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bioRxiv · 10.1101/2025.03.24.644956

Totum-448, a polyphenol-rich plant extract, decreases hepatic steatosis and inflammation in diet-induced MASLD mice

Lambooij, J. M.·Chavanelle, V.·Vallier, M.·van der Zande, H. J.·Otero, Y. F.·Otto, F.·Schuurman, R.·Le Joubioux, F.·Maugard, T.·Giera, M.·Peltier, S. L.·Zaldumbide, A.·Sirvent, P.·Guigas, B.
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Abstract

The increasing prevalence of obesity-driven metabolic dysfunction-associated steatotic liver disease (MASLD) urges the development of new therapeutic strategies. Totum-448 is a unique patented combination of polyphenol-rich plant extracts designed to reduce hepatic steatosis, a risk factor for steatohepatitis and type 2 diabetes. In this study, we investigated the effects of Totum-448 on metabolic homeostasis and steatohepatitis in diet-induced MASLD mice. For this purpose, male C57Bl6/J mice were fed a high-fat diet in combination with sucrose-containing drinking water for 12 weeks, followed by diet supplementation with or without Totum-448 for 4 weeks. Body weight/composition, caloric intake, plasma parameters and whole-body glucose tolerance were measured throughout the study and fecal microbiota composition was determined by 16S sequencing. Hepatic steatosis, transcriptomic/lipidomic profiles and immune cell composition were assessed by histological/biochemical assays, RNA sequencing, MS-based lipidomics, and spectral flow cytometry. We found that Totum-448 significantly lowered hyperinsulinemia and systemic glucose intolerance in MASLD mice without affecting body weight, fat mass, calorie intake, feces production or fecal microbiota composition. Furthermore, a decrease in liver MASLD activity score and macrovesicular steatosis, hepatic triglycerides and cholesterol contents, and plasma alanine aminotransferase levels were observed. Totum-448 also reduced the liver inflammatory and pro-fibrotic transcriptomic signatures and decreased both MASLD-induced loss in tissue-resident Kupffer cells and recruitment of monocyte-derived pro-inflammatory macrophages. Altogether, Totum-448 reduces hepatic steatosis and inflammation in insulin-resistant, steatotic, obese mice, a dual effect that likely contributes to improved whole-body metabolic homeostasis. Supplementation with Totum-448 may therefore constitute a promising novel nutritional approach for MASLD patients.

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Lambooij, J. M., Chavanelle, V., Vallier, M., van der Zande, H. J., Otero, Y. F., Otto, F., Schuurman, R., Le Joubioux, F., Maugard, T., Giera, M., Peltier, S. L., Zaldumbide, A., Sirvent, P., Guigas, B.. 2025-03-27. Totum-448, a polyphenol-rich plant extract, decreases hepatic steatosis and inflammation in diet-induced MASLD mice. https://doi.org/10.1101/2025.03.24.644956

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