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the unfermentable enantiomer of glucose (i.e., L-glucose), indicating that the cellular energy state is crucial
[53]
for this enhanced gastric stress tolerance . These findings may imply that the co-administration of FOS
[8]
with L. plantarum ATCC202195 employed by Panigrahi et al. may have enhanced the survival of the
probiotic strain during gastric passage by energizing the probiotic strain based on the use of the low-DP
constituents of this prebiotic (i.e., fructose, sucrose, and 1-kestose, see above [12,29,41] ), supporting more
effective in situ delivery in the infant gut. Therefore, the administration of FOS could have influenced the
outcome of the trial by improving the gastric survival and intestinal delivery of the probiotic, but this effect
is probably not specific for FOS and is likely to be also achieved with a simple sugar such as glucose. In
conclusion, it remains unclear to what extent this landmark study should be regarded as a true synbiotic
study or could actually better be seen as a probiotic study, because it seems likely that the effect of the co-
administered FOS simply depends on the energy state of the probiotic rather than any form of selective
fitness advantage.

The above-mentioned concept of precision prebiotics is particularly relevant in view of the advances in our
knowledge of the human intestinal microbiota. Traditional prebiotic applications have commonly targeted
the stimulation of the endogenous populations of members of the Bifidobacterium genus or the
Lactobacillaceae family based on their associations with health benefits. Precision prebiotics may offer
opportunities to selectively stimulate the growth of other health-promoting members of the endogenous
[54]
microbiome . As an example, high abundance of Faecalibacterium prausnitzii (F. prausnitzii) has been
inversely associated with flare incidence in inflammatory bowel disease (IBD) patients, and specific strains
of the species (A2-165 and HTRF-F) were shown to alleviate inflammation in murine colitis models [55,56] .
Moreover, F. prausnitzii is one of the main butyrate producers in the intestine , an essential short chain
[57]
fatty acid involved in the regulation of a wide spectrum of health-promoting effects (e.g., trans-epithelial
fluid transport, amelioration of mucosal inflammation, reinforcement of epithelial defense barriers, and
intestinal motility) . Strains of F. prausnitzii display a high degree of genetic diversity, particularly reflected
[58]
in diverse carbohydrate utilization and immunomodulatory phenotypes , suggesting their strain-specific
[59]
response to prebiotic supplementation. Extending the characterization of the genomic and phenotypic
diversity of strains belonging to this species could offer new avenues toward the application of the species as
[60]
candidates for next-generation probiotics . Intriguingly, both FOS and inulin were shown to have
stimulatory effects on F. prausnitzii in humans [61,62] , and the capacity to utilize the substrate was confirmed
for F. prausnitzii strain A2-165 in vitro . Similarly, there is also evidence that GOS consumption can
[63]
stimulate endogenous F. prausnitzii populations in humans [64,65] , although GOS could not effectively support
the growth of F. prausnitziii A2-165 in vitro, which led to the suggestion that GOS-mediated stimulation of
F. prausnitzii would depend on bifidobacterial degradation of GOS and cross feeding [63,66] . However, the lack
of growth of F. prausnitzii A2-165 is potentially meaningless in explaining the stimulatory effect of GOS
supplementation on the relative abundance values of the endogenous populations of F. prausnitzii in
humans, which may simply reflect the high diversity in carbohydrate utilization capacities in the strains of
this species . The genomic information available for this species is rapidly expanding, and at present, more
[60]
than 700 F. prausnitzii genomes are available at NCBI [747 F. prausnitzii genome assemblies, including a
large amount of metagenome-assembled genomes (MAGs), in July 2024]. Analogous to what is described
above for L. plantarum, F. prausnitzii prebiotic matchmaking screening combined with detailed substrate
utilization analysis by HPAEC-PAD and UPLC-MS can generate data that enable gene-trait matching to
identify the genetic loci in F. prausnitzii that are required for the utilization of specific prebiotic
constituents. Knowledge about the F. prausnitzii genes required for utilization of specific prebiotic
constituents, offers the possibility of predicting which prebiotic substrates could selectively stimulate an
individual’s endogenous F. prausnitzii populations by metagenome mining for its carbohydrate utilization
genes. In addition, following the further development of F. prausnitzii strains as next-generation probiotics,
the acquired knowledge could facilitate the design of synergistic synbiotics to enhance the delivery of these