Who’s knocking on the door to tomorrow?
Probiotic or Next-Generation Probiotic?
Probiotics, according to the 2001 FAO/WHO definition, reinforced by ISAPP consensus statement in 2014, are “live microorganisms which, when administered in adequate amounts, confer a health benefit to the host”.
Next-generation probiotics (NGP), on the other hand, were defined by O’Toole et al., in 2017 as “well-characterized probiotic strains which could be used as delivery vehicles for a specific molecule abrogating the disease phenotype and thus promoting health” — highlighting a difference in the perception of the health benefit, here more oriented towards diseases.
Rebeca Martin and Philippe Langella gave this other definition of next generation probiotics in 2019 : “live microorganisms identified on the basis of comparative microbiota analyses that, when administered in adequate amounts, confer a health benefit on the host” thus pointing the finger rather on the next-gen method of identification than on the scope of use.
In general, the term NGP refers to new microorganisms with no history of safe use, which are typically commensal strains naturally found in a healthy gut, and often anaerobic.
To grasp the difference between traditional probiotics and next-generation probiotics, it is important to understand how the first generation of probiotics was developed. Typically, samples of different sources (foods or healthy people’s feces, mostly) were sent to the laboratory and inoculated on petri dishes. The bacteria that grew were then considered candidates for further fermentation and development. This is the story behind most Lactobacilli, Bifidobacteria and spores. However, as highlighted as early as 1985 in samples of soil and water bacteria, as little as 0.1 to 1% of bacteria can grow and be enumerated by plating procedure on petri dishes. The same can be expected from gut bacteria: the colon being normally deprived of oxygen, bacteria that grew in the lab, exposed to oxygen, do not represent the typical inhabitants of a healthy gut microbiota. Indeed, Bifidobacteria and Lactobacilli generally represent less than 1% of the total taxonomic units, or species, found in gut microbiota analyses.
Next-generation probiotics could thus include a lot more variability in genus and function, and more abundant and typical taxa of the human gut.
Who Are the Main Next-Generation Probiotics?
Most people in the probiotics industry know just 2 or 3 of the leading next-generation bacteria — Akkermansia muciniphila, Faecalibacterium prausnitzii, maybe Eubacterium hallii or Bacteroides thetaiotaomicron, but there are many more in development and you should know about them for a better vision of probiotics’ future — or for nerdy talks at dinner!
1. Akkermansia muciniphila
Akkermansia muciniphila, the mucus degrader, is the most famous of the next-generation gang. First described by Derrien et al. in 2004, it has since then been named in plenty of publications, mostly aiming at identifying its abundance in relation to health or disease, but also investigating mechanism of action, potential applications and efficacy.
Akkermansia modulates host metabolism ans immunity, could increase lifespan, enhance immunotherapy and could be an adjuvant in immunotherapy against tumors, showed benefits for amyotrophic lateral sclerosis (SLA) in mice and, in pasteurized version, improved metabolic parameters in a human pilot study.
Akkermansia muciniphila is already on the market in the USA.
2. Faecalibacterium prausnitzii
Faecalibacterium prausnitzii (Fprau) is a special bug in that it is the most abundant in a healhthy gut, with about 5–15%, and is a major butyrate producer, butyrate being a short chain fatty acid key to intestinal health. It was first described under the name Faecalibacterium prausnitzii in 2002.
In a context in which modernity has promoted low-grade chronic inflammation in a large part of the population, the anti-inflammatory potential of this species makes it very promising.
Low levels of Fprau were associated with inflammatory bowel diseases (IBD: Crohn’s disease and ulcerative colitis) and the species is a candidate for the treatment of IBD and as an adjuvant in celiac disease, diabetes (linked to the important roles of butyrate in glucose metabolism) and colorectal cancer.
Most Fprau isolates were found resistant to certain antibiotics leading to questions regarding the balance benefit/risk: in the context of the human gut, as opposed to the context of animal breeding in which the non-resistance to antibiotics safety rule was first established, should such a resistance impede a useful therapeutic tool from getting to market?
Key player: Exeliom Biosciences.
Bacteroides represents a very abundant genus, comprising commensal organisms and pathogens, and includes a number of candidates as next-generation probiotics:
- Bacteroides fragilis, the most prevalent of Bacteroides, could be protective against Inflammatory Bowel Diseases (IBD) and colorectal cancer (CRC) but also present a very virulent pathogen Doppelgänger, which notoriously caused the death of Harry Houdini. A complex aspect of its pathogenicity is that it could come from its location rather than strain.
- Bacteroides thetaiotaomicron was first sequenced in 2003 and is thought to be able to protect against gastrointestinal diseases. With its broad genome, it can switch from plant polysaccharide degradation to glucose degradation, making it a resilient organism, and it seems a cross-feeder promoting the development of beneficial Bifidobacteria. Thetaiotaomicron could also exert anti-pathogen activity.
- Bacteroides uniformis can ameliorate metabolic disorder and immunological dysfunction in obese mice
- Bacteroides ovatus is thought to have potential in cancer and could prevent lipopolysaccharide-associated inflammation.
- Bacteroides dorei which could protect in autoimmune diseases such as type 1 diabetes
As Fprau, a lot of Bacteroides raise questions regarding antibiotic resistance.
4. Christensenella minuta
Christensenella minuta was first discovered more recently, in 2012, and its abundance was found to negatively correlate with body mass index. This next-generation probiotic is currently studied for its potential in the management of obesity and associated metabolic diseases.
Key player: Ysopia Bioscience.
5. Clostridium species
Clostridium is a very large family including, like Bacteroides, good bacteria and deadly pathogens, such as Clostridium difficile and Clostridium perfringens. Importantly, even strains among the same species, as is the case for E. coli, can be probiotic or cause enteric diseases.
Clostridium butyricum was reported to reduce chemotherapy-induced diarrhea and antimicrobials-induced diarrhea in humans — but was also associated with occurrences of necrotizing enterocolitis.
Clostridium butyricum CBM 588 was first discovered by Dr. Miyairi in 1933 and obtained the novel food status in Europe in 2014 but so far has been used in animal farming and since very recently the species is available in human supplements in the US, thanks to Pendulum Therapeutics.
Other interesting Clostridia include Clostridium acetobutylicum, beijerinckii, cellulolyticum, ljungdahlii and thermocellum.
6. Eubacterium hallii
Eubacterium hallii is an important butyrate producer which, thanks to its versatility (it is also able to produce propionate from a broad range of substrates), can bring resilience to gut homeostasis. Through butyrate production, it could be helpful in the management or prevention of diabetes, and in inflammatory disorders.
7. Eubacterium rectale
Eubacterium rectale is another butyrate producer thought to be involved in positive cross-feeding interactions with beneficial bactria such as B. longum. However, it was recently identified as potentially cancer-promoting.
8. Propionibacterium freudenreichii
Propionibacterium freudenreichii has a long history of safe use as it is implemented in the manufacture of dairy products such as Swiss cheeses. It has both European QPS (Qualified Presumption of Safety) and GRAS (Generally Recognized as Safe) status. Its probiotic properties according to recent literature, include anti-pathogen activity, anticancer potential and immunomodulatory properties.
9. Parabacteroides goldsteinii
A preclinical study in high-fat-diet mice showed a potential for Parabacteroides glodsteinii for the reduction of weight gain and fat mass gain, and a reduction of endotoxemia.
Atopobium vaginae is associated with bacterial vaginosis in women, but the genus Atopobium (Atopobium minutum) is also a candidate biotherapeutic agent against cancer, and could be of interest in endometrial cancer.
11. Prevotella copri
Prevotella is not such a common feature of the Western gut microbiota but is the signature of enterotype 2, typical of more rural lifestyles and fiber-rich diets. Some strains of Prevotella copri were found to improve glucose homeostasis but others were found associated with insulin resistance, so the determinants of its properties need further evaluation.
12. Dysosmobacter welbionis
Dysosmobacter means stinky bacterium (dysosmo: that smells bad in Greek) and it is the most recent next-gen candidate, isolated for the first time in 2020. Gut microbiota studies from 4 cohorts showed the bacterium is present in nearly 70% of the population, and that it is less present in people with type 2 diabetes. Preclinical studies in mice showed that live Dysosmobacter (but not pasteurized) partially counteracted diet-induced obesity development (fat mass gain, insulin resistance and inflammation).
Key player: Louvain Drug Research Institute
Eggerthellaceae were reported to convert ellagitannins from foods like walnuts and berries to anti-inflammatory, anti-carcinogenic, cardioprotective and neuroproective compounds (isolecithine-A). There could be great potential for the development of nutraceutical combined solutions with the next-generation probiotic and its substrate.
Eggerthellaceae are also notorious for the interaction of Eggerthella lenta with the heart failure drug digoxin. The bacterium converts the drug into an inactive form, limiting the drug’s efficacy and paving the way towards personalized medicine, a way of practicing medicine taking into account the patient’s uniqueness, genetically and microbially.
14. Hafnia alvei
Hafnia alvei HA4597 is a novel strain in the sense that it has never been used as a probiotic prior to 2018 and has been referred to as a next-generation probiotics in multiple occurrences (here, here and here for example). However, it is an exception in this group because this species has been used since the 1990s as a starter culture to bring flavor to French cheeses such as camembert. Hafnia thus benefits from a long history of safe use in food, while it was only recently identified as a precision probiotic supporting weight loss.
Key player: TargEDys. Hafnia alvei is commercialized by TargEDys — where I work — and is already available on the market in several countries.
This article is the fruit of a quick research and does not pretend to be exhaustive. New strains are identified probably on a daily basis, and the level of data available for each of these vary a lot. This review focuses only on the species levels, while we can expect variability from two strains of the same species, as for traditional probiotics.
Regulatory limitations imply that such strains need to be evaluated for safety by authorities prior to arrive on the market, this is why there is currently a lot of discussion and research around these strains, but only very few have made it to the shelves until now (Hafnia alvei, Akkermansia muciniphila in the USA and soon to come to the EU, any other? — please do comment if so). Questions around the regulatory criteria for safety will be key ones for this sector to develop and reach patients.