By Mike Montemarano, Associate Editor04.05.23
Synbiotics have emerged as a promising nutraceutical category in the ever-expanding field of research on the human gut microbiome.
According to the International Scientific Association for Probiotics and Prebiotics (ISAPP), a synbiotic is defined as “a mixture comprising live microorganisms and substrate(s) selectively utilized by host microorganisms that confers a health benefit on the host.”
Two subsets of synbiotics include complementary and synergistic. A “synergistic synbiotic” is one in which the substrate is designed to be selectively utilized by the co-administered microorganism(s); these are difficult to test and less commonly used in clinical trials.
A “complementary synbiotic” is composed of a probiotic combined with a prebiotic, designed to work together to lead to desired health outcomes. It should be tested together in order to be labeled as a synbiotic.
At a recent seminar hosted by the Global Prebiotics Association (GPA), Hannah D. Holscher, PhD, RD, associate professor of nutrition at the University of Illinois Urbana-Champaign, discussed what makes synbiotics and their components unique from pre-, pro-, and postbiotics. She also covered research on health outcomes.
“I sat on the (ISAPP) panel to develop a definition for synbiotics, which is a mixture of live microorganisms and substrates which are selectively used by the host microorganisms in order to confer a health benefit on the host,” Holscher said. “There was a lot of dialogue and reasoning behind why we didn’t use a previous definition, which was a combination of prebiotics and probiotics.”
“A complementary synbiotic contains an established prebiotic and probiotic, and each component works independently to provide at least one health benefit,” said Holscher. “Synergistic synbiotics is a newer term, made to include the newer science. This is why we chose to use the term substrate instead of ‘prebiotic,’ and live microorganisms in place of ‘probiotic.’ To call the combination a synbiotic is to infer that the components are working together, and that the substrate is selectively utilized by the microorganism in order to confer a health benefit.”
according to Holscher.
With complementary synbiotics, dosages of the experimental formula must contain the established efficacious dosages for both the prebiotic and probiotic components. Since each ingredient has been linked to benefits in previous studies, complementary synbiotics can be evaluated in a two-arm study design, in which the formula is tested against a control arm.
Synergistic synbiotics must be investigated through a four-arm study design, involving a group supplementing with the microbe, the substrate, the combination of the two, and a placebo. This is because the study must demonstrate that the mixture confers superior performance compared to either of the individual components.
Following ISAPP’s published definition of synbiotics in 2020, approximately 20 relevant meta-analyses have been published. Collectively, 16 studies have found that synbiotics reduced respiratory tract infections, 11 studies linked synbiotics to reduced systolic blood pressure in adults, and 23 studies linked synbiotic formulations to decreased body weight and
waist circumference.
Across 18 studies, synbiotics exhibited some potential to improve glycemic control; across nine studies, they exhibited some potential to ameliorate oxidative stress. However, for each of these outcomes, the evidence was unclear due to the fact that analyses looked at both probiotic and synbiotic formulations, said Holscher.
“My conclusion here is that there is limited evidence supporting synbiotics,” said Holscher.
Few studies have met the established criteria to deliver conclusive evidence for complementary or synergistic synbiotics. And most complementary synbiotics don’t contain a sufficient dose of prebiotic substrate.
“There are essentially no four-arm clinical trials which show unique health benefits of a synbiotic combination that don’t exist for the use of just a substrate or microorganism,” Holscher said.
Galactooligosaccharides (GOS), fructooligosaccharides (FOS), and inulin are each established as prebiotics based on research over the past 30 years. Other oligosaccharides, phenolics and other phytochemicals, conjugated linoleic acid, and polyunsaturated fatty acid all serve as candidate materials with potential prebiotic activity.
Early entrants into the synbiotics market will also likely utilize the most well-established probiotic strains, such as Bifidobacterium, Lactobacilli, and Saccharomyces boulardii. Other emerging species include Faecaelebacterium prausnitzii, Akkermansia muciniphila, Bacteroides fragilis, and Dysosmobacter welbionis.
To develop research-backed synergistic synbiotics, it will be important to conduct preclinical work in in vitro systems or artificial models of the human gut, ahead of expensive four-arm clinical studies. This preclinical work can be supported by computational approaches such as artificial intelligence (AI) in order to discover microbes and substrates at a rapid pace, Holscher noted.
“It’s important to be very confident in these types of formulations through the SHIME (Simulator of the Human Intestinal Microbial Environment) model, zebrafish, and rodent models,” she said. “As is the case with the rest of the industry, a week in the library will save you a month in the lab.”
Publishing the finer details of a formulation within studies is necessary to drive this category forward, she added.
“Reporting and reproducibility is imperative. Researchers need to report what preparations contain, what the storage methods are, an analysis of the synbiotic as consumed, and details about participants’ consumption and compliance measures. We need to think very carefully before a study begins on what is needed in order to establish causal relationships.”
According to the International Scientific Association for Probiotics and Prebiotics (ISAPP), a synbiotic is defined as “a mixture comprising live microorganisms and substrate(s) selectively utilized by host microorganisms that confers a health benefit on the host.”
Two subsets of synbiotics include complementary and synergistic. A “synergistic synbiotic” is one in which the substrate is designed to be selectively utilized by the co-administered microorganism(s); these are difficult to test and less commonly used in clinical trials.
A “complementary synbiotic” is composed of a probiotic combined with a prebiotic, designed to work together to lead to desired health outcomes. It should be tested together in order to be labeled as a synbiotic.
At a recent seminar hosted by the Global Prebiotics Association (GPA), Hannah D. Holscher, PhD, RD, associate professor of nutrition at the University of Illinois Urbana-Champaign, discussed what makes synbiotics and their components unique from pre-, pro-, and postbiotics. She also covered research on health outcomes.
“I sat on the (ISAPP) panel to develop a definition for synbiotics, which is a mixture of live microorganisms and substrates which are selectively used by the host microorganisms in order to confer a health benefit on the host,” Holscher said. “There was a lot of dialogue and reasoning behind why we didn’t use a previous definition, which was a combination of prebiotics and probiotics.”
Working Definitions
Synbiotics can include microbes and substrates which, on their own, don’t confer any health benefits. This doesn’t exclude established prebiotics and probiotics from being components of a synbiotic formulation, however.“A complementary synbiotic contains an established prebiotic and probiotic, and each component works independently to provide at least one health benefit,” said Holscher. “Synergistic synbiotics is a newer term, made to include the newer science. This is why we chose to use the term substrate instead of ‘prebiotic,’ and live microorganisms in place of ‘probiotic.’ To call the combination a synbiotic is to infer that the components are working together, and that the substrate is selectively utilized by the microorganism in order to confer a health benefit.”
Study Designs
The two categories of synbiotics require their own respective study protocols,according to Holscher.
With complementary synbiotics, dosages of the experimental formula must contain the established efficacious dosages for both the prebiotic and probiotic components. Since each ingredient has been linked to benefits in previous studies, complementary synbiotics can be evaluated in a two-arm study design, in which the formula is tested against a control arm.
Synergistic synbiotics must be investigated through a four-arm study design, involving a group supplementing with the microbe, the substrate, the combination of the two, and a placebo. This is because the study must demonstrate that the mixture confers superior performance compared to either of the individual components.
‘It’s important to be very confident in these types of formulations through the SHIME (Simulator of the Human Intestinal Microbial Environment) model, zebrafish, and rodent models. As is the case with the rest of the industry, a week in the library will save you a month in the lab.’
Scientific Standing
The strongest evidence supporting synbiotic formulations today involves health outcomes related to metabolism and immune function, said Holscher.Following ISAPP’s published definition of synbiotics in 2020, approximately 20 relevant meta-analyses have been published. Collectively, 16 studies have found that synbiotics reduced respiratory tract infections, 11 studies linked synbiotics to reduced systolic blood pressure in adults, and 23 studies linked synbiotic formulations to decreased body weight and
waist circumference.
Across 18 studies, synbiotics exhibited some potential to improve glycemic control; across nine studies, they exhibited some potential to ameliorate oxidative stress. However, for each of these outcomes, the evidence was unclear due to the fact that analyses looked at both probiotic and synbiotic formulations, said Holscher.
“My conclusion here is that there is limited evidence supporting synbiotics,” said Holscher.
Few studies have met the established criteria to deliver conclusive evidence for complementary or synergistic synbiotics. And most complementary synbiotics don’t contain a sufficient dose of prebiotic substrate.
“There are essentially no four-arm clinical trials which show unique health benefits of a synbiotic combination that don’t exist for the use of just a substrate or microorganism,” Holscher said.
Product Development
While there may be a lack of evidence supporting synergistic synbiotics, complementary synbiotics have plenty of established substrates and microbes to leverage.Galactooligosaccharides (GOS), fructooligosaccharides (FOS), and inulin are each established as prebiotics based on research over the past 30 years. Other oligosaccharides, phenolics and other phytochemicals, conjugated linoleic acid, and polyunsaturated fatty acid all serve as candidate materials with potential prebiotic activity.
Early entrants into the synbiotics market will also likely utilize the most well-established probiotic strains, such as Bifidobacterium, Lactobacilli, and Saccharomyces boulardii. Other emerging species include Faecaelebacterium prausnitzii, Akkermansia muciniphila, Bacteroides fragilis, and Dysosmobacter welbionis.
To develop research-backed synergistic synbiotics, it will be important to conduct preclinical work in in vitro systems or artificial models of the human gut, ahead of expensive four-arm clinical studies. This preclinical work can be supported by computational approaches such as artificial intelligence (AI) in order to discover microbes and substrates at a rapid pace, Holscher noted.
“It’s important to be very confident in these types of formulations through the SHIME (Simulator of the Human Intestinal Microbial Environment) model, zebrafish, and rodent models,” she said. “As is the case with the rest of the industry, a week in the library will save you a month in the lab.”
Publishing the finer details of a formulation within studies is necessary to drive this category forward, she added.
“Reporting and reproducibility is imperative. Researchers need to report what preparations contain, what the storage methods are, an analysis of the synbiotic as consumed, and details about participants’ consumption and compliance measures. We need to think very carefully before a study begins on what is needed in order to establish causal relationships.”
