Simply put, it creates robot guts.
“What we do is we feed the robot gut whatever the product is,” Dr. Peter Azmi, PhD, ProDigest’s business development lead for North America, told NutraIngredients.
“This could be drugs. This could be supplements. This could be any sort of functional food product. We can see how that product would behave in the gastrointestinal system. We’re able to ask the question, ‘how does an individual gut microbiome respond to what it’s being fed?’”
The company explores how a product affects the microbiome and how a product is affected by the microbiome. This is important when looking at the creation of byproducts as in the case of drugs that can be activated, or inactivated, or rendered toxic by the microbiome.
The company’s motto: ‘If you can ingest it, we can test it.’
Uncertain beginnings
In some ways ProDigest’s existence seems unlikely. The original ‘robot’ technology—the model of the gut that was the prototype for the iterations used today— was left buried in the recesses of a basement.
It was 1993, and a professor at the Ghent University, an expert in wastewater treatment plants, had an idea. He noted how plants extracted waste but allowed bacteria to feed off the excess nutrients, mimicking the workings of the human colon.
The professor was convinced that his laboratory model of a wastewater treatment plant could be adapted to parallel what happens in the body’s intestinal tract. He created the first version of the simulator of the human intestinal microbial ecosystem (SHIME).
However, the system was somewhat forgotten, left to collect dust in the university’s basement.
“At that time there was absolutely no interest in the gut microbiome,” Dr. Massimo Marzorati, PhD, CEO of ProDigest, said. “The original SHIME remained in the basement for many years.”
An evolution occurred at the beginning of this century as a growing number of students started conducting research on the microbiome. The research was purely academic and had not yet been translated into commercial application, Dr. Marzorati said.
That changed when a significant development occurred in Europe. In 2007, the European Union implemented a new regulation, which required that nutrition and health claims made on products be based on clear evidence.
Dr. Marzorati, who had been a student of the original SHIME creator, had joined the faculty of Ghent University at that same time. Companies attempting to comply with new regulations began to contact Dr. Marzorati after reading initial journal articles about SHIME, asking researchers to study products and their effects on the gut.
He and his colleagues decided to build SHIME 2.0. They also established a spin-off company from the university.
ProDigest was born.
Its first clients were companies in the prebiotic space interested in the impact of fibers that reached the colon and were fermented there by the bacteria. The business momentum continued as the ProDigest team spent its time building trust through word of mouth in the scientific community and among firms. Though Dr. Marzorati is a scientist, he spent the company’s first years as a salesperson, making cold calls to firms. He also took university courses on how to create business plans, how to learn the art of negotiation and rules of intellectual property protection.
However, ProDigest was not alone in the intestinal gut modeling space. The Netherlands Organization for Applied Scientific Research (TNO) was a major competitor. It has one simulation of the upper gastrointestinal tract and one simulation of the large intestine. SHIME differs in that it encompasses the entire gastrointestinal tract, according to Dr. Marzorati.
The SHIME model, a computer-controlled device that allows users to record several parameters, was initially offered in service to universities and research centers in 2015 and the company has continued to work with these agencies. ProDigest is currently on its fourth iteration of the technology.
A dynamic model of the gut, it is best used when chronic, daily dosing is important to a scientific outcome, like for a supplement with complex combination of fibers, phytonutrients, polyphenols, proteins, probiotics or substances meant to condition someone’s gut over time. The model provides long-term study capabilities, and researchers can feed it daily and run the study for weeks.
ProDigest could not create SHIME and other tools without a team of experts knowledgeable about reactor technology, cell biology, microbial ecology, predictive analytics, statistics, bioinformatics and multi-omics, Dr. Marzorati said.
“The driver behind the evolution of ProDigest has always been the same from the very beginning, which is being able to predict the fate and the effect of an ingredient once it’s been ingested,” he added. “The technology copes with this need. It evolves very quickly.”
Definitions
The International Scientific Association for Probiotics and Prebiotics (ISAPP) defines a prebiotic as “a substrate that is selectively utilized by host microorganisms conferring a health benefit” (Nat Rev Gastroenterol Hepatol 14, 491–502 (2017)).
Probiotics are “live microorganisms which when administered in adequate amounts confer a health benefit on the host” (FAO/WHO, ISAPP).
A postbiotic is a “preparation of inanimate microorganisms and/or their components that confers a health benefit on the host”. (ISAPP, Nat Rev Gastroenterol Hepatol 18, 649–667 (2021)).
Colon-on-a-plate
Over the years, the company has expanded its technologies to answer different research questions from its clients, offering high throughput technologies to address those. This led to the development of Colon-on-a-plate, a simplified version of SHIME that allows users to screen hundreds of test conditions in parallel without any limitation to scalability.
Colon-on-a-plate can use many test arms simultaneously, but it relies on a single dose of substance for a 48-hour acute study. Companies can determine how consistent their product works across many different gut types.
“It’s always a constant effort to either find new approaches or to constantly improve what we have in our hands,” Dr. Marzorati said. “It’s more like I get in contact with the client, the client has a need, they send us the products. We do the research, and we deliver the results.”
ProDigest later launched a kinetic version of Colon-on-a-plate where users can collect multiple samples from the same reactor. The kinetic version can analyze the response of the gut microbiota to specific treatments over moments in time.
Samples are then analyzed through a multi-omics approach. Researchers also use shotgun sequencing and an in-house metabolomics platform called MetaKey.
“We are not positioned as a replacement of the in vivo study,” Dr. Marzorati said. “However, by using our technologies, you can understand how an ingredient is working and potentially understand why.”
Clients and markets
ProDigest works with startup, biotech, food, functional food and pet companies. Fifty percent of its clients come from the food and functional food industries, and about 35% from pharmaceutical and biotech companies.
Although its primary markets are Europe and the United States, ProDigest has clients in Australia, China, Japan, India, Mexico and other parts of South America.
Clients come to ProDigest at different points, either at the early stage of development where they might have multiple ingredients and want to test which one to move forward. Maybe they have already completed a clinical trial and have seen a specific effect and have no idea why its occurring.
“We’re a precursor to clinical studies,” Dr. Azmi said. “We are an ex vivo preclinical model ahead of a clinical study. More companies, as they become aware of us, are turning away from traditional animal studies, which is where many companies would normally start. However, when you work in an animal model, you’re not working in a system that is physiologically relevant to a human being.”
Animal studies may not predict clinical outcomes well, which translates into failed clinical trials and added costs, he noted.
“You pay with your time, you pay with the reliability of the data, you pay with the control of the information,” Dr. Azmi said.
ProDigest technologies align with the ethical framework supported by the U.S. Food and Drug Administration, which encourages organizations to use non-animal methods instead of live animals when alternatives exist for research.
Biobank
In addition to the microbiome analysis, the company has offered clients access to its biobank since 2021, which complies with the Belgium government’s requirements that such a bank be provided when human fecal samples are stored.
The biobank is also essential to study personalized nutrition and medicine, including conditions such as ulcerative colitis, metabolic syndrome or inflammatory bowel disease.
Looking to future, Dr. Marzorati said the company will incorporate more artificial intelligence, using bioinformatics.
“Those things are key because nowadays every company in our space generates a huge amount of data,” he said. “Clients do not need more data. What they do need is to better extract information from the data that is generated and basically use this information for practical applications. We’re making a big step in this field to move ahead.”
