Hepatic and systemic tryptophan metabolism in mice with congenital portosystemic shunt

Congenital portosystemic shunt (PSS) is a vascular anomaly in which the portal vasculature bypasses the liver and connects directly to the systemic circulation. PSS has been reported to occur sporadically in about 10% of C57BL/6J mice (1). As such, mice with PSS and associated metabolic alterations could confound research studies as outliers. PSS in mice can be detected non-invasively by acidic urine due to higher concentrations of certain organic acids (1). Concomitantly with these changes in organic acids, we expect that other aspects of hepatic metabolism are likely impacted by PSS. For example, the liver plays a central role in catabolism of the essential amino acid tryptophan. Tryptophan contributes to neurological and immune homeostasis through pathways regulated by hepatic tryptophan 2,3-dioxygenase (TDO), the rate-limiting enzyme in tryptophan catabolism. In mice with PSS, in which portal blood bypasses the liver, this mode of regulation could be compromised, potentially leading to elevated plasma tryptophan levels. We hypothesized that mice with PSS would have impaired ability to efficiently metabolize tryptophan. To investigate this, we screened wild-type C57BL/6J mice for low urine pH and measured plasma tryptophan levels in mice suspected to have PSS and in littermate controls. We found a 14% prevalence of low urine pH as a diagnostic marker for suspected PSS among 171 mice tested. Interestingly, the prevalence of PSS among males was more than two times higher than among females (chi-square test, p=0.014). Further validation of the presence and the severity of the shunts will be characterized by vascular corrosion casts. There was no statistically significant difference in plasma tryptophan concentrations in mice with and without PSS under ad lib fed conditions. To further assess the ability of these mice to respond to elevated tryptophan, mice with PSS and controls were subjected to a tryptophan tolerance test with plasma tryptophan levels assessed 10 to 90 minutes after intraperitoneal injection of tryptophan. So far, we have found no significant difference in plasma tryptophan levels between mice with PSS and controls, contrary to the hypothesis that PSS mice would have impaired tryptophan metabolism, suggesting compensatory mechanisms may be at play. We are following up with biochemical analysis of liver (including testing TDO abundance and activity) and plasma (as tryptophan is predominantly transported in the circulation bound to albumin) to better understand how tryptophan is metabolized in the context of PSS. Understanding tryptophan metabolism in mice with PSS may provide further insight into metabolic alterations in human PSS. Ultimately, this could help guide future therapeutic strategies for metabolic dysregulation in PSS and conditions such as hypertryptophanemia. 1. Yeoh BS, Golonka RM, Saha P, et al. Urine-based detection of congenital portosystemic shunt in C57BL/6 mice. Function. 2023;4(5). Funding provided by Williams College. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.