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Page 14 of 18 Monaco et al. J Environ Expo Assess 2024;3:18 https://dx.doi.org/10.20517/jeea.2024.10

From a translational perspective, it is interesting to note that the effects of DEHP on the microbiota were
more apparent in the AC contents compared to the RC contents, the latter of which is reflective of a fecal
sample in humans. A higher number of phyla that differed in AC vs. RC (5 vs. 0) were observed between
CON and DEHP200. Additionally, 6 and 13 bacterial genera differed between CON and DEHP20, and
between CON and EDHP200, respectively, in AC, while only 1 and 4 differential genera were observed in
RC between CON and DEHP20, and between CON and DEHP200, respectively. In this study, bacterial
genera in the phyla Firmicutes were more affected by DEHP than those in the phylum Bacteroidota in
samples from both the AC and RC. However, within the Bacteroidota, both Odoribacter and
Sanguibacteroides were affected in AC and RC, whereas Bacteroides were also affected in the AC vs. Alistipes
in the RC. Within the Bacillota, there were about an equal number of genera with differential abundance in
response to DEHP. This should be considered when evaluating the impact of DEHP on the microbiome in
human studies, as microbial dysbiosis in more proximal regions of the gut is likely underappreciated.

This study revealed for the first time notable alterations in small intestine structure and disaccharidase
activity, as well as changes in colonic bacteria due to DEHP exposure, in the piglet model. However, several
limitations warrant consideration. First, the doses administered exceeded typical DEHP exposure levels
observed in healthy infants and children, although the DEHP20 dose reflected that found in the urine of
[72]
pregnant women . Second, we did not factor in potential secondary phthalate exposure from other dietary
sources, plastic materials in the feeding system, or uncontrolled environmental factors. However, any
additional exposure to phthalate contaminants affected all groups equally, minimizing potential
compounding effects on the outcomes. Third, microbial taxonomy was assessed by 16S rRNA gene
sequencing, and we did not measure fecal VFAs and other metabolites, which could have provided
additional insights into the impact of microbiota functional changes. In addition, 16S rRNA gene
sequencing does not capture the genetic differences that are known to exist in different strains of the same
bacterium, as observed among the different strains of E. coli, with some being highly pathogenic while
others are not. A recent study in mice concluded that DEHP exposure causes an imbalance of intestinal
[56]
microbial homeostasis, which results in a decrease in beneficial bacteria and an expansion of pathogenic
bacteria abundance. The analyses of fecal metabolome indicated metabolic profiles were also changed due to
DEHP and caused intestinal barrier dysfunction and activation of the AhR/NF-κB pathway to induce
intestinal inflammation. Unfortunately, it is still unclear if the change in the metabolic profile was caused by
DEHP or by dysbiosis . Future studies could use gnotobiotic animals not directly exposed to DEHP but
[56]
implanted with microbiota from DEHP-exposed animals. This approach would enable the determination of
the specific effects of a DEHP-modified microbiota on host health. Future studies should use DEHP infant
exposure levels and should incorporate metagenomic sequencing and metabolomic analyses to gain broader
insight into the potential effects of DEHP on microbiome function.

CONCLUSION
This study documented that DEPH, a widely recognized endocrine-disrupting chemical, alters both the
structure and function of the small intestine and induces changes in the colonic microbial community. The
extent to which these microbiota structural changes contribute to alterations in intestinal development
requires further study. Herein, we confirmed that the neonatal piglet is a suitable model for investigating
how phthalate impacts development in early life. Building on previous findings , this study sheds light on
[19]
the complex effects of phthalates, emphasizing the importance of continued inquiry into their biological
ramifications. Furthermore, our findings highlight the potential health risks associated with DEHP exposure
during critical periods of development. Future research should focus on the long-term consequences of
early-life exposure to DEHP and other phthalates, including potential impacts on growth, immune function,
and overall health. Additionally, exploring interventions to mitigate these effects could be valuable.