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Page 14 of 18 Chen et al. Microbiome Res Rep 2025;4:8 https://dx.doi.org/10.20517/mrr.2024.44

between the two feeding groups. This apparent incongruity might be due to the relatively small sample size
(61 samples, of which 14 samples were from the DHM group) included for 16S rRNA sequencing compared
[37]
to the other included studies .

At the taxonomic level, there was large heterogeneity in reporting methods. While some studies reported
outcomes at the phylum level, others reported at the order, family, genus and/or species levels. Despite this
methodological heterogeneity, consistent evidence emerges regarding several compositional differences.
DHM feeding appeared to be associated with an increased abundance of the Staphylococcaceae family,
possibly attributable to elevated levels of the Staphylococcus genus, as well as the Clostridiaceae family, likely
attributable to the increased abundance of the Clostridium genus.

Conversely, a decreased abundance was observed in the Bifidobacterium genus and the Bacteroidetes
phylum in DHM-fed preterm infants compared to those fed predominantly MOM. In addition to a
metabolites linked to intestinal immune and endocrine responses, among different types of feeding .
diminished overall abundance of Bifidobacterium, Arboleya et al. showed several differences in the relative
abundances of various Bifidobacterial species present between both feeding groups, with differences starting
to occur as early as the second day of life .
[31]
The observed differences in the gut microbiota between both subgroups might be associated with different
health outcomes through various (patho)physiological processes. While reduced alpha diversity levels have
[40]
been linked to adverse health outcomes in adults, it is unknown if it pertains to preterm infants as well . At
the compositional level, the observed summarized differences in this systematic review have been linked to
adverse health outcomes. An increased abundance of the Staphylococcaceae family or Staphylococcus genus
has been linked to late-onset sepsis in preterm infants [41,42] . Similarly, increased abundances of different
genera and species within the Clostridia order have been linked to NEC in preterm infants [43-46] . Moreover,
reduced Bacteroidetes and Bifidobacterium abundance have also been associated with NEC [47-51] . Notably,
these compositional differences are not only confined to short-term neonatal outcomes; the abundance of
Bifidobacterium, Staphylococcus, and Bacteroidetes during the neonatal period has been linked to adverse
neurodevelopmental outcomes at two years of corrected age [24,52-54] . In addition, term-born infants generally
have higher abundances of Bacteroidetes and Bifidobacterium and lower abundances of Staphylococcus
[55]
compared to preterm infants . Therefore, the results of this systematic review may indicate greater
deviance from a healthy full-term microbiome when infants are provided with DHM as compared to MOM.

However, recent studies show that not only microbiome composition, but also its metabolic activity and
effects on the host’s immune system influence different health outcomes [56,57] . This is underscored by some
studies included in this systematic review. One study highlights different concentrations of fecal SCFAs,
[31]
Another study showed higher calprotectin levels, indicative of more intestinal inflammation in the DHM
group .
[34]

To the best of our knowledge, this is the first systematic review focusing solely on the difference in gut
microbiome composition between infants predominantly fed MOM or DHM. One other systematic review
on health outcomes between MOM- and DHM-exposed infants provides information on gut microbiome
[18]
diversity only when it is mentioned in the included articles . However, that review was designed to find
health outcomes rather than microbiome outcomes, so key publications reporting only gut microbiota are
not included. In addition, two other recent systematic reviews on the associations of feeding practices and
the gut microbiome in preterm infants did not focus on DHM, resulting in the omission of relevant studies
on this topic [58,59] . However, the findings in these reviews are coherent with our results.