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Page 2 of 14 Kleerebezem et al. Microbiome Res Rep 2024;3:46 https://dx.doi.org/10.20517/mrr.2024.48

SYNBIOTICS
The term “synbiotic” refers to “synergy” and the Greek word for life “bios”, effectively meaning “synergistic
life” and is an obvious nod to the terms prebiotic and probiotic and their potential synergy in the host’s
digestive tract. Accordingly, the initial definition of synbiotics was “probiotics and prebiotics that
[1]
beneficially affect the host” . In 2020, an expert panel assembled by the International Scientific Association
for Probiotics and Prebiotics (ISAPP) refined the synbiotics definition as “a mixture comprising live
microorganisms and substrate(s) selectively utilized by host microorganisms that confers a health benefit on
the host”. The panel discriminated between complementary and synergistic synbiotics. In complementary
synbiotics, the components non-cooperatively exert their synergistic health-promoting effects in the host,
whereas in synergistic synbiotics, the substrate is designed to be selectively utilized by the co-administered
microorganisms to enhance their health-promoting effects . Notably, the latter concept does not exclude
[2]
enrichment of other beneficial members of the endogenous microbiota, but identifies the co-administered
microbe as the main target of the prebiotic substrate. Additionally, the synergy underlying the synbiotic
concept intrinsically implies that these functional foods elicit a superior effect compared to those elicited by
the separate administration of their constituents. However, due to the complications in scientifically
establishing a synergistic effect on health, the consensus described by the expert panel specifies that for
[2]
synergistic synbiotics, it would be sufficient to demonstrate selective use of the prebiotic substrate by the
co-administered microorganism.

Health effects associated with the consumption of synbiotics include the general improvement of
anthropometric, cardiometabolic, and inflammatory markers , as well as the eradication of
[3]
[4]
Helicobacter pylori and symptom improvement in various patient groups, including those suffering from
[7]
[6]
atopic dermatitis , nonalcoholic fatty liver disease , and colorectal cancer . Notably, in most of these
[5]
studies, it remains unclear whether consumption of the synbiotic product has an added value over the
consumption of its individual ingredients [i.e., the probiotic(s) or prebiotic(s)], and it is often not specified
whether the synbiotic would classify as a complementary or synergistic synbiotic. Therefore, despite the
refined definition of synbiotics, most synbiotic designs (i.e., the choice of pre- and probiotics that are
combined) remain poorly rationalized and their health-promoting efficacy relative to their individual
constituents often remains unclear.

Synbiotics can improve general health in newborns at risk
The most striking health impact associated with the administration of a synbiotic product has undoubtedly
been described by Panigrahi et al., reporting on a large-scale, double-blind, placebo-controlled randomized
synbiotic administration trial (N > 4,500) in infants recruited in Odisha, India, achieving significantly
decreased neonatal sepsis and mortality in the synbiotic group compared to the placebo group .
[8]
Additionally, the synbiotic-treated group also displayed a significantly reduced incidence of lower
respiratory tract infections and diarrhea, indicating that the overall health status of the synbiotic-treated
children was improved compared to the placebo group . The synbiotic product used in this landmark study
[8]
was composed of Lactiplantibacillus plantarum (L. plantarum) ATCC202195 in combination with fructo-
oligosaccharides (FOS), which was administered to newborns for 7 consecutive days starting 2-4 days after
[9]
birth. Both this study and earlier work by the same group established that this synbiotic administration
[8]
regimen succeeded in establishing long-term colonization (several months) of the L. plantarum strain in the
intestines of these children. However, the synergistic interaction of the individual pre- and probiotic
constituents in this study remains undetermined, and it was not reported whether the ATCC202195 strain
could effectively utilize FOS as a substrate for growth. Analysis of the available genome sequence of this
strain (NCBI: genome/GCF_004354995.1) indicates that it lacks a gene encoding an extracellular
β-fructosidase (FosE), which has been shown to be required for the utilization of longer chain fructo-oligo-
and polysaccharides [10-12] . This finding suggests that L. plantarum ATCC202195 would only utilize the short-