Breakthroughs and Bottlenecks in Microbiome Research

doi:10.1016/j.molmed.2021.01.003

Trends in Molecular Medicine

Volume 27, Issue 4, April 2021, Pages 298-301

https://doi.org/10.1016/j.molmed.2021.01.003 Get rights and content

Over the past 15 years, the research community has witnessed unprecedented progress in microbiome research. We review this increasing knowledge and first attempts of its clinical application, and also limitations and challenges faced by the research community, in mechanistically understanding host–microbiome interactions and integrating these insights into clinical practice.

Section snippets

Metagenomic Sequencing and Analysis

High-throughput sequencing endowed an unmatched ample view on complex commensal communities. Initiatives such as the Human Microbiome Project (HMP), MetaHIT, American Gut, and Flemish Gut have uncovered links between microbial taxa and human health outcomes [1]. Notwithstanding the opportunities next-generation sequencing provides (NGS), it also exposes the limits of sequencing-based community profiling. A compelling question is whether quantitative and transcriptional microbiome profiling is

Diet–Microbiota–Host Interactions

Diet is of paramount importance among the factors shaping the gut microbiome configuration. Dietary habits represent a crucial source of interpersonal gut microbiome variation. In turn, the gut microbiome plays the role of a ‘signaling hub’ generating a wealth of diet-derived signals to the host. Over the last years, it has become increasingly salient that there may be no ‘one-size-fits-all’ dietary recommendations to achieve a health benefit. Microbiome-based machine learning predictions of

Towards Metagenomic Clinical Diagnostics

An individual’s commensal microbial repertoire also holds great promise as a clinical diagnostic modality. Metagenomics sequencing of stool or blood has a powerful, noninvasive, diagnostic capacity in infections or malignancy. In the case of infections, for example, metagenomic sequencing of infected body fluids was demonstrated to both expedite pathogen detection and to have potentially greater diagnostic sensitivity compared to gold-standard culture-based methods [9]. A prompt pathogen

Resurgence of Phage Therapy

Much of the microbiome research has focused on bacterial community members, mainly due to the technical challenges by which the study of commensal representatives of other kingdoms is burdened. Nevertheless, emerging evidence points towards a crucial role of commensal protozoa, fungi, archaea, and viruses in homeostasis and disease. Over 100 years have passed since the discovery of bacteriophages (phages), prokaryotic viruses that attack bacteria in a host-specific manner. However, reproducible

Fecal Microbiota Transplantation and Beyond

The metagenomic leap has revitalized interest in the ‘new old tool’ of fecal microbiome transplantation (FMT). The interest in FMT is exemplified by more than 350 completed or planned clinical trials (NIH, December 2020). The most credible data to date on FMT is available for recurrent Clostridioides difficile infection, and potentially for ulcerative colitis. Currently, its applicability is limited only to selected patients with a previous failure of conventional treatment [11]. All randomized

Probiotics in the Era of Metagenomic Sequencing

The metagenomic breakthrough has shed new light on the old notion of probiotics, live microorganisms that upon consumption may confer a health benefit [14]. A vast body of studies dissects the clinical outcomes associated with the consumption of various types of commercially available probiotics strains. However, the mixed results and the consequent lack of regulatory approval as medical interventions is in part explained by insufficient characterization, lack of a mechanistic understanding of

Concluding Remarks

Research on the human microbiome has so far yielded valuable insights but has also produced an abundance of insufficiently characterized observations and correlations. Although microbiome research has matured remarkably over the last couple of years and can no longer be considered in its infancy, it has yet to fulfill the high hopes of revolutionizing clinical practice and prevention of dysbiosis-associated diseases. We strongly believe that the advent of more mechanistically focused microbiome

Acknowledgments

We thank the members of the Elinav lab, and the members of the DKFZ cancer-microbiome division for discussions. T.L. is funded as postdoctoral fellow by the German Research Foundation (DFG, 420943353). E.E. is the incumbent of the Sir Marc and Lady Tania Feldmann Professorial Chair; a senior fellow, Canadian Institute of Advanced Research (CIFAR); and an international scholar, The Bill & Melinda Gates Foundation and Howard Hughes Medical Institute (HHMI). The original figure was made by a

Declaration of Interests

E.E. is an editorial boards member in Cell, Cell Host & Microbe, American Journal of Clinical Nutrition, and Med.

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Personalized gut mucosal colonization resistance to empiric probiotics is associated with unique host and microbiome features
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A forward chemical genetic screen reveals gut microbiota metabolites that modulate host physiology
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There are more references available in the full text version of this article.

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Biological function, regulatory mechanism, and clinical application of mannose in cancer
2023, Biochimica et Biophysica Acta - Reviews on Cancer
Studies examining the regulatory roles and clinical applications of monosaccharides other than glucose in cancer have been neglected. Mannose, a common type of monosaccharide found in human body fluids and tissues, primarily functions in protein glycosylation rather than carbohydrate metabolism. Recent research has demonstrated direct anticancer effects of mannose in vitro and in vivo. Simply supplementing cell culture medium or drinking water with mannose achieved these effects. Moreover, mannose enhances the effectiveness of current cancer treatments including chemotherapy, radiotherapy, targeted therapy, and immune therapy. Besides the advancements in basic research on the anticancer effects of mannose, recent studies have reported its application as a biomarker for cancer or in the delivery of anticancer drugs using mannose-modified drug delivery systems. This review discusses the progress made in understanding the regulatory roles of mannose in cancer progression, the mechanisms underlying its anticancer effects, and its current application in cancer diagnosis and treatment.
Expanded microbiome niches of RAG-deficient patients
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The complex interplay between microbiota and immunity is important to human health. To explore how altered adaptive immunity influences the microbiome, we characterize skin, nares, and gut microbiota of patients with recombination-activating gene (RAG) deficiency—a rare genetically defined inborn error of immunity (IEI) that results in a broad spectrum of clinical phenotypes. Integrating de novo assembly of metagenomes from RAG-deficient patients with reference genome catalogs provides an expansive multi-kingdom view of microbial diversity. RAG-deficient patient microbiomes exhibit inter-individual variation, including expansion of opportunistic pathogens (e.g., Corynebacterium bovis, Haemophilus influenzae), and a relative loss of body site specificity. We identify 35 and 27 bacterial species derived from skin/nares and gut microbiomes, respectively, which are distinct to RAG-deficient patients compared to healthy individuals. Underscoring IEI patients as potential reservoirs for viral persistence and evolution, we further characterize the colonization of eukaryotic RNA viruses (e.g., Coronavirus 229E, Norovirus GII) in this patient population.
Engineered biosensors for the quorum sensing molecule 3,5-dimethyl-pyrazine-2-ol (DPO) reveal its presence in humans, animals, and bacterial species beyond Vibrio cholerae
2023, Biosensors and Bioelectronics
A biosensor was engineered to enable the study of the novel quorum sensing molecule (QSM), 3,5-dimethylpyrazin-2-ol (DPO), employed by Vibrio cholerae to regulate biofilm formation and virulence factor production. Investigations into bacterial quorum sensing (QS), a form of communication based on the production and detection of QSMs to coordinate gene expression in a population dependent manner, offer a unique window to study the molecular underpinnings of microbial behavior and host interactions. Herein, we report the construction of an engineered microbial whole-cell bioluminescent biosensing system that incorporates the recognition of the VqmA regulatory protein of Vibrio cholerae with the bioluminescent reporting signal of luciferase for the selective, sensitive, stable, and reproducible detection of DPO in a variety of samples. Importantly, using our newly developed biosensor our studies demonstrate the detection of DPO in rodent and human samples. Employing our developed biosensor should help enable elucidation of microbial behavior at the molecular level and its impact in health and disease.
Anthropogenic activities and seasonal properties jointly drive the assemblage of bacterial communities in subtropical river basins
2022, Science of the Total Environment
Citation Excerpt :
Over the past decade, the technological advances of high-throughput sequencing (HTS) have facilitated development of environmental microbial research, providing researchers with a more comprehensive view of microbial community composition in environments (Natarajan and Bhatt, 2020). Big data originated from environmental microbiome shed light into response of microbial community to disturbance of surrounding environment and ecological adaptability of microbial function (Liwinski et al., 2021; Garner et al., 2021). However, the ecological implications of microbial diversity are still poorly understood (Li et al., 2021).
Anthropogenic activities have inevitably impacted riverine ecosystems, yet their overall contribution to the assemblage of bacterial communities at a large river basin scale remains unclear. In this study, 16S amplicon sequencing was implemented to investigate the bacterial ecosystems in paired water and sediment of North River and West River basins in South China., which contains various anthropogenic environments (e.g., rural/urban area, mining area and livestock area). Subsequently, the links between bacterial community and various types of emerging pollutants in river water were analyzed. The results show that the bacterial assemblage of water and sediment had their own properties that the bacterial community of sediment were mainly affected by seasonal properties, while the bacterial community of water were affected by both seasons and anthropogenic activities. Therein, the aquatic bacterial compositions and abundances were driven by changes in temperature, dissolved oxygen and the emerging pollutants. The dominant phyla Proteobacteria and Firmicutes exhibited adaptability to the mining-affected regions, therein many clades (e.g., Beijerinckiaceae, Acetobacteraceae and Mycobacteriaceae) were also prevalent in the livestock-affected and densely-populated regions. In addition, these two phyla presented associations to the antibiotic resistance in water. The levels of antibiotics, relative antibiotic resistance gens (ARGs) and non-antibiotic pharmaceuticals (NAPs) were closely related to bacterial community composition, diversity and functional diversity, indicating their drive in shifting bacterial communities. Collectively, this work provides a basis for understanding the contribution of anthropogenic activities in shifting bacterial community at a large river basin scale. Further, the results provide new insights for expansion of ecological assessment.
The Gut Microbiome
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The gut microbiome is the collection of microorganisms, including bacteria, archaea, viruses and fungi, found within the gut and their overall genetic information. Our gut microbiota has broad effects on our health and well-being, impacting our immune system and metabolism, detoxifying various ingested components, and even affecting behavior. Changes in gut microbiota composition are correlated with different life stages, diet and geographical location, exercise, use of antibiotics and a wide range of disease states. In the next years, this rapidly growing research field is likely to provide more detailed mechanisms on how the gut microbiome affects the host in these different conditions.
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Advances in the field of microbiology made it possible to identify bacterial causative agents for a number of conditions in the foregut, such as chronic gastritis and peptic ulcer disease. Modern-era microbiome research requires a robust characterization of complex microbial communities in different ecosystems to disentangle their impact on host physiology in health and disease. The expansion toward sites like the esophagus with a low abundance of resident microbes remains challenging for both culture-dependent and -independent detection techniques. Exceptional culture conditions for fastidious organisms, the strict control for contamination, and the host nucleic acid background in genomic approaches are some of the factors to be considered. Recent advancements in next-generation sequencing of bacterial genomes, high-throughput bacterial culture coupled with state-of-the-art detection methods (“culturomics”), and bioinformatics pipelines to account for contaminants may enable to characterize microbial patterns in the esophagus and evaluate their association with diseases of this organ.

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⁵: These authors contributed equally

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Trends in Molecular Medicine

Section snippets

Metagenomic Sequencing and Analysis

Diet–Microbiota–Host Interactions

Towards Metagenomic Clinical Diagnostics

Resurgence of Phage Therapy

Fecal Microbiota Transplantation and Beyond

Probiotics in the Era of Metagenomic Sequencing

Concluding Remarks

Acknowledgments

Declaration of Interests

References (15)

Efficacy of sterile fecal filtrate transfer for treating patients with Clostridium difficile infection

Gastroenterology

Personalized gut mucosal colonization resistance to empiric probiotics is associated with unique host and microbiome features

Cell

A forward chemical genetic screen reveals gut microbiota metabolites that modulate host physiology

Cell

Population-level analysis of gut microbiome variation

Science

Quantitative microbiome profiling links gut community variation to microbial load

Nature

Dynamics of metatranscription in the inflammatory bowel disease gut microbiome

Nat. Microbiol.

Microbial strain-level population structure & genetic diversity from metagenomes

Genome Res.

Cited by (20)

Biological function, regulatory mechanism, and clinical application of mannose in cancer

Expanded microbiome niches of RAG-deficient patients

Engineered biosensors for the quorum sensing molecule 3,5-dimethyl-pyrazine-2-ol (DPO) reveal its presence in humans, animals, and bacterial species beyond Vibrio cholerae

Anthropogenic activities and seasonal properties jointly drive the assemblage of bacterial communities in subtropical river basins

The Gut Microbiome

Gastrointestinal microbiome: Evaluation of testing technologies

Trends in Molecular Medicine

ForumForum Series: Bottlenecks and Breakthroughs in Molecular MedicineBreakthroughs and Bottlenecks in Microbiome Research

Section snippets

Metagenomic Sequencing and Analysis

Diet–Microbiota–Host Interactions

Towards Metagenomic Clinical Diagnostics

Resurgence of Phage Therapy

Fecal Microbiota Transplantation and Beyond

Probiotics in the Era of Metagenomic Sequencing

Concluding Remarks

Acknowledgments

Declaration of Interests

Gastroenterology

Cell

Cell

Population-level analysis of gut microbiome variation

Science

Quantitative microbiome profiling links gut community variation to microbial load

Nature

Dynamics of metatranscription in the inflammatory bowel disease gut microbiome

Nat. Microbiol.

Microbial strain-level population structure & genetic diversity from metagenomes

Genome Res.

Forum
Forum Series: Bottlenecks and Breakthroughs in Molecular Medicine
Breakthroughs and Bottlenecks in Microbiome Research