Gut microbiota transplantation from db/db mice induces diabetes-like phenotypes and alterations in Hippo signaling in pseudo germ-free mice.

Fan Yu,Wei Han,Xiaolin Xu,Qin Zhou,Bin Zhu,Riyue Jiang,Fei Hua,Shoukui Xiang,Cunming Liu,Xiaohong Jiang,Chun Yang,Long Wang,Gaofeng Zhan

doi:10.18632/aging.104101

Abstract

Type 2 diabetes mellitus (T2DM) is an age-related metabolic disease that is of increasing concern. Gut microbiota might have a critical role in the pathogenesis of T2DM. Additionally, Hippo signaling has been associated strongly with the progression of T2DM and the aging process. We adopted db/db male mice as a T2DM model, and the gut microbiota of db/db and m/m mice were transplanted successfully into pseudo germ-free mice. Furthermore, Hippo signaling, including mammalian sterile 20-like protein kinases 1 (MST1), large tumor suppressors 1 (LATS1), Yes-associated protein (YAP), and phosphorylation of YAP (p-YAP) in peripheral tissues were significantly altered and highly correlated with blood glucose in db/db mice. Interestingly, the host after gut microbiota transplantation from db/db mice showed decreased MST1 and LATS1 levels, and p-YAP/YAP ratio in the heart, liver, and kidney compared to those from m/m mice. Negative correlations between fasting blood glucose and Hippo signaling levels in selected peripheral tissues also were identified. These findings suggest that alterations in Hippo signaling in selected peripheral tissues may contribute to the development of T2DM, and that therapeutic interventions improving Hippo signaling by gut microbiota transplantation might be beneficial for the treatment of T2DM and other age-related metabolic diseases.

Highlights

Worldwide, type 2 diabetes mellitus (T2DM) in individuals older than 65 years is gradually becoming a prevalent public concern [1, 2] because of its severe disability and mortality in the aging population [3]
Considering the critical role of liver and muscle tissues in energy synthesis and metabolism [32, 33], combined with the close relationship between gut microbiota and T2DM, we identified expressions of Hippo signaling in selected peripheral tissues, including heart, liver, kidney, muscle, and gut in db/db mice and pseudo germ-free mice after gut microbiota transplantation
Expressions of Hippo signaling, consisting of mammalian sterile 20-like protein kinases 1 (MST1), large tumor suppressors 1 (LATS1), phosphorylation of Yes-associated protein (YAP) (p-YAP), and YAP were determined in selected peripheral tissues between db/db and m/m mice (Figure 2A−2E)

Summary

Introduction

Type 2 diabetes mellitus (T2DM) in individuals older than 65 years is gradually becoming a prevalent public concern [1, 2] because of its severe disability and mortality in the aging population [3]. Increasing age aggravates the risk of impaired fasting glycemia associated with glucose intolerance level, which potentially contributes to the onset of T2DM [4,5,6]. In this regard, T2DM is an age-related metabolic disorder involving severe complications, especially cardiovascular and neurodegenerative diseases occurring in the elderly [7, 8]. It is that gut microbiota might be highly related with neurodegenerative diseases attributing to its environmental role in energy metabolism

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Conclusion