Background
We have recently shown in both non-human primates and in rodents that fetal and neonatal
hepatic expression of the circadian transcription factor, Npas2, is modulated by a high fat maternal diet and plays a critical role in establishing
life-long metabolic homeostasis. Similarly, we and others have also established the
importance of the maternal and early postnatal diet on establishment of the early
gut microbiome.
Objective
We hypothesized that altered circadian gene expression solely in the neonatal liver
would result in gut microbiome dysbiosis, especially with diet-induced metabolic stress
(ie, restricted feeding). Using a murine model in which we conditionally knock out
Npas2 in the neonatal liver, we aimed to determine the role of the circadian machinery
in gut dysbiosis with restricted feeding.
Study Design
We collected fecal samples from liver Npas2 conditional knockout (n = 11) and wild-type (n = 13) reproductive-aged mice before
(study day 0) and after the restricted feeding study (study day 17). Extracted DNA
was sequenced using the MiSeq Illumina platform using primers specific for the V4
region of the 16S ribosomal DNA gene. The resulting sequences were quality filtered,
aligned, and assigned taxonomy. Principal coordinate analysis was performed on unweighted
and weighted UniFrac distances between samples with a permutation analysis of variance
to assess clustering significance between groups. Microbial taxa that significantly
differ between groups of interest was determined using linear discriminate analysis
effect size and randomForrest.
Results
Principal coordinate analysis performed on weighted UniFrac distances between male
conditional knockout and wild-type cohorts revealed that the gut microbiome of the
mice did not differ by genotype at the start of the restricted feeding study but did
differ by virtue of genotype at the end of the study (P = .001). Moreover, these differences could be at least partially attributed to restricted
feeding–associated alterations in relative abundance of the Bacteroides genus, which has been implicated as crucial to establishing a healthy gut microbiome
early in development.
Conclusion
Here we have provided an initial key insight into the interplay between neonatal establishment
of the peripheral circadian clock in the liver and the ability of the gut microbiome
to respond to dietary and metabolic stress. Because Npas2 expression in the liver is a target of maternal high-fat diet–induced metabolic perturbations
during fetal development, we speculate that these findings have potential implications
in the long-term metabolic health of their offspring.
Key words
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Article info
Publication history
Published online: March 31, 2017
Accepted:
March 23,
2017
Received in revised form:
March 3,
2017
Received:
January 2,
2017
Footnotes
This study was partially supported by the National Institutes of Health (grants 1RO1DK089201-01A [to K.M.A.], R24DK090964-06 [to K.M.A.], T32GM088129 [to D.S.O.], and T32GM07526-37 [to D.S.O.]).
The authors report no conflicts of interest.
Cite this article as: O’Neil DS, Stewart CJ, Chu DM, et al. Conditional postnatal deletion of the neonatal murine hepatic circadian gene, Npas2, alters the gut microbiome following restricted feeding. Am J Obstet Gynecol 2017;217:218.e1-15.
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