I — Gut Instincts: Unlocking Health’s Frontier Through the Microbiome Market

Part I (Science and Developments)

TL;DR:

The burgeoning field of microbiome research is revolutionising our understanding of health and disease, presenting unprecedented investment opportunities. From gut health and immune function to the intriguing gut-brain axis, the microbiome’s vast potential is just beginning to be tapped. We dive into the scientific advancements and developments that are shaping a new frontier in health and wellness, highlighting why the microbiome market is ripe for investment. We also shed light on one specific area within the microbiome field, the gut-brain axis, which particularly excites us.

Introduction

In the vast expanse of human health research, the microbiome stands out as a frontier yet to be fully explored and understood. This complex ecosystem of bacteria, viruses, fungi, and their genes within us is a testament to the symbiotic relationship we share with microscopic life. The implications of this relationship are profound, influencing everything from digestion and immunity to our mood and cognitive functions. As we delve deeper into this field, the fusion of science and technology has started to unlock the secrets of the microbiome, revealing not just the intricacies of human health but also opening doors to groundbreaking therapeutic interventions and lucrative investment opportunities. The journey through this narrative emphasises not only the current state of microbiome research and its application but also casts a focused beam on the emerging frontier of the gut-brain axis — a promising area of study that bridges our understanding of gastrointestinal microbiota with neurological health.

We dove deep into the space and have identified challenges and opportunities. Around 2016, the first wave of microbiome therapeutics took place — with many of them failing. A combination of clinical failures, depriorisation of corporate partner agendas, and limited public knowledge have halted its widespread adoption. Now, there seems to be a second wave: better equipped with learnings, science, and commercially viable pathways. In this article, Part I, we are setting the stage for the science and developments in the last decade. In Part II we will map out the market and companies innovating in the space.

💡 What is the microbiome?

The microbiome is the collection of all microbes, such as bacteria, fungi, viruses, and their genes, that naturally live on our bodies and inside us.

These microbes play essential roles in health and disease. Here are some of the key locations where microbiomes are found:

• Gut: The largest and most studied microbiome resides in the gastrointestinal tract, especially the colon. It plays crucial roles in digestion, immune function, and even influences behavior and mood through the gut-brain axis.
• Skin: The skin microbiome protects against pathogens, influences skin health and disease, and helps in wound healing. It varies significantly across different areas of the body due to variations in moisture, temperature, and sebum production.
• Oral Cavity: The mouth hosts a diverse microbiome involved in oral health, including tooth decay, gum disease, and can influence diseases elsewhere in the body.
• Respiratory Tract: The nasal and lung microbiomes are involved in filtering air and protecting against respiratory infections. The composition of these microbiomes can influence respiratory health and disease susceptibility.
• Urogenital Tract: The microbiome of the urogenital tract, including the vaginal microbiome, plays a role in reproductive health and disease. In women, the vaginal microbiome is crucial for maintaining vaginal health and preventing infections.
• Reproductive Organs: Beyond the vaginal microbiome, other parts of the reproductive system also harbor unique microbes that may play roles in health and disease, though these are less well understood.

The microbiome’s impact on health is far-reaching. It aids in digestion, modulates the immune system, influences metabolism, protects against pathogens, and even affects mental health through the gut-brain axis. However, modern lifestyle factors like diet changes, antibiotic overuse, reduced exposure to microorganisms, and environmental pollutants can disrupt this delicate balance, leading to a plethora of health issues.

Our microbial “garden” is a key to our health.

Key functions

1. Digestive Health: The microbiome aids in the digestion of foods that the stomach and small intestine have not been able to digest, helps with the production of some vitamins (B and K), and plays a critical role in the extraction of energy and nutrients from food.
2. Immune System Modulation: It is essential for the development and functioning of the immune system. The microbiome educates the immune system to distinguish between pathogens and non-harmful antigens and to develop appropriate responses, thereby preventing autoimmune diseases.
3. Metabolic Regulation: The microbiome influences the body’s metabolism, affecting how dietary fats and sugars are processed, which can impact the risk of developing conditions like obesity, diabetes, and cardiovascular diseases.
4. Protection Against Pathogens: By occupying niches that pathogens might colonize, producing antimicrobial substances, and modulating the immune system, the microbiome helps protect the body from infections.
5. Mental Health and Behavior: Research suggests a link between the gut microbiome and the brain, known as the gut-brain axis. This connection implies that the microbiome can influence brain health, mood, and behavior, potentially affecting conditions like depression, anxiety, and autism spectrum disorders.
6. Drug Metabolism: The microbiome can affect the efficacy and toxicity of drugs by metabolising medications, influencing treatment outcomes.

Negative impacts

1. Dietary Changes: Modern diets, high in processed foods and low in fibre, reduce the diversity of the gut microbiome. A diverse microbiome is crucial for metabolic health and immune function.
2. Antibiotic Overuse: Excessive and inappropriate use of antibiotics can disrupt the microbiome, killing beneficial bacteria and promoting antibiotic resistance, which can lead to health issues such as increased susceptibility to infections.
3. Reduced Exposure to Microorganisms: Increased hygiene practices and less contact with natural environments limit exposure to beneficial microorganisms that can help develop and maintain a healthy microbiome.
4. Environmental Pollutants: Exposure to pollutants, pesticides, and chemicals can alter microbiome composition and function, potentially leading to diseases.

But we currently have limited tools to understand or replant our “garden”.

Limitations

1. Complexity of the Microbiome: The human microbiome is incredibly complex, consisting of trillions of microorganisms with diverse roles. Fully understanding this complexity and how different microbes interact with each other and the host is challenging, making targeted interventions difficult.
2. Individual Variation: There is significant variability in microbiome composition among individuals, influenced by genetics, diet, lifestyle, and environmental factors. This variability means that a one-size-fits-all approach may not be effective for microbiome restoration.
3. Lack of Standardization: For interventions like fecal microbiota transplantation (FMT) and probiotics, there is a lack of standardization regarding the strains of bacteria used, dosages, and treatment protocols, which can lead to inconsistent outcomes.
4. Regulatory Challenges: The regulation of microbiome-based therapies, including probiotics and FMT, is complex and varies by region. This can slow down the development and approval of new treatments.
5. Incomplete Understanding of Mechanisms: While we know the microbiome affects health in numerous ways, the exact mechanisms by which it does so are not fully understood. This incomplete knowledge limits the development of targeted interventions.
6. Safety Concerns: Introducing live microorganisms into the body can have unintended consequences, including the potential for infections, especially in immunocompromised individuals. Ensuring the safety of microbiome interventions is a significant concern.
7. Resistance and Resilience of the Microbiome: The ability of the microbiome to resist change or quickly return to its baseline state after disturbance can limit the effectiveness of interventions aimed at altering its composition.

The Human Microbiome: Developments in the Last Decade

1. Transactions in the bacterial products segment around 2017 saw broad pharma interest but moderate results

→ Indication targets: mostly rCDI (recurrent Clostridium difficile infection); IBD (inflammatory bowel disease); and oncology.

• Takeda ended its $180M collaboration with Finch in 2022
• Janssen gave back full rights to the program to Vedanta in 2020 from the $339M in deal volume
• Bristol Myers Squibb discontinued the Vedanta partnership in 2021 (no details)

💡 A clear first wave of companies with first initial results in the late 2010s got pharma excited, but results have not been living up to expectations and a lot of the companies have either gone bankrupt or their corporate partnerships stopped.

2. The first microbiome drug got approved by the FDA in 2022

→ From the first wave of microbiome companies, Rebiotix managed to get the drug approved first for CDI (clostridioides difficile infection) in 2022, Rebyota (RBX2660). Seres Therapeutics then brought their drug, Vowst (SER-109) to the market in 2023.

3. There is an increase of microbiome-based research therapies and for various diseases

💡 The main drivers include technical breakthroughs in working with microorganisms (sequencing and CRISPR-Cas9); a deeper understanding of the cross-talk between hosts (humans) and microbiota; and industry<>research collaboration.

As we have noted, advances in sequencing technologies and synthetic biology in recent decades have transformed the human microbiome R&D landscape and the view on their immense therapeutic potential. At the same time, increasingly health-conscious and aware consumers provide a vast potential market for a widening range of clinically approved microbiome-based therapies and over-the-counter products for diseases and conditions that extend well beyond the digestive system (source). Additionally, an expansion of microbiome therapeutics beyond the digestive system and a rise in interest from big pharma count to the identified trends in the market (source).

Spotlight: The Microbiome Gut-Brain Axis

TL;DR: The gut-brain-axis is still an early field of research. Early signs of connection have been shown. However, “in the absence of specific microbial targets for more effective therapies, current approaches are limited to dietary interventions and centrally targeted pharmacological and behavioral approaches. A more comprehensive understanding of causative influences within the gut–brain–microbiome system and well-designed randomized controlled trials are needed to translate these exciting preclinical findings into effective therapies.” (2022. Mayer et al. The Gut-Brain Axis. Annual Review of Medicine.)

Market size

It’s only very recently that the gut-brain interaction has started to be explored. GI doctors have prescribed antidepressants to mitigate some symptoms of Irritable Bowel Syndrome, but it is still very early days, and the market is not yet existent for the brain gut axis.

Scientific Evidence

The microbiota-gut-brain axis is a bidirectional communication pathway through which bacterial metabolites can enter the brain, influence neurodevelopment and are proposed to be linked to neurodegenerative disease including Alzheimer’s Disease (AD), Parkinson’s Disease (PD) or Multiple Sclerosis (MS).37 GI symptoms have been long-known to be linked to PD — even years before the actual diagnosis. Probiotics have already been shown to have a positive effect on patients’ GI symptoms.38 Neurodegenerative diseases are themselves inherently complex and the underlying disease causes not well understood. The microbiome is adding another layer of complexity and thus it will remain to be seen whether microbiome modulation will be a viable therapeutic option in PD or others. We are only at the beginning to fully comprehend the role of the microbiome across therapeutic areas. Although, the scientific basis ranges from proven clinical efficacy to loose correlation. More translational research is needed to fill the evidence gap for future microbiome therapeutics in oncology, autoimmune or CNS conditions. (IQVIA; 2022. Liu, Huh, Shah.; 2022. Hong, Chen, Huang.)

The brain connectome, gut connectome, and gut microbiome make up the three nodes in the GBM network. All nodes are connected by bidirectional edges with multiple feedback loops generating a nonlinear system. The gut microbiota can communicate with the brain either directly via different signaling molecules or indirectly via the gut–brain axis. Similarly, the brain can modulate the microbiome either directly or via alterations of the gut microbial environment.

2022. Mayer, Nance, Chen. → Systems view of gut–brain–microbiome (GBM) interactions.

→ The gut microbiota can signal to the nervous system via three categories of signalling molecules.

• In immune signalling, components of the gut microbial membrane (lipopolysaccharide, MAMPs) or intact microbes can either travel through the systemic circulation to the brain, where they activate TLRs on microglia or neurons, or come into contact with TLRs on immune cells in the gut, triggering cytokine release locally and into the systemic circulation.
• Host-derived signalling molecules generated by the host and excreted into the small intestine are converted into absorbable neuroactive metabolites that reenter the systemic circulation.
• Diet-derived molecules are metabolites of amino acids, polysaccharides, and polyphenols are that metabolised by microbes into absorbable molecules with local and systemic effects.

(Abbreviations: ANS, autonomic nervous system; MAMP, microbe-associated molecular pattern; TLR, Toll-like receptor.)

💡 Does the gut-brain axis refer to the link between the gut microbiome and the brain, or also the microbiome in the brain?

When we talk about the gut-brain axis, we primarily refer to the communication pathway between the gut microbiome and the brain. This involves complex interactions that include the nervous system, the immune system, and endocrine pathways. The gut microbiome communicates with the central nervous system through various mechanisms, such as the production of neurotransmitters, modulation of the immune response, and direct neural pathways via the vagus nerve.

There’s currently no established evidence of a resident microbiome within the healthy brain itself, as the brain is considered a sterile environment protected by the blood-brain barrier. However, research has shown that microbial metabolites and components can cross the blood-brain barrier and that changes in the gut microbiome composition can influence brain function and behaviour. This interaction is crucial for understanding how variations in the gut microbiota might contribute to neurological diseases and mental health conditions, such as depression, anxiety, autism spectrum disorder, Parkinson’s disease, and Alzheimer’s disease.

So, the term “gut-brain axis” specifically denotes the bidirectional communication between the gastrointestinal tract and the brain, mediated largely through the actions and influences of the gut microbiome, rather than implying a microbiome residing within the brain itself.

We are highly excited about this yet-to-be fully explored field and cannot wait to see fascinating companies emerge therein. Drop us a message if you are interested to chat!