The Everything Therapy

Could poop be more valuable than SaaS? New research suggests that augmenting existing gut microbiomes by eating the right microbes in a pill could treat 20 different diseases - or more, in a market worth $500B per year (almost double the size of SaaS).

Today, microbiome treatments rely on fecal transplants. This is where doctors take a donor’s poop and put it into a patient, either in pill or through a tube up the colon. While fecal transplants are only FDA-approved to treat Clostridioides difficile infections, doctors are investigating using them for everything from Alzheimer's to diabetes to cancer.^[1] But the current technique of taking poop from one person and putting it into another person is shitty because it isn’t standardized. Microbes can vary wildly donor to donor and can bring new problems along, such as multi-drug resistant pathogenic bacteria or viruses^[2].

To improve things, we explored a soon-to-be future where a cocktail of microbes is grown in the lab and given to patients as a first-line defense against 20 different diseases. First we dove into the research on each of these diseases, estimating a causal probability based on meta-analyses of microbes addressing disease. Then we found market sizes and patient populations for these diseases, and put all of it into a handy spreadsheet here. The result: A treatment that creates a healthy gut microbiome would be a first-line treatment for markets totalling over $500B per year and impacting more than a billion people.

This is trillion dollar poop.

Why are we exploring this? We’re on a mission to map impactful underinvested spaces and share them with the world. The majority of brilliant founders and investors are focused on pure software, which represents a tiny slice of U.S. GDP. Occasionally these technologies support critical moments in people’s lives, but more often they’re systems that provide a small headcount reduction or encourage frivolous purchases. There are better places to put that brainpower and capital.

Pure SaaS is a tiny part of the U.S. economy.

At the same time, U.S. healthcare spend is out of control. It’s common knowledge that Americans' health outcomes are some of the worst in the developed world, despite us spending the most per-capita on healthcare.

A microbe cocktail addresses both points. It’s tackling an absolutely massive market for the most vulnerable people among us. And it has the potential to drop healthcare spend in the long term by addressing disease far closer to the cause, rather than treating symptoms or by-products generated by an unhealthy microbiome.

So how would one make a cocktail like this?

Bioengineers would need to identify and manufacture an ensemble of microbes that’s safe, consistent from patient to patient and tuned for healthy microbiome function. Despite $1.7B in research funding^[3] and over $2 billion^[4] in startup funding over the last 10 years, this doesn’t exist yet.^[5] When this works, it’s going to treat a billion people. Because the ensemble represents a healthy baseline, a doctor won’t even necessarily need a full diagnosis. If a problem is vaguely related to inflammation, metabolism or neurology? Just give them a few pills full of microbes and see if it helps.^[6]

A microbe a day keeps the doctor away.

Let’s explore all the diseases that microbe ensembles can treat.

Just like with C. diff, replacing your gut biome helps treat other infectious diseases, in the gut or not. This includes cholera, salmonella, recurrent UTIs and multidrug resistant infections.^[7] Microbial ensembles also prevent various bacteria from causing gastric cancer, and generally block colon cancer progression.^[8] 

The gut is also the largest immune organ in the body, and effective communication between the immune system and the gut is critical for health.^[9] Raising mice without a microbiome cripples their immune system,^[10] and dysbiosis (an unhealthy microbiome) is just as bad.^[11] If your cells in your gut attack you, that can lead to an autoimmune disorder which can be treated by a fecal transplant.^[12] This insight reaches multiple indications, including arthritis^[13], chronic fatigue^[14], allergies^[15], baldness^[16], and aging^[17] on top of the obvious ones like colitis and Crohn's^[18].

In addition to directly treating these diseases, chemotherapies (a $10B market) and immunotherapies (an $110B market) can both be modified by the gut microbiome, and microbial ensembles can turn non-responders into responders.^[19] This would give a microbial ensemble a multiplicative effect on existing therapeutics.

Your microbiome processes all of the food that you eat, and how it does that is critical to regulating hunger and nutrient absorption. If your microbiome keeps you hungry, you’re going to gain weight.^[20] On top of that, a microbial ensemble can change how your body processes sugars, helping deal with diabetes and other metabolic disorders,^[21] as well as reducing the risk of the biggest killer in the world - heart disease.^[22] 

The new hot obesity drug: GLPoop-1

In neurological health, the root cause of multiple sclerosis is potentially Clostridium perfringens^[23], and fecal transplants have treated MS effectively in small studies.^[24] There hasn’t been as much study for Parkinson’s^[25] and Alzheimer’s,^[26] but there’s good evidence that an unhealthy microbiome can contribute to both. It’s possible microbial ensembles will slow or even stop these neurodegenerative disorders.^[27] It likely won’t reverse damage already done, but even slowing these diseases would impact tens of millions of people globally.

The immune system forms early on in life, so microbial ensembles for children would have benefits for many of the indications listed here. In addition, setting the microbiome early could prevent autoimmune disorders that cause everything from diabetes to acne. Persephone Biosciences is doing just this by sequencing the gut microbiomes of healthy infants to discover a set of microbes that could foster a healthy microbiome. While industrialization, changing diets, and antibiotics are all partially to blame for microbial changes, C-sections and lack of breast-feeding also both play a role. Persephone will initially treat babies born via C-section (27 million^[28] each year!), and then expand to treat all children, reversing thousands of years of microbial evolution, and preventing many of the diseases mentioned. This will be a market worth at least tens of billions of dollars annually as the science matures, given 130 million children are born each year.

Unfortunately, making an effective standardized fecal transplant is hard. Several microbiome companies have failed, including Seres, Evelo, and Finch,^[29] highlighting the challenges in making a good microbiome therapy. This is a new clinical space without significant precedent, and there are numerous question marks from strain selection to manufacturing and delivery.

But for every company that’s failed, two have sprung up in their place.^[30] Some have even raised hundreds of millions: Seres Therapeutics has raised $537M, and Vedanta Biosciences has raised $433M. Both academic and industrial research into the microbiome is accelerating. This is spurred on by hurricane-strength tech tailwinds. Sequencing costs have dropped 1,000,000,000x in the last 25 years alongside other -omics. At the same time, AI model parameter counts have improved at least 10,000,000x, and omics have proliferated. The microbiome is a high-dimensional stew of microbes, nutrients and proteins, and we need every tool we can get to understand it well enough to rebuild it from the ground up.

While it’s been common to investigate microbiomes via in-vivo testing, in-vitro testing is rapidly gaining popularity. Gut-on-chip technology is in the lead, able to capture important interactions in vitro.^[31] While currently rare, this market is expected to 5x in the next 5 years.^[32] Other high-throughput microfluidic approaches are also contributing, allowing combinatorial testing of strain combinations and conditions to test thousands of interactions at once.^[33] 

The organ-on-a-chip market is expected to grow 40% per year.

The development of metagenomics gave us a way to see what microbes are present in the microbiome, but it’s not enough information. Metabolomics is the next tool, as it reveals the metabolism and chemistry in our internal bioreactors. That’s led to significant advances like understanding the role of butyrate, but there are far more metabolites to map.^[34]  There’s also been some incredible advances in metaproteomics,^[35] as well as direct genetic manipulation of the microbiome that provide pieces of the puzzle.^[36]

All of these new techniques generate an enormous amount of high-dimensional data, which is hard to process and harder to generate appropriate models from. But artificial intelligence is well-suited to help us build effective synthetic microbial communities that can replace unbalanced microbiomes.^[37] And AI technology is getting vastly cheaper.

Parameter count (Y axis) is a log scale!

The first company to properly take advantage of these technologies and make an effective and scalable synthetic fecal transplant will have a massive first-mover advantage. Doctors will try it to treat everything named above - and more. Positive results will get that same microbial ensemble approved for more indications beyond the first, and negative results will provide valuable data to improve the treatment.  There will likely also be challenges in manufacturing initially, and so the first mover will have massive demand that facilitates scale-up financing. These factors mean that followers will have to spend far more capital per indication, both for running studies and for manufacturing microbial ensembles. Being the first mover could be exceptionally profitable.

Underinvested spaces like the microbiome have huge potential for company-builders, investors, and ultimately patients or customers. To find more massively impactful spaces like this, we created the Progress Map. We examined 50 major industries in the US and globally, and analyzed how much startup funding had gone into each industry in the last 10 years. We found that some markets are more than 1000x more crowded than others. The least crowded markets tend to be ones where strong tech tailwinds haven’t existed in the last 20 years, like Structural Metal Product Manufacturing, Petrochemicals, or Paper.

Markets ranked by competitiveness, with tech tailwinds on the right.

But the times they are a-changin. DNA sequencing, DNA synthesis, robotics, and transformer models are dropping some of the input costs in these industries by 10-1000x over the coming years, enabling new modes of production and unicorn startups. Solugen, Twelve, Dandelion Energy, and Via Separations - all in the top 6 least-crowded markets - have cumulatively raised over a billion dollars.

If you’re interested in trillion dollar poop, or another underfunded idea, reach out! We’d love to chat.