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Page 6 of 14 Kreuze et al. Microbiome Res Rep 2025;4:7 https://dx.doi.org/10.20517/mrr.2024.51

[33]
even be regulated by phage induction itself . It is, therefore, possible that conjugative elements and phages
may cross the colonization bottleneck by promoting their own conjugation and horizontal transfer.

P-Ps are hybrids between the MGEs they are named after, as they tend to encode both phage and plasmid
genes [55-57] . While their diversity is only beginning to be uncovered, they mostly follow a lifestyle similar to
temperate phages: they can enter lytic or temperate life cycle, but differ in that as a prophage, they form an
extrachromosomal plasmid. While cultured P-Ps are only known to transfer horizontally through lysis,
similar to phages, a subset of P-Ps encode genes necessary for conjugation and may therefore be able to
transmit via conjugation [Figure 3].

Even though the abundance and diversity of P-Ps have only recently been studied [55,58] , evidence suggests
that infant gut P-Ps might also be maternally inherited. First, P1-like P-Ps, relatives of the well-studied P1
[59]
phage , were found in clinical and porcine-derived E. coli isolates, with the latter being isolated from the
[69]
stool of a healthy 4-month-old piglet [60,61] . Additionally, some of the plasmids predicted to be N15-like P-Ps,
[62]
relatives of the well-studied N15 phage , were isolated from bacterial hosts in dogs, giant pandas, and
humans . Finally, at least a fraction of phages of the family Crassvirales, the most abundant phage family
[56]
in the human gut, appears to be P-P and members of this phage family can be transmitted from mother to
[63]
child . While this evidence is intriguing, targeted studies confirming the presence and transmission of P-Ps
[64]
between the mother and infant guts are required.
High bacterial turnover, stress, and phage induction levels suggest that MGEs can transmit horizontally
between bacteria during infant gut colonization. While such dynamics may be necessary for MGEs in
crossing the colonization bottleneck, they may also come at a fitness cost for their bacterial hosts, given that
MGE spread, excess conjugation, and phage lysis can inhibit bacterial growth [31,65] , emphasizing a parasitic
interaction. However, such fitness costs are dependent on the ecological context. For example, while
conjugative plasmids and phages can be costly to maintain, they can also provide fitness benefits to their
bacterial hosts even in the absence of obvious selection pressures [66-68] . Most commonly, however, MGEs are
thought to be maintained by carrying genes that can increase the fitness of their hosts . In the next section,
[68]
we explore the fitness-enhancing genes carried by MGEs and investigate how they could aid bacterial hosts
in crossing the colonization bottleneck.

MGES CONTRIBUTE TO BACTERIAL COLONIZATION SUCCESS IN THE INFANT GUT
Some bacterial taxa only temporarily colonize the sparsely seeded infant gut and are subsequently
outcompeted by other bacterial taxa [11,13,30] . Thus, the ability to aid in host metabolism, inhibit competitor
growth, and protect oneself from competitors and parasites is important in influencing the successful
crossing of the colonization bottleneck [Figure 4] . Fitness-enhancing genes providing such functions can
be encoded by MGEs and could, therefore, be co-selected with their hosts.

While direct evidence of MGEs aiding their hosts to increase their metabolic capacity through novel genes is
lacking, metagenomic studies provide some tentative evidence. Specifically, prophages in the infant gut
encode several auxiliary metabolic genes (AMGs) , including carbohydrate-active enzymes (CAZymes)
[70]
related to carbon, amino acid, and energy metabolism [71-74] [Figure 4A]. These genes are likely involved in
processes such as HMO and mucin attachment and degradation, as well as increasing growth rate by
[75]
encoding more copies of rate-limiting genes . Regarding conjugative elements, a recent study found that
plasmids in the infant gut encode proportionally more unique metabolism-related genes compared to their
bacterial hosts . Additional bioinformatic and functional evidence suggests that conjugative elements can
[21]
provide metabolic benefits to bacterial strains found in the gut microbiome [18,35,76-78] . In addition to this, most