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Page 8 of 14 Kleerebezem et al. Microbiome Res Rep 2024;3:46 https://dx.doi.org/10.20517/mrr.2024.48

functionality when these products are delivered to the consuming host organism. However, the reviewed
work above raises doubts about the reliability of such rational and experimentally driven design of
synergistic synbiotics, which may eventually turn out to act as complementary synbiotics. Analogous to
what is described for L. plantarum, competition experiments in GOS-fed gnotobiotic mice did not reveal a
competitive advantage for Limisilactobacillus reuteri 6475 that is able to utilize this prebiotic substrate
[51]
compared to its isogenic mutant-derivative that is unable to utilize GOS . Nevertheless, irrespective of the
precise nomenclature used for synbiotic concepts, the findings described above do support the usefulness of
synbiotics in the intention to enhance the delivery of health-promoting microorganisms to their site of
action (e.g., the human or animal intestinal tract). However, their selectivity in enhancing a specific
microbial strain is unlikely to be achievable, especially when employing prebiotic substrates that are
“commonly” degraded by endogenous microbiota members (e.g., GOS, FOS or inulin). Refinement of the
substrate to chemically pure prebiotics rather than the current mixtures of prebiotic constituents such as
IMOS and GOS (see above and ref [29,32] ) may enhance the selectivity of such substrates in stimulating a
specific strain or species. However, purification and/or chemical synthesis of these chemically pure
prebiotics to generate more selective prebiotic substrates could be laborious and costly, which may
compromise the economic feasibility of this scenario. Still, identifying more selective substrate compounds
would provide more credible approaches to creating synergistic synbiotics compared to the canonically used
prebiotics such as GOS, FOS, and inulin. In addition, selecting substrates that require an extensive
enzymatic pathway for their degradation and utilization may contribute to the selectivity in stimulating only
microorganisms that encode the entire enzyme repertoire required for substrate utilization. Besides the
stimulation of the co-administered microorganism (i.e., the synergistic synbiotic concept), high specificity
and selectivity substrates may also be very attractive compounds to stimulate an endogenous microbiota
member in a precision-prebiotic approach. As an example, the endogenous Bifidobacterium population in
the intestine was apparently selectively stimulated in healthy human volunteers by the consumption of
synthetic human milk oligosaccharide (HMO) constituents 2’-fucosyllactose (2’FL) and/or Lacto-
[52]
neotetraose (LNnT) . However, and in view of the diversity of microbiome responses in individuals, one
can question whether the Bifidobacterium stimulation is not simply the only common response in the
participants rather than a truly selective response remains unclear, since additional microbiome responses
may simply have remained undetected due to a lack of conservation among (i.e., distinct microbiome
species reacting in individual participants prevents their detection in community-based microbiome
response analyses) the participants. Extending this line of research toward chemically defined and pure
prebiotics could determine to what extent certain single or mixed carbohydrate constituents of a prebiotic
could selectively stimulate particular microbes in situ.

Irrespective of their use as part of a synergistic synbiotic mixture or as precision prebiotic, the proposed
substrate compounds and their claims toward selectivity should be rigorously evaluated using robust in vivo
nutrient-competition models to ensure that observed fitness enhancement effects are driven by direct
interaction between substrate and microorganism. Experimental verification of the selectivity of synergistic
synbiotics or the precision prebiotic requires that ecosystem interaction and nutrient competition concepts
are taken into account and controlled for, e.g., “cooperative traits” and their role in generating “public
goods”, the substrate monopolization as “personalized goods”, and the nutrient competition capacity
redundancy and abundance, as well as the corresponding substrate affinity and utilization rates [Figure 2].

How do the arguments raised above influence our perspective on the spectacular health effects of the
administration in newborn infants of L. plantarum combined with FOS synbiotic, reported by Panigrahi
et al. ? The administration regiment employed in that study provides this synbiotic to infants during their
[8]
first weeks of life, which was demonstrated to achieve the engraftment of the L. plantarum strain in the