The Human Microbiome: Our Second Genome

Each one of us harbors a vast and delicately balanced community comprising trillions of microorganisms. This unique collection of bacteria, viruses, fungi, and archaea reside across a variety of body sites, including the gut, skin, and mouth. Essential for numerous bodily functions, from digestion and metabolism to immune regulation and protection against pathogens, this microbial congregation, known as the microbiota, has a profound influence on our health.

 The genomic content of these collective organisms is known as the human microbiome— often referred to as our second genome. Understanding the human microbiome is crucial. Disruptions or imbalances in these microbial communities—known as dysbiosis—can contribute to a range of health problems, from metabolic and autoimmune diseases to neurological disorders and cancers. In light of this, the microbiome has emerged as a significant arena for medical research and a target for novel therapeutic interventions.

Genomics approaches like shotgun metagenomic sequencing are helping us unravel and understand this complex ecosystem. They enable researchers to analyze the genetic landscape of entire microbial communities and provide a comprehensive view of the microbiome’s composition and functional potential. These insights are critical for identifying ‘beneficial’ and ‘harmful’ microbes, understanding their interactions with the human host, and developing personalized therapies based on individual microbiome profiles.

In this blog, we will delve into the importance of the human microbiome, explore its impact on health and disease and highlight how genomics is helping to inform the development of novel therapeutic interventions.

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The human microbiome explained

 The human microbiome is a complex ecosystem of trillions of microorganisms that colonize diverse body sites, including the skin, mucosa, gastrointestinal tract, respiratory tract, urogenital tract, and mammary gland. These microorganisms adapt to physiological and environmental niches, forming a discrete and dynamic community. Remarkably, the microbes that make up our microbiota constitute 90% of the total number of cells in the human body; with only 10% representing human cells [1].

From childbirth, humans begin a symbiotic relationship with their microbiota. These interactions are crucial for maintaining health and wellbeing. Through coevolution, the microbiota has adapted to specific habitats within the body, resulting in distinct microbial communities in different body sites [2].

The microbiota plays several vital roles in maintaining human health:

• Digestion and nutrient absorption: Microbes in the gut help break down complex carbohydrates, synthesize essential vitamins, and aid in nutrient absorption.
• Immune system regulation: The microbiota interacts with the immune system, helping to regulate immune responses and protect against infections.
• Protection against pathogens: ‘Beneficial’ microbes compete with pathogenic organisms, resisting colonization and reducing the risk of infections.
• Production of essential vitamins and metabolites: Microbial metabolism produces vitamins such as B12 and K, plus other metabolites that are crucial for human health.

The human microbiome is constantly evolving in response to various factors, including age, nutrition, lifestyle, hormones, and genetics. The highest concentration of the human microbiome can be found in the gastrointestinal tract, where up to 100 trillion symbiotic microbes reside at a density of around 10¹² cells per mL [3].

The gut microbiota thrives on food residues that our bodies cannot digest, as well as dead cells and mucus secreted by the gut. In return, the active gut microbiota produces a range of physiologically-active substances, including short-chain fatty acids (SCFAs), vitamins, and other health-beneficial products like anti-inflammatory, analgesic, and antioxidant compounds. However, it can also produce harmful substances such as neurotoxins, carcinogens, and immunotoxins. All these products can potentially enter the bloodstream, regulate gene expression, and impact immune and metabolic processes.

While a well-balanced gut microbiota has shown to play a crucial role in human health, disturbing this delicate balance can rapidly induce dysbiosis, in which changes in the types and numbers of microbes and/or loss of overall microbial diversity can give rise to a variety of serious health issues.

Figure 1. Normal healthy intestine (A) contains a diverse microbiota. Dysbiosis (B) is characterized by a disruption to the microbiome, giving rise to an imbalance in the microbiota. Typical signs include reduced microbial diversity, imbalance of microbial populations, increased pathogenic bacteria, leading to altered metabolic activity, increased intestinal permeability and inflammation.

The microbiome in health and disease

The human microbiome’s influence extends far beyond the gut, impacting diverse aspects of health and disease. From metabolic health, to immune-related diseases and brain health, understanding the relationship between microbiome traits and diseases can help to inform novel treatments and preventive strategies.

Impact on metabolic health

The microbiome has a major influence on our metabolic health. The gut microbiota in particular affects energy balance and fat storage by interacting with host metabolic pathways. The diversity of species that comprise an individual’s gut microbiota has shown to be an important factor in obesity – studies have shown that obese individuals often have a less diverse gut microbiome compared to healthy individuals [4]. Interestingly, the gut microbiota can also produce metabolites that modulate insulin sensitivity, thereby influencing the risk of diabetes [5].

Connection to immune-related diseases

A balanced microbiome is crucial for proper immune regulation and the prevention of immune-related diseases. The gut microbiota regulates and helps to ‘train’ the immune system to distinguish between harmful pathogens and harmless antigens while mediating inflammatory immune responses. Dysbiosis in the gut can lead to inappropriate immune responses, and in those with a genetic predisposition, can contribute to the pathogenesis of autoimmune diseases.

 For instance, in Crohn’s disease, dysbiosis contributes to immune system dysregulation, leading to the destruction of the gut lining, causing severe inflammation. Similarly, in ulcerative colitis, dysbiosis leads to continuous inflammation of the colon. A dysbiotic gut has also been linked with autoimmune diseases away from the gut, such as rheumatoid arthritis and systemic lupus erythematosus [6].

 Influence on brain health

The gut-brain axis, a bidirectional communication pathway between the gut microbiome and the brain, plays a crucial role in brain health. This connection influences neurodegeneration, mental health, and cognitive functions. Some microbial metabolites, such as SCFAs, can cross the blood-brain barrier and affect brain function.

Dysbiosis has been linked to conditions such as depression and anxiety, as well as neurodegenerative diseases like Parkinson’s Disease (PD). Clinical trials have identified common characteristics in gut microbiota profiles in PD patients, while preclinical studies in animal models have demonstrated that gut dysbiosis can increase intestinal permeability and oxidative stress, promote neuroinflammation and abnormal protein aggregation, and reduce neurotransmitter production [7].

Association with cancers

The microbiome also impacts cancer development and response to therapy. Dysbiosis has been observed in numerous cancers, including colorectal cancer, where an overgrowth of harmful bacteria like Fusobacterium nucleatum is common. Microbes and their metabolites can promote tumorigenesis via DNA damage, epigenetics alterations, promotion of abnormal signaling pathways, and immune suppression [8].

Certain microbial communities can also influence the efficacy of cancer treatments. Specific bacterial species can metabolize chemotherapy drugs, limiting their potency and efficacy. Meanwhile, some gut microbes have shown to aid anticancer therapies. As such, the gut microbiota presents a novel therapeutic target, that is, by modulating the gut microbiota, it may be possible to enhance the effectiveness of chemotherapies.

Figure 2. Dysbiosis of the gut microbiota can have a substantial impact on a variety of human health issues.

Genomics and the microbiome

Our understanding of the human microbiome has been transformed by advancements in omics technologies. From metagenomics to proteomics, these tools are empowering researchers to explore how microbial genetic traits contribute to pathogenesis, drug resistance, and disease. They enable novel insights into human microbial ecology and evolution, including critical factors to human health, such as antimicrobial resistance.

Microbiome species profiling

One of the primary applications of genomics in microbiome research is species profiling. Techniques like 16S rRNA, 18S rRNA, and ITS sequencing for bacteria, eukaryotes, and fungi respectively enable the identification of microbial species and their relative abundances within the microbiome. These techniques usually focus on target genes and provide insights into species and diversity of microbiome constituents, and their impact on health and disease.

More than any other technique however, shotgun metagenomic sequencing has made an unparalleled contribution to microbiome research. Unlike more focused sequencing methods targeting specific genes or regions, shotgun metagenomics can sequence all the genetic material present in a sample. This approach allows researchers to identify and characterize the entire spectrum of microorganisms present in the microbiome.

One of the key advantages of shotgun metagenomic sequencing is its ability to detect a wide range of microbial species, including those that are rare or previously unknown. The technique has been instrumental in identifying microbial signatures associated with various diseases, helping to link specific bacterial strains with inflammatory bowel disease (IBD), obesity, and type 2 diabetes [9].

A valuable application of shotgun metagenomic sequencing is tracking the spread of antimicrobial resistance genes. By analyzing environmental and clinical samples, researchers can monitor the expression and spread of resistance genes within microbial communities. This information is essential for developing strategies to combat antibiotic resistance and ensure the efficacy of current treatments [10].

Functional microbiome research

Beyond DNA sequencing, proteomics is another major tool that can be leveraged to uncover the functional roles of distinct microbial communities. By identifying proteins involved in their nutrient metabolism, immune modulation, and communication, proteomics can reveal how gut bacteria contribute to digestion, protect against pathogens, and maintain immune homeostasis.

Metaproteomics expands the study to entire microbial communities, analyzing the collective protein content of a microbiome. This approach provides a comprehensive view of the functional activities within a microbial ecosystem, offering insights into how different microbial species interact and contribute to the overall function of the community.

One significant advantage of metaproteomics is its ability to link microbial functions to specific environmental conditions or disease states. For example, metaproteomic analysis of the human gut microbiome has revealed alterations in protein expression associated with IBD. Researchers identified proteins related to immune response, stress resistance, and pathogenicity that are differentially expressed in IBD patients, providing potential biomarkers for diagnosis and therapeutic targets [11].

Transcriptomics and metabolomics are also commonly used in functional microbiome research. Metabolomics, in particular, has been widely used to study the gut microbiota, focusing on disease-related metabolites to gain detailed insights into gut metabolic pathways [12].

Future prospects and opportunities in human microbiome research

The future of human microbiome research looks bright. Omics technologies are enabling comprehensive microbiome profiling and functional analysis like never before, and this can be leveraged to inform personalized therapies. For instance, personalized probiotic therapies can be designed to enhance beneficial bacteria or reduce harmful ones, based on a person’s unique microbial composition. Similarly, dietary interventions can be customized to support optimal gut health, considering the specific needs of an individual’s microbiome.

Microbiome-based therapies is an emerging arena of therapeutics. Probiotics and prebiotics are being refined to more effectively restore healthy microbial balance and treat conditions such as irritable bowel syndrome, IBD, and even mental health disorders. Fecal microbiota transplants (FMT) are gaining traction as a treatment for Clostridium difficile infections and are being explored for their potential in other diseases, including autoimmune disorders and obesity [13].

Another contemporary area of microbiome research is the development of microbiome-based diagnostics. Using microbial signatures as a biomarker of disease or pre-disease, new diagnostic tests are being developed to detect microbiome issues like dysbiosis at an early stage. These diagnostics enable timely and targeted interventions like dietary or probiotic treatments, preventing the progression of diseases associated with microbial imbalances.

The human microbiome: From symbiosis to dysbiosis

The future of microbiome research holds immense promise for transforming healthcare. It offers the potential for new ways of preventing, diagnosing, and treating a wide array of diseases through a better understanding of the microbial world within us.

Driven by advances in omics technologies, we are now able to interrogate and understand this fascinating ecosystem and its impact on human health like never before. As we delve deeper into the complexities of the human microbiome, the potential for groundbreaking discoveries and therapeutic interventions grows.

At Eremid^®, we’re at the forefront of genomic microbiome research. Our high-complexity genomics lab is equipped with a range of cutting-edge technology, including those from Illumina, PacBio, and Oxford Nanopore. We can offer you our expertise in shotgun metagenomic sequencing, as well as 16S and 18S rRNA and ITS sequencing. Our science team has considerable expertise in extracting, analyzing, and interpreting sequencing data from microbiome samples, and can perform metagenomic analysis for functional characterization. Take advantage of our experience to drive forward your microbiome research.

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References

1. Grice, E. A., Segre, J. A. (2012). The human microbiome: our second genome. Annual review of genomics and human genetics, 13,151–170. https://doi.org/10.1146/annurev-genom-090711-163814
2. Ogunrinola, G. A., Oyewale, J. O., Oshamika, O. O., Olasehinde, G. I. (2020). The Human Microbiome and Its Impacts on Health. International journal of microbiology, 2020, 8045646. https://doi.org/10.1155/2020/8045646
3. Bäckhed, F., Ley, R. E., Sonnenburg, J. L., Peterson, D. A., Gordon, J. I. (2005). Host-bacterial mutualism in the human intestine. Science, 307(5717), 1915–1920. https://doi.org/10.1126/science.1104816
4. Liu, B. N., Liu, X. T., Liang, Z. H., Wang, J. H. (2021). Gut microbiota in obesity. World journal of gastroenterology, 27(25), 3837–3850. https://doi.org/10.3748/wjg.v27.i25.3837
5. Sadagopan, A., Mahmoud, A., Begg, M., Tarhuni, M., Fotso, M., et al. (2023). Understanding the Role of the Gut Microbiome in Diabetes and Therapeutics Targeting Leaky Gut: A Systematic Cureus, 15(7), e41559. https://doi.org/10.7759/cureus.41559
6. De Luca, F., Shoenfeld, Y. (2019). The microbiome in autoimmune diseases. Clinical and experimental immunology, 195(1), 74–85. https://doi.org/10.1111/cei.13158
7. Zhu, M., Liu, X., Ye, Y., Yan, X., Cheng, Y., et al. (2022). Gut Microbiota: A Novel Therapeutic Target for Parkinson’s Disease. Frontiers in immunology, 13, 937555. https://doi.org/10.3389/fimmu.2022.937555
8. Zhao, L. Y., Mei, J. X., Yu, G., Lei, L., Zhang, W. H., et al. (2023). Role of the gut microbiota in anticancer therapy: from molecular mechanisms to clinical applications. Signal transduction and targeted therapy, 8(1), 201. https://doi.org/10.1038/s41392-023-01406-7
9. Lloyd-Price, J., Arze, C., Ananthakrishnan, A. N., Schirmer, M., Avila-Pacheco, J., et al. (2019). Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature, 569(7758), 655–662. https://doi.org/10.1038/s41586-019-1237-9
10. Sanabria, A. M., Janice, J., Hjerde, E., Simonsen, G. S., Hanssen, A. M. (2021). Shotgun-metagenomics based prediction of antibiotic resistance and virulence determinants in Staphylococcus aureus from periprosthetic tissue on blood culture bottles. Scientific reports, 11(1), 20848. https://doi.org/10.1038/s41598-021-00383-7
11. Armengaud J. (2023). Metaproteomics to understand how microbiota function: The crystal ball predicts a promising future. Environmental microbiology, 25(1), 115–125. https://doi.org/10.1111/1462-2920.16238
12. Vernocchi, P., Del Chierico, F., Putignani, L. (2016). Gut Microbiota Profiling: Metabolomics Based Approach to Unravel Compounds Affecting Human Health. Frontiers in microbiology, 7, 1144. https://doi.org/10.3389/fmicb.2016.01144
13. Park, S. Y., Seo, G. S. (2021). Fecal Microbiota Transplantation: Is It Safe?. Clinical endoscopy, 54(2), 157–160. https://doi.org/10.5946/ce.2021.072