What is a Microbiome?

Microbiomes are communities of microorganisms that have adapted over millions of years of co-evolution through dynamic interactions with hosts and among themselves to form synergistic relationships. The interactions of these microorganisms determine the composition of the microbiome, as well as the ecosystem characteristics where they reside. For humans, there are microbiome populations with gut, oral, skin, urogenital, lung, and nasal origins – the gut having the largest and most diverse microbiota community.

Within frequently used microbiome terminology, prebiotics and probiotics are used interchangeably, despite stark differences.

Probiotics are types of 'living' bacteria while prebiotics are 'non-living'.

Probiotics are types of ‘living’ bacteria that are comparable to those that may inhabit our digestive tract. Probiotics are not only great for maintaining healthy levels of good bacteria in the gut, but it also supports our immune system and restores good bacteria after antibiotic events. Prebiotics are ‘non-living’ compounds that help feed the good bacteria in our gut in order to increase the levels of helpful bacteria, reducing disease risk and improving our general well being.

In this emerging interest, there are many movements to utilize what the microbiome has to offer. From metagenomics to live bacterial therapeutics to personalized nutrition, the microbiome field is a burgeoning force that has penetrated the health and agriculture industries.

The ‘Meta-omics’ of Microbiome

The Human Microbiome Project (HMP) has greatly advanced the metagenomic analysis of the microbiota in the human body. The most diverse and largest population of the microbiota is the gastrointestinal tract, where the gut microbiome plays a significant role in the state of health of the host. By identifying factors in the gut microbiome that differentiate between healthy and diseased microbiota, it is possible to ascertain certain predictive associations. uBiome is a startup that contributed largely to this new realm of genomics, as they have developed a key technology for sequencing-based clinical microbiome tests to identify microbes in the gut that could be affecting the host’s health.

By understanding all the ‘meta-omics’ regarding the microbiome, we can further understand the mechanisms and interactions that define the effects of the microbiome on the host. 

However, recently there has been an initiative to not only explore the microbiome, but also the metatranscriptomics, metaproteomics, and metabolomics. The metatranscriptomics describes how active the genes are in the microorganisms that inhabit a particular environment. Metaproteomics describe which proteins are found in the microorganisms inhabiting a particular environment and how they might interact with each other. Lastly, metabolomics describes which metabolites are produced by the microorganisms that inhabit a particular environment. By understanding all the ‘meta-omics’ regarding the microbiome, we can further understand the mechanisms and interactions that define the effects of the microbiome on the host. The current status of microbiome research is growing at a rapid pace, with a wide variety of studies looking at microbiomes in humans and their respective environments.

In addition, there is an initiative to catalog the evolutionary history of the microbiome by comparative analysis. They are currently using single-cell genomics to track individual bacterial lineages within the convoluted environment of their hosts. By tracking individual bacterial lineages, different evolutionary forces can be identified (e.g., mutations, selection, migration, drift, the shape of contents, metabolic capabilities). There are two central areas of research that will guide the future of microbiome profiling: 

(1) The application of metabolomics to microbiota studies. 

(2) The ability to modulate particular microbes within a particular microbiota community.

Microbiome-Based Therapeutics and Microbiome Engineering

Mirroring the field of genomic editing, microbes, and phages can also be engineered to amplify probiotic benefits, such as preventing infections, resolving inflammation, or treating metabolic disorders. Smart microbes can be created that possess novel functionalities, such as killing pathogenic strains or providing similar benefits to vaccinations. Engineered probiotic strains can also be improved for efficiencies, such as altering pathways that could increase production of secondary compounds (e.g.., vitamins, delivery of bioactive payloads).

There are several types of microbiome-based therapeutics: modulatory, additive, and subtractive. Modulatory therapies are used for altering the composition or activity of endogenous populations of microbiota, usually in the form of administration of prebiotics, probiotics (additive), or the use of bacteriophages to reduce harmful populations of bacteria (subtractive). The simplest form of additive microbiome-based therapeutics is probiotics and/or prebiotics in the form of supplements and in certain fermented foods. Supplemental pills mostly aim to repopulate the colon with desirable bacteria, especially after a course of antibiotics. 

There are several startups, such as Sun Genomics and Zbiotics, aspiring to build tailored probiotics based on each individual’s microbiota sequencing data. Other forms of additive applications include microbiota designed for metabolic diseases (e.g., microbiota synthesizing precursors of appetite-suppressing lipids). There are many startups within the live bacterial therapeutic space, including Microbiotica, Seres Therapeutics, Vedanta Biosciences, and Eligo Bioscience. The most severe additive microbiota therapeutic is fecal microbiota transplantation (FMT), which is usually used to relieve chronic intestinal infection by Clostridium difficile bacteria. A startup called Maat Pharma has been using FMT to help patients recover from leukemia and joint infections after their gut microbiome has been wiped from intensive chemotherapy and antibiotics.

The development of synthetic phages may offer the promise of modulating certain populations of bacteria that have negative effects on human health. 

On the other hand, there are several subtractive approaches to eliminate deleterious members of the microbiome. These methods are fueled by metagenomic studies of the fecal virome (virus population) for phage diversity, variability, and stability. The development of synthetic phages may offer the promise of modulating certain populations of bacteria that have negative effects on human health. Startups that focus on synthetic bacteriophages include C3J Therapeutics, EpiBiome, and BiomX. There are also proposals for experimenting with bacteriophages to manipulate the gut microbiome to prevent malnutrition in children in developing parts of the world.

Additionally, microbiomes could have a huge impact on cancer. Some microorganisms can render cancer drugs ineffective, while other microorganisms might be necessary to make these drugs work. The patient having the right microbiome could largely affect their chances of survival. It is predicted that 2018 will be the biggest clinical year in microbiome oncology, where microbiome-based therapeutics will be utilized to maximize cancer treatments.

Microbiome and Agriculture

Regarding agricultural industries, microbiome engineering of livestock by using feed enzymes, prebiotics, and probiotics to alter microbiota composition can improve animal health. Instead of stimulating the emergence of antibiotic-resistant bacteria and ethical concerns of residual antibiotics in meat products, microbiome engineering can be utilized as a safer alternative.

Apart from livestock, engineering of root-associated microbiomes in the rhizosphere (interface between plant roots and soil) can create improved phenotypes such as plant growth, fitness, and health. The roots of land plants thrive in soil, which is one of the richest and most diverse microbial reservoirs on Earth. Even the root itself is a site of colonization for microbes that can enhance mineral uptake from the plant by synthesizing and modulating the plant’s synthesis of phytohormones. These are chemical compounds that modulate plant growth and development, therefore protecting plants from soil-derived pests and pathogens. A startup that has been penetrating the agricultural microbiome space is SymSoil. There are many comparative studies occurring that indicate soil characteristics, such as nutrient and mineral availability as major determinants of the root microbiome.

Microbiome and Personalized Nutrition

Lately, microbiomes have had a disruptive effect on the current mindset of human nutrition. Because of the interrelationship between the foods we consume and the property of specific gut microbial communities, a new realm of personalized nutrition has emerged. Based on microbiome sequencing or genomic sequencing, diets are formulated to have the healthiest effect on the microbiome and overall wellness. Earlier startups that have not utilized the microbiome, such as Habit, provide nutrition tests that analyze DNA and blood to determine how a particular individual will react metabolically to macronutrients (i.e., carbohydrates, fat, protein). With numerous biomarkers and a holistic approach, a personalized eating plan is created for the unique individual. More recently, startups like DayTwo and Viome, have created personalized nutrition plans based specifically on one’s gut microbiome. The microbiome is utilized to predict blood sugar responses towards different foods, helping the user to discover which foods are healthiest for themselves by balancing blood sugar – a marker of increased risk of obesity and diabetes.

Future of Microbiome

Where is the microbiome headed? There is a future where “smart” cell-based therapeutics, synthetic biology, and autonomous sensors will rule the microbiome realm. Fully autonomous “smart” cell-based therapeutics will be able to restore the health of a human host through the help of clinically relevant sensors. These biosensors with luminescent, fluorescent, or colorimetric outputs could eventually lead to transcriptional regulation, or even permanently coupled to genomic alterations. Through synthetic biology engineering, smart microbes and phages will have the ability to modulate populations within the microbiota community – increasing the productivity or amounts of secondary molecules or destroying harmful bacteria that are negatively affecting the host’s health. With the advancements of these technologies and applications, the possibilities are endless.