencing was performed to assess the characteristics of the intestinal microbiome in diabetic mini‐pigs.ResultsThe results showed that microbial structure in diabetic mini‐pigs was altered, reflected by increases in levels of Coprococcus_3 and Clostridium_sensu_stricto_1, which were positively correlated with diabetes, and decreases in levels of the bacteria Rikenellaceae, Clostridiales_vadinBB60_group, and Bacteroidales_RF16_group, which were inversely correlated with blood glucose and insulin resistance. Moreover, PICRUSt‐predicted pathways related to the glycolysis and Entner‐Doudoroff superpathway, enterobactin biosynthesis, and the l‐tryptophan biosynthesis were significantly elevated in the DM group.ConclusionThese results reveal the composition and predictive functions of the intestinal microbiome in the mini‐pig diabetes model, further verifying the relationship between HFD, gut microbiome, and diabetes, and providing novel insights into the application of the mini‐pig diabetes model in gut microbiome research.

Host, Microbiome, and Complex Space: Applying Population and Landscape Genetic Approaches to Gut Microbiome Research in Wild Populations.

In recent years, emerging sequencing technologies and computational tools have driven a tidal wave of research on host-associated microbiomes, particularly the gut microbiome. These studies demonstrate numerous connections between the gut microbiome and vital host functions, primarily in humans, model organisms, and domestic animals. As the adaptive importance of the gut microbiome becomes clearer, interest in studying the gut microbiomes of wild populations has increased, in part due to the potential for discovering conservation applications. The study of wildlife gut microbiomes holds many new challenges and opportunities due to the complex genetic, spatial, and environmental structure of wild host populations, and the potential for these factors to interact with the microbiome. The emerging picture of adaptive coevolution in host-microbiome relationships highlights the importance of understanding microbiome variation in the context of host population genetics and landscape heterogeneity across a wide range of host populations. We propose a conceptual framework for understanding wildlife gut microbiomes in relation to landscape variables and host population genetics, including the potential of approaches derived from landscape genetics. We use this framework to review current research, synthesize important trends, highlight implications for conservation, and recommend future directions for research. Specifically, we focus on how spatial structure and environmental variation interact with host population genetics and microbiome variation in natural populations, and what we can learn from how these patterns of covariation differ depending on host ecological and evolutionary traits.

Material Engineering in Gut Microbiome and Human Health.

Tremendous progress has been made in the past decade regarding our understanding of the gut microbiome's role in human health. Currently, however, a comprehensive and focused review marrying the two distinct fields of gut microbiome and material research is lacking. To bridge the gap, the current paper discusses critical aspects of the rapidly emerging research topic of “material engineering in the gut microbiome and human health.” By engaging scientists with diverse backgrounds in biomaterials, gut-microbiome axis, neuroscience, synthetic biology, tissue engineering, and biosensing in a dialogue, our goal is to accelerate the development of research tools for gut microbiome research and the development of therapeutics that target the gut microbiome. For this purpose, state-of-the-art knowledge is presented here on biomaterial technologies that facilitate the study, analysis, and manipulation of the gut microbiome, including intestinal organoids, gut-on-chip models, hydrogels for spatial mapping of gut microbiome compositions, microbiome biosensors, and oral bacteria delivery systems. In addition, a discussion is provided regarding the microbiome-gut-brain axis and the critical roles that biomaterials can play to investigate and regulate the axis. Lastly, perspectives are provided regarding future directions on how to develop and use novel biomaterials in gut microbiome research, as well as essential regulatory rules in clinical translation. In this way, we hope to inspire research into future biomaterial technologies to advance gut microbiome research and gut microbiome-based theragnostics.

Introduction of Industry-driven pre-competitive consortium activities to promote Microbiome Based Drug Discovery in Japan

The human microbiome is an emerging research area of interest with a series of reports on associations with various diseases and health, mainly due to advances in comprehensive analysis with the advent of next-generation sequencers. Fecal microbiota transplantation, a powerful method for modulating gut microbiota, has been reported to be surprisingly effective for certain disease populations that cannot be treated with conventional drugs. These results provide the possibility of microbiome modulation as a new approach for drug discovery. In the United States, the Human Microbiome Project was initiated in 2010 and many human microbiome data have been acquired, archived, and published. This has led to the emergence of a number of biopharmaceutical companies with clinical stage pipelines. Some of the most advanced pipelines are in the late clinical stage. However, issues such as the variability of data generated by different assays/protocols and the lack of data from healthy individuals as a reliable reference dataset should be addressed to further facilitate microbiome research and drug discovery based on human microbiome research. In Japan, in particular, established pharmaceutical companies tend to be reluctant to use these new approaches, as seen in human genome-based drug discovery. This may result in increased barriers to entry into emerging markets and a potential loss of opportunity. Since human microbiome research, especially gut microbiome research, has long been addressed by various research groups in Japan, microbe expertise and technology is high mainly in academia. It is important for Japanese industry to utilize the existing expertise of academic research groups. To accelerate the industrial use, Japan Microbiome Consortium (JMBC) was established in 2017, and its member companies include 33 pharmaceutical, chemical, food, and testing companies in Japan, including major companies and bio-venture companies. In this lecture, I will introduce the background of the establishment of JMBC and share the activities of the project for establishment of the measurement infrastructure and the project for construction of the database of healthy persons, which have been common goals. I would like to summarize the recent global trends and activities on drug discovery based on the human microbiome, as well as issues for obtaining approval and launching the drug. We would also like to discuss how we can activate drug discovery activities as one of JMBC's activities and lead to the creation of innovative new drugs.

Recent insights into the role of microbiome in the pathogenesis of obesity

Obesity is a risk factor for many chronic diseases and its rising prevalence the last couple of decades is a healthcare concern in many countries. Obesity is a multifactorial problem that is not only limited in its causation by diet and lack of exercise. Genetics but also environmental factors such as the gut microbiome should similarly be taken into account. A plethora of articles have been published, that from various different angles, attempt to disentangle the complex interaction between gut microbiota and obesity. Examples range from the effect of the gut microbiota on the host immune system to the pathophysiological pathways in which microbial-derived metabolites affect obesity. Various discordant gut microbiota findings are a result of this complexity. In this review, in addition to summarizing the classical role of the gut microbiome in the pathogenesis of obesity, we attempt to view both the healthy and obesogenic effects of the gut microbiota as a consequence of the presence or absence of collective guilds/trophic networks. Lastly, we propose avenues and strategies for the future of gut microbiome research concerning obesity.

Human Gut Microbiome as an Indicator of Human Health

The undeniable achievement in the study of the gut microbiome as an association of different microorganisms, including viruses, that colonize various organs and systems of the body, is the establishment of the fact that some diseases that were consmicrobiotaidered as non-infectious can also be transmitted through microorganisms. This resulted in the gut microbiome being called a forgotten organ that could serve as an additional and kind of missing link for a more objective and better diagnosis and treatment of many diseases that were not considered infectious. The rapid development of gut microbiome research in recent years not only is connected with better understanding of the functioning of the microbiome by the scientific community, but also inseparable from the strategic support of each country. Global investment in researches, related to the human microbiome, has exceeded $1.7 billion over the past decade. These researches contribute to the development of new diagnostic methods and therapeutic interventions. Our review is dedicated to the analysis of the possibilities of application of the human gut microbiome for the diagnosis of diseases, and the role of the intestines in the provocation and causing of certain diseases. Significant differences in the composition and diversity of the human microbiome are shown depending on geographical location and the change of socio-economic formations towards a gradual decrease in the diversity of the gut microbiome due to three stages of human population’s existence: food production, agriculture and industrial urban life. We analyze the influence of dietary patterns, various diseases (including malignant neoplasms) and viral infections (in particular, coronavirus) on the gut microbiome. And vice versa – the influence of the gut microbiome on the drugs effect and their metabolism, which affects the host's immune response and course of the disease.

The Role of the Gut Microbiome in Neuromodulation Therapies as a Potential Treatment Adjunct for Multiple Sclerosis

Gut microbiome research has surged in popularity over the past decade. These studies have found local and distal effects of micro organisms such as fungi and bacteria on human physiology, including the nervous, immune, and endocrine systems. A number of studies have demonstrated the potential for gut microbiota to combat classical diseases such as clinical depression and autism spectrum disorder. The impact of gut-produced metabolites on the secretion of various cytokines has presented a new-found opportunity for future disease therapy through these micro-organisms. This review examines recent evidence for the use of gut bacteria in neurological rehabilitation, specifically for Multiple Sclerosis (MS) patients. Available data has shown overwhelming support for microbiota-based MS therapy, but the lack of comprehension regarding the specific physiological mechanisms of these microbiota suggests that clinical trials may be far off. Furthermore, there has been minimal research investigating the consequences of using microbiotic therapy in tandem with current therapies such as neurostimulation or drug therapy. Factors including the mechanisms and restorative capability of specific species of microbiota must be studied in depth in order to successfully manipulate the gut microbiome for the treatment of neurological disorders.

In vitro interaction network of a synthetic gut bacterial community

A key challenge in microbiome research is to predict the functionality of microbial communities based on community membership and (meta)-genomic data. As central microbiota functions are determined by bacterial community networks, it is important to gain insight into the principles that govern bacteria-bacteria interactions. Here, we focused on the growth and metabolic interactions of the Oligo-Mouse-Microbiota (OMM12) synthetic bacterial community, which is increasingly used as a model system in gut microbiome research. Using a bottom-up approach, we uncovered the directionality of strain-strain interactions in mono- and pairwise co-culture experiments as well as in community batch culture. Metabolic network reconstruction in combination with metabolomics analysis of bacterial culture supernatants provided insights into the metabolic potential and activity of the individual community members. Thereby, we could show that the OMM12 interaction network is shaped by both exploitative and interference competition in vitro in nutrient-rich culture media and demonstrate how community structure can be shifted by changing the nutritional environment. In particular, Enterococcus faecalis KB1 was identified as an important driver of community composition by affecting the abundance of several other consortium members in vitro. As a result, this study gives fundamental insight into key drivers and mechanistic basis of the OMM12 interaction network in vitro, which serves as a knowledge base for future mechanistic in vivo studies.

Next steps after 15 stimulating years of human gut microbiome research.

SummaryGut microbiome research has bloomed over the past 15 years. We have learnt a lot about the complex microbial communities that colonize our intestine. Promising avenues of research and microbiome‐based applications are being implemented, with the goal of sustaining host health and applying personalized disease management strategies. Despite this exciting outlook, many fundamental questions about enteric microbial ecosystems remain to be answered. Organizational measures will also need to be taken to optimize the outcome of discoveries happening at an extremely rapid pace. This article highlights our own view of the field and perspectives for the next 15 years.

Therapeutic Advances in Gut Microbiome Modulation in Patients with Inflammatory Bowel Disease from Pediatrics to Adulthood.

There is mounting evidence that the gut microbiota plays an important role in the pathogenesis of inflammatory bowel disease (IBD). For the past decade, high throughput sequencing-based gut microbiome research has identified characteristic shifts in the composition of the intestinal microbiota in patients with IBD, suggesting that IBD results from alterations in the interactions between intestinal microbes and the host’s mucosal immune system. These studies have been the impetus for the development of new therapeutic approaches targeting the gut microbiome, such as nutritional therapies, probiotics, fecal microbiota transplant and beneficial metabolic derivatives. Innovative technologies can further our understanding of the role the microbiome plays as well as help to evaluate how the different approaches in microbiome modulation impact clinical responses in adult and pediatric patients. In this review, we highlight important microbiome studies in patients with IBD and their response to different microbiome modulation therapies, and describe the differences in therapeutic response between pediatric and adult patient cohorts.

Diurnal oscillations in gut bacterial load and composition eclipse seasonal and lifetime dynamics in wild meerkats

Circadian rhythms in gut microbiota composition are crucial for metabolic function, yet the extent to which they govern microbial dynamics compared to seasonal and lifetime processes remains unknown. Here, we investigate gut bacterial dynamics in wild meerkats (Suricata suricatta) over a 20-year period to compare diurnal, seasonal, and lifetime processes in concert, applying ratios of absolute abundance. We found that diurnal oscillations in bacterial load and composition eclipsed seasonal and lifetime dynamics. Diurnal oscillations were characterised by a peak in Clostridium abundance at dawn, were associated with temperature-constrained foraging schedules, and did not decay with age. Some genera exhibited seasonal fluctuations, whilst others developed with age, although we found little support for microbial senescence in very old meerkats. Strong microbial circadian rhythms in this species may reflect the extreme daily temperature fluctuations typical of arid-zone climates. Our findings demonstrate that accounting for circadian rhythms is essential for future gut microbiome research.

Consumption of Butylated Starch Alleviates the Chronic Restraint Stress-Induced Neurobehavioral and Gut Barrier Deficits Through Reshaping the Gut Microbiota.

The beneficial effect of short-chain fatty acids (SCFAs) on host health has been well recognized based on the booming knowledge from gut microbiome research. The role of SCFA in influencing psychological function is highlighted in recent years but has not been fully elucidated. In this study, the SCFA-acylated starches were used to accomplish a sizeable intestine-targeted release of the SCFAs, and the neurobehavioral, immunological, and microbial effects were further investigated. Acetylated-, butylated-, and isobutylated-starch could attenuate the depression-like behaviors and excessive corticosterone production in chronically stressed mice. Butylated- starch significantly reduced the colonic permeability via increasing the tight junction proteins (including ZO-1, Claudin, and Occludin) gene expression and reduced the level of the inflammatory cytokines (including IL-1β and IL-6). The butylated starch’s neurological and immunological benefits may be derived from the gut microbiome modifications, including normalizing the abundance of certain beneficial microbes (Odoribacter and Oscillibacter) and metabolomic pathways (Tryptophan synthesis and Inositol degradation). The present findings further validate the brain-beneficial effect of butyrate and offer novel guidance for developing novel food or dietary supplements for improving mental health.

Using naso- and oro-intestinal catheters in physiological research for intestinal delivery and sampling in vivo: practical and technical aspects to be considered.

ABSTRACTIntestinal catheters have been used for decades in human nutrition, physiology, pharmacokinetics, and gut microbiome research, facilitating the delivery of compounds directly into the intestinal lumen or the aspiration of intestinal fluids in human subjects. Such research provides insights about (local) dynamic metabolic and other intestinal luminal processes, but working with catheters might pose challenges to biomedical researchers and clinicians. Here, we provide an overview of practical and technical aspects of applying naso- and oro-intestinal catheters for delivery of compounds and sampling luminal fluids from the jejunum, ileum, and colon in vivo. The recent literature was extensively reviewed, and combined with experiences and insights we gained through our own clinical trials. We included 60 studies that involved a total of 720 healthy subjects and 42 patients. Most of the studies investigated multiple intestinal regions (24 studies), followed by studies investigating only the jejunum (21 studies), ileum (13 studies), or colon (2 studies). The ileum and colon used to be relatively inaccessible regions in vivo. Custom-made state-of-the-art catheters are available with numerous options for the design, such as multiple lumina, side holes, and inflatable balloons for catheter progression or isolation of intestinal segments. These allow for multiple controlled sampling and compound delivery options in different intestinal regions. Intestinal catheters were often used for delivery (23 studies), sampling (10 studies), or both (27 studies). Sampling speed decreased with increasing distance from the sampling syringe to the specific intestinal segment (i.e., speed highest in duodenum, lowest in ileum/colon). No serious adverse events were reported in the literature, and a dropout rate of around 10% was found for these types of studies. This review is highly relevant for researchers who are active in various research areas and want to expand their research with the use of intestinal catheters in humans in vivo.

Plant‐based foods and the gut microbiome: A research profile of Franck Carbonero

Plant‐based foods and the gut microbiome: A research profile of Franck Carbonero

The Diversity, Composition, and Metabolic Pathways of Archaea in Pigs.

Simple SummaryArchaea is identified as the key link in the interaction between gut microbiota and host metabo-lism. Studies on human and mice have reported archaea, especially methanogenic archaea, makes an important impact on the energy harvesting capacity of the host by improving fermentation. But, in pigs, the metabolic potential of archaea at different production stages are still largely unknown. Herein, we re-analyzed 276 metagenomic samples to explore the diversity, composi-tion, and potential functions of archaea in pigs. The results showed significant regional variations in archaeal composition. Furthermore, the Metacyc pathway related to hydrogen consumption (METHANOGENESIS-PWY) was only observed in archaeal reads, and archaea may be involved in carbohydrate metabolism and de novo synthesis of some kinds of essential amino acid. Overall, metagenomic re-analysis revealed that the composition and functional potential of archaea in the swine gut and suggested that archaea may make an important function in pigs.Archaea are an essential class of gut microorganisms in humans and animals. Despite the substantial progress in gut microbiome research in the last decade, most studies have focused on bacteria, and little is known about archaea in mammals. In this study, we investigated the composition, diversity, and functional potential of gut archaeal communities in pigs by re-analyzing a published metagenomic dataset including a total of 276 fecal samples from three countries: China (n = 76), Denmark (n = 100), and France (n = 100). For alpha diversity (Shannon Index) of the archaeal communities, Chinese pigs were less diverse than Danish and French pigs (p < 0.001). Consistently, Chinese pigs also possessed different archaeal community structures from the other two groups based on the Bray–Curtis distance matrix. Methanobrevibacter was the most dominant archaeal genus in Chinese pigs (44.94%) and French pigs (15.41%), while Candidatus methanomethylophilus was the most predominant in Danish pigs (15.71%). At the species level, the relative abundance of Candidatus methanomethylophilus alvus, Natrialbaceae archaeon XQ INN 246, and Methanobrevibacter gottschalkii were greatest in Danish, French, and Chinese pigs with a relative abundance of 14.32, 11.67, and 16.28%, respectively. In terms of metabolic potential, the top three pathways in the archaeal communities included the MetaCyc pathway related to the biosynthesis of L-valine, L-isoleucine, and isobutanol. Interestingly, the pathway related to hydrogen consumption (METHANOGENESIS-PWY) was only observed in archaeal reads, while the pathways participating in hydrogen production (FERMENTATION-PWY and PWY4LZ-257) were only detected in bacterial reads. Archaeal communities also possessed CAZyme gene families, with the top five being AA3, GH43, GT2, AA6, and CE9. In terms of antibiotic resistance genes (ARGs), the class of multidrug resistance was the most abundant ARG, accounting for 87.41% of archaeal ARG hits. Our study reveals the diverse composition and metabolic functions of archaea in pigs, suggesting that archaea might play important roles in swine nutrition and metabolism.

From the Literature

From the Literature