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Kleerebezem et al. Microbiome Res Rep 2024;3:46 https://dx.doi.org/10.20517/mrr.2024.48 Page 11 of 14

bacteria to the intestine in a viable and metabolically active form, which would stimulate their engraftment
and persistence. Similar to what is described for L. plantarum, evidencing the selectivity of F. prausnitzii
stimulation is crucial; this can be facilitated by the expansion of our knowledge about the specific genes
involved in the utilization of specific substrates. Such efforts would build toward the concept of precision
prebiotics, as well as next-generation probiotic-containing synergistic synbiotics.

CONCLUSION
Although the research track using L. plantarum started with the ambition to design synergistic synbiotics
for specific strains of this species, it ended up with complementary synbiotics that could enhance the
intestinal delivery and persistence of L. plantarum in a general rather than a strain-specific manner. The
generation of convincing evidence for the selectivity of the direct interaction between the substrate and the
microorganism that are combined in synergistic synbiotics requires dedicated in vivo competition
experiments. Such experiments should include the analysis of potential confounding factors that may
disrupt the “synergistic” characteristic of the synbiotic. Part of these confounding effects can be anticipated
by taking ecosystem interaction and nutrient competition mechanisms [Figure 2] into account and
specifically addressing them in the measurements included in the experimental design.

The concept of precision prebiotics using highly defined and pure prebiotic compounds (rather than the
current substrate mixtures) combined with identification of the genes required for their utilization, offers a
promising approach toward metagenomics-based, and thereby individualized selective stimulation of
endogenous members of the microbiome that are associated with a healthy host. Moreover, a similar
genome-based precision-substrate matching approach can support the design of truly selective synergistic
synbiotics, containing either the classical Bifidobacterium and Lactobacillaceae probiotics or the emerging
next-generation probiotics. A substantial amount of research will be required to progress our knowledge to
a level that would enable these strategies. Additionally, it should be realized that profitable bulk production
of the eventually identified precision prebiotic substrates in a chemically pure form may be challenging.

DECLARATIONS
Authors’ contributions
Design of this review, writing of the manuscript and the construction of the supporting figures:
Kleerebezem M, Fuhren J
Both authors approved the submission of this version of the manuscript for publication.

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
Both authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.