Urine-based Detection of Congenital Portosystemic Shunt in C57BL/6 Mice

Yeoh, Beng San; Golonka, Rachel M.; Saha, Piu; Kandalgaonkar, Mrunmayee R.; Tian, Yuan; Osman, Ibrahim; Patterson, Andrew D.; Gewirtz, Andrew T.; Joe, Bina; Vijay‐Kumar, Matam

doi:10.1093/function/zqad040

Cited by 2 publications

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“…It may be congenital, or surgically created to alleviate portal hypertension in cirrhotic patients. Intriguingly, some liver cirrhosis patients develop spontaneous PSS and exhibit hyperammonemia and HE (Jayakumar & Norenberg, 2018 ; Lv et al., 2022 ; Yeoh et al., 2022 , 2023 ). Since the liver is bypassed in the presence of PSS, it is interesting to speculate unprocessed diet and gut microbe‐derived metabolites in the circulation.…”

Section: Macronutrient Metabolism By the Gut Microbiota And The Livermentioning

confidence: 99%

“…Mice with congenital PSS are highly susceptible to cholestatic liver cancer when fed diets containing inulin, a plant‐derived fermentable fiber. Further, mice deficient in AhR have 100% incidence of PSS (Yeoh et al., 2023 ). Thus, PSS underscores the importance of connectivity between gut, gut microbiota, and liver.…”

Section: Macronutrient Metabolism By the Gut Microbiota And The Livermentioning

confidence: 99%

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Digestive dynamics: Unveiling interplay between the gut microbiota and the liver in macronutrient metabolism and hepatic metabolic health

Kandalgaonkar,

Kumar,

Vijay‐Kumar

2024

Physiological Reports

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Although the liver is the largest metabolic organ in the body, it is not alone in functionality and is assisted by “an organ inside an organ,” the gut microbiota. This review attempts to shed light on the partnership between the liver and the gut microbiota in the metabolism of macronutrients (i.e., proteins, carbohydrates, and lipids). All nutrients absorbed by the small intestines are delivered to the liver for further metabolism. Undigested food that enters the colon is metabolized further by the gut microbiota that produces secondary metabolites, which are absorbed into portal circulation and reach the liver. These microbiota‐derived metabolites and co‐metabolites include ammonia, hydrogen sulfide, short‐chain fatty acids, secondary bile acids, and trimethylamine N‐oxide. Further, the liver produces several compounds, such as bile acids that can alter the gut microbial composition, which can in turn influence liver health. This review focuses on the metabolism of these microbiota metabolites and their influence on host physiology. Furthermore, the review briefly delineates the effect of the portosystemic shunt on the gut microbiota–liver axis, and current understanding of the treatments to target the gut microbiota–liver axis.

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Section: Macronutrient Metabolism By the Gut Microbiota And The Livermentioning

confidence: 99%

Section: Macronutrient Metabolism By the Gut Microbiota And The Livermentioning

confidence: 99%

Digestive dynamics: Unveiling interplay between the gut microbiota and the liver in macronutrient metabolism and hepatic metabolic health

Kandalgaonkar,

Kumar,

Vijay‐Kumar

2024

Physiological Reports

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Physiological and behavioural implications of the portosystemic shunt in C57Bl/6J mice

Lehtimäki,

Rytkönen,

Pussinen

et al. 2024

The Journal of Physiology

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A significant fraction of the popular inbred C57Bl/6J mice show structural and biochemical features of the congenital portosystemic shunt (PSS). How this hepatic abnormality affects physiological and behavioural parameters has not been explored in detail. Here, we confirmed the frequent occurrence of the PSS in C57Bl/6J mice by three different methods. We screened a cohort of 119 C57Bl/6J mice for total bile acids (TBA) in plasma, identified 11 animals (9.2%) with high TBA (>11 µm; 171.1 ± 76.8 µm), and confirmed PSS presence in that subset by magnetic resonance angiography and 1H‐magnetic resonance spectroscopy of brain metabolites in the hippocampal area. In addition to the high glutamine and low myo‐inositol levels, we detected lower levels of several neurotransmitters and metabolites in the hippocampus, higher brain weight and volume, as well as enhanced brain glucose utilisation in the PSS mice. We also observed differences in peripheral organ weights, haematological cell counts and clinical chemistry parameters in C57Bl/6J mice with and without PSS. Animals with PSS were slightly hyperlocomotive, had better balance on the rotarod, showed altered gait properties, and displayed attenuated fear memory in the fear conditioning test. Furthermore, we revealed a significant alteration of the pharmacokinetic profile of diazepam in C57Bl/6J mice with PSS. Our data support previous reports of hepatic disturbances and demonstrate an altered neurobiological phenotype in C57Bl/6J mice with PSS. Such congenital differences between inbred C57Bl/6J littermates may significantly distort experimental outcomes of pharmacological, behavioural and genetic studies. imageKey points A significant proportion of C57Bl/6J mice, an inbred strain popular in preclinical research, have congenital portosystemic shunts (PSS) that allow venous blood to enter systemic circulation bypassing the liver. In this study, we extended existing knowledge of PSS consequences, particularly with respect to the effects on brain structure and function. We demonstrated that C57Bl/6J mice with PSS differ from their normal counterparts in brain size and contents of several neuroactive substances, as well as in peripheral organ weights, rate of glucose utilisation, blood cell counts and blood clinical chemistry parameters. C57Bl/6J mice with PSS showed altered locomotor behaviour, performed worse in a memory test and had abnormal blood pharmacokinetics of a benzodiazepine drug after a single administration. PSS presence may significantly complicate the interpretation of experiments in C57Bl/6J mice; therefore, we propose that before their use in biomedical studies, these mice should be screened with a simple blood test.

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Urine-based Detection of Congenital Portosystemic Shunt in C57BL/6 Mice

Cited by 2 publications

References 42 publications

Digestive dynamics: Unveiling interplay between the gut microbiota and the liver in macronutrient metabolism and hepatic metabolic health

Digestive dynamics: Unveiling interplay between the gut microbiota and the liver in macronutrient metabolism and hepatic metabolic health

Physiological and behavioural implications of the portosystemic shunt in C57Bl/6J mice

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