Urinary Bile Acid Profile of Newborns Born by Cesarean Section Is Characterized by Oxidative Metabolism of Primary Bile Acids: Limited Roles of Fetal-Specific CYP3A7 in Cholate Oxidations

Abstract

This work aims to investigate how the bile acid metabolism of newborns differs from that of adults along the axis of primary, secondary, and tertiary bile acids (BAs). The total unconjugated BA profiles were quantitatively determined by enzyme digestion techniques in urine of 21 newborns born by cesarean section, 29 healthy parturient women, 30 healthy males, and 28 healthy nonpregnant females. As expected, because of a lack of developed gut microbiota, newborns exhibited poor metabolism of secondary BAs. Accordingly, the tertiary BAs contributed limitedly to the urinary excretion of BAs in newborns despite their tertiary-tosecondary ratios significantly increasing. As a result, the primary BAs of newborns underwent extensive oxidative metabolism, resulting in elevated urinary levels of some fetal-specific BAs, including 3-dehydroCA, 3b,7a,12a-trihydroxy-5b-cholan-24-oic acid, 3a,12-oxo-hydroxy-5b-cholan-24-oic acid, and nine tetrahydroxy-cholan-24-oic acids (Tetra-BAs). Parturient women had significantly elevated urinary levels of tertiary BAs and fetalspecific BAs compared with female control, indicating that they may be excreted into amniotic fluid for maternal disposition. An in vitro metabolism assay in infant liver microsomes showed that four Tetra-BAs and 3-dehydroCA were hydroxylated metabolites of cholate, glycocholate, and particularly taurocholate. However, the recombinant cytochrome P450 enzyme assay found that the fetalspecific CYP3A7 did not contribute to these oxidation metabolisms as much as expected compared with CYP3A4. In conclusion, newborns show a BA metabolism pattern predominated by primary BA oxidations due to immaturity of secondary BA metabolism. Translational studies following this finding may bring new ideas and strategies for both pediatric pharmacology and diagnosis and treatment of perinatal cholestasis-associated diseases. SIGNIFICANCE STATEMENTThe prenatal BA disposition is different from adults because of a lack of gut microbiota. However, how the BA metabolism of newborns differs from that of adults along the axis of primary, secondary, and tertiary BAs remains poorly defined. This work demonstrated that the urinary BA profiles of newborns born by cesarean section are characterized by oxidative metabolism of primary BAs, in which the fetal-specific CYP3A7 plays a limited role in the downstream oxidation metabolism of cholate.

Compensatory Transition of Bile Acid Metabolism from Fecal Disposition of Secondary Bile Acids to Urinary Excretion of Primary Bile Acids Underlies Rifampicin-Induced Cholestasis in Beagle Dogs

“…Most recently, we reported that human newborns show a BA metabolism pattern predominated by primary BA oxidations due to immaturity of the secondary BA metabolism . As far as we know, the RFP induced compensatory transition of the BA metabolism from the fecal disposition of secondary BAs to the urinary excretion of primary BAs in dogs looks intriguingly like the BA metabolism pattern of newborns.…”

“…Most recently, we reported that human newborns show a BA metabolism pattern predominated by primary BA oxidations due to immaturity of the secondary BA metabolism. 58 As far as we know, the RFP induced compensatory transition of the BA metabolism from the fecal disposition of secondary BAs to the urinary excretion of primary BAs in dogs looks intriguingly like the BA metabolism pattern of newborns. Because newborns have a specific pathway of primary BA oxidation to produce the fetal-specific tetrahydroxy-cholan-24-oic acids (Tetra-BAs), we investigated the raw data to clarify whether Tetra-BAs were also elevated in dogs by RFP treatments.…”

A systematic review and meta‐analysis of environmental factors associated with juvenile idiopathic arthritis

“…[36][37][38] An atopic immune response increases the risk of JIA when exposure to fetal microorganisms is interfered with. 39 Maternal smoking of more than 20 cigarettes per day and smoking during pregnancy were found to be associated with a reduced risk of JIA in meta-analyses. Prenatal smoking is generally associated with poor offspring health.…”

Sex, puberty, and the gut microbiome

“…In humans, the bile acid profiles of newborn infants (infants less than 48 h old) were largely composed of primary bile acids and were markedly different from adult bile acid profiles (Wang et al 2020b). In mice and rats, the gut microbiota and bile acid pool both diversify rapidly after birth.…”

“…Since mice show the opposite pattern, this difference is important to consider when using mice as a model for the effects of bile acids on physiology. While there are consistent sex differences in the total bile acid pool in humans, the reported sex differences in terms of the types of primary and secondary acids vary among studies (Fisher & Yousef 1973, Bennion et al 1978, Wang et al 2020b). In addition, little is known about how age interacts with sex differences in primary and secondary bile R67 Reproduction (2023) 165 R61-R74 acid metabolism although one study indicated that sex steroids, which change in concentration throughout the lifespan, may indirectly affect secondary bile acid metabolism (Ridlon et al 2010).…”