Telmisartan induces a specific gut microbiota signature which may mediate its antiobesity effect

Beckmann, Laura; Künstner, Axel; Freschi, M; Huber, G; Stölting, Ines; Ibrahim, Saleh M.; Hirose, Misa; Freitag, Miriam; Langan, Ewan A.; Matschl, Urte; Galuska, Christina E.; Fuchs, Beate; Knobloch, J; Busch, Hauke; Raasch, Walter

doi:10.1016/j.phrs.2021.105724

Cited by 7 publications

(11 citation statements)

References 70 publications

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“…Bacteroidetes phylum [102] and the levels of beneficial microbiota such as Bifidobacterium genus [109][110][111], anti-inflammatory Faecalibacterium, and butyrate-producing Ruminococcaceae were reduced due to obesity [109]. Contrary to T1D and T2D, Firmicutes levels were mostly increased in human and mice models of obesity-induced by HFD [102][103][104]108]. However, animal data related to the changes in gut microbiota profiles due to obesity are not consistent and seem to depend on the diet type, and genetic background of the animal used [105].…”

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confidence: 99%

“…Similarly, Turnbaugh et al demonstrated that colonization of germ-free mice with obese microbiota increased total body fat [107], supporting the role of microbiota in the development of obesity. Stool transplantation from telmisartan-treated mice to obese mice attenuated body weight due to HFD [104]. Interestingly, Collado et al demonstrated an increase in microbial counts during pregnancy.…”

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confidence: 99%

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The Role of the Gut Microbiome in Diabetes and Obesity-Related Kidney Disease

Zaky

Glastras

Wong

et al. 2021

IJMS

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Diabetic kidney disease (DKD) is a progressive disorder, which is increasing globally in prevalence due to the increased incidence of obesity and diabetes mellitus. Despite optimal clinical management, a significant number of patients with diabetes develop DKD. Hence, hitherto unrecognized factors are likely to be involved in the initiation and progression of DKD. An extensive number of studies have demonstrated the role of microbiota in health and disease. Dysregulation in the microbiota resulting in a deficiency of short chain fatty acids (SCFAs) such as propionate, acetate, and butyrate, by-products of healthy gut microbiota metabolism, have been demonstrated in obesity, type 1 and type 2 diabetes. However, it is not clear to date whether such changes in the microbiota are causative or merely associated with the diseases. It is also not clear which microbiota have protective effects on humans. Few studies have investigated the centrality of reduced SCFA in DKD development and progression or the potential therapeutic effects of supplemental SCFAs on insulin resistance, inflammation, and metabolic changes. SCFA receptors are expressed in the kidneys, and emerging data have demonstrated that intestinal dysbiosis activates the renal renin-angiotensin system, which contributes to the development of DKD. In this review, we will summarize the complex relationship between the gut microbiota and the kidney, examine the evidence for the role of gut dysbiosis in diabetes and obesity-related kidney disease, and explore the mechanisms involved. In addition, we will describe the role of potential therapies that modulate the gut microbiota to prevent or reduce kidney disease progression.

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confidence: 99%

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confidence: 99%

The Role of the Gut Microbiome in Diabetes and Obesity-Related Kidney Disease

Zaky

Glastras

Wong

et al. 2021

IJMS

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“…Addressing this interaction between mucus composition and gut microbiota, the genera Parabacteroides and Blautia increased in fecal samples of rats in response to Ang II, while Ruminococcus and Oscillospira decreased, and moreover, the thickness of the jejunum of small intestine showing tunica muscularis increased, while the numbers of goblet cells and villi length decreased ( Sharma et al, 2019 ). In this regard, the findings on Blautia seem particularly interesting, as in our recent paper we were able to show an increase in the abundance of Blautia in CD-fed rats and a normalization of Blautia when the rats were simultaneously treated with TEL ( Beckmann et al, 2021 ). Also considering the above-mentioned relationships between gut microbiota and intestinal trans-epithelial permeability ( Allam-Ndoul et al, 2020 ), the aim of the present study was to investigate whether TEL influenced mucus itself.…”

Section: Introductionmentioning

confidence: 66%

“…For the sake of brevity, we refrain from such a detailed discussion here and refer to the corresponding publications. We intended here to follow-up on our recently published data showing that TEL induces a specific gut microbiota signature that may mediate its anti-obesity effect ( Beckmann et al, 2021 ). Since HFDs damage endothelial barrier properties by alterations in microbiota ( Araújo et al, 2017 ), the aim of the present study was to investigate whether TEL has protective effects with respect to endothelial barrier function.…”

Section: Discussionmentioning

confidence: 99%

“…Hence, LPS levels increase in plasma and intestine, thereby suggesting that LPS is a triggering factor for low-grade inflammation in obesity ( Cani et al, 2007 ). Further addressing the interaction between the RAS and obesity, we recently identified that the anti-obese action of TEL is attributed to diet-independent alterations in gut microbiota, as we found that: 1) the F/B ratio and the abundancies of Blautia , Allobaculum , and Parasutterella were higher in rats that were fed with cafeteria diet (CD) than in rats that were additionally treated with TEL; 2) that enterotype-like clustering analyses, Kleinberg’s hub network scoring, and random forest analyses also indicated that TEL induced a specific signature of gut microbiota; and 3) that in response to stool transfer from TEL-pretreated donor to high-fat fed acceptor mice, body weight gain was slightly attenuated ( Beckmann et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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The AT1 Receptor Blocker Telmisartan Reduces Intestinal Mucus Thickness in Obese Mice

et al. 2022

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The angiotensin II (type 1) (AT1) receptor blocker telmisartan (TEL) is beneficial for the treatment of individuals suffering from metabolic syndrome. As we have shown that TEL has an impact on gut microbiota, we investigated here whether TEL influences gut barrier function. C57BL/6N mice were fed with chow or high-fat diet (HFD) and treated with vehicle or TEL (8 mg/kg/day). Mucus thickness was determined by immunohistochemistry. Periodic Acid-Schiff staining allowed the number of goblet cells to be counted. Using western blots, qPCR, and immunohistochemistry, factors related to mucus biosynthesis (Muc2, St6galnac), proliferation (Ki-67), or necroptosis (Rip3) were measured. The influence on cell viability was determined in vitro by using losartan, as the water solubility of TEL was too low for in vitro experiments. Upon HFD, mice developed obesity as well as leptin and insulin resistance, which were prevented by TEL. Mucus thickness upon HFD-feeding was diminished. Independent of feeding, TEL additionally reduced mucus thickness. Numbers of goblet cells were not affected by HFD-feeding and TEL. St6galnac expression was increased by TEL. Rip3 was increased in TEL-treated and HFD-fed mice, while Ki-67 decreased. Cell viability was diminished by using >1 mM losartan. The anti-obese effect of TEL was associated with a decrease in mucus thickness, which was likely not related to a lower expression of Muc2 and goblet cells. A decrease in Ki-67 and increase in Rip3 indicates lower cell proliferation and increased necroptosis upon TEL. However, direct cell toxic effects are ruled out, as in vivo concentrations are lower than 1 mM.

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Characteristics of gut microbiota in representative mice strains: Implications for biological research

Guo

Song

Liu

et al. 2022

Anim Models and Exp Med

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Background: Experimental animals are used to study physiological phenomena, pathological mechanisms, and disease prevention. The gut microbiome is known as a potential confounding factor for inconsistent data from preclinical studies. Although many gut microbiome studies have been conducted in recent decades, few have focused on gut microbiota fluctuation among representative mouse strains.Methods: A range of frequently used mouse strains were selected from 34 isolation packages representing disease-related animal (DRA), immunity defect animal (IDA), or gene-editing animal (GEA) from the BALB/c and C57BL/6J backgrounds together with normal mice, and their microbial genomic DNA were isolated from mouse feces to sequence for the exploration of gut microbiota.Results: Mouse background strain, classification, introduced source, introduced year, and reproduction type significantly affected the gut microbiota structure (p < 0.001 for all parameters), with background strain contributing the greatest influence (R 2 = 0.237). In normal groups, distinct gut microbiota types existed in different mouse strains. Sixty-four core operational taxonomic units were obtained from normal mice, and 12 belonged to Lactobacillus. Interestingly, the gut microbiota in C57BL/6J was more stable than that in BALB/c mice. Furthermore, the gut microbiota in the IDA, GEA, and DRA groups significantly differed from that in normal groups (p < 0.001 for all). Compared with the normal group, there was a significantly higher Chao1 and Shannon index (p < 0.001 for all) in the IDA, GEA, and DRA groups. Markedly changed classes occurred with Firmicutes and Bacteroidetes. The abundances of Helicobacter, Blautia, Enterobacter, Bacillus, Clostridioides, Paenibacillus, and Clostridiales all significantly decreased in the IDA, GEA, and DRA groups, whereas those of Saccharimonas, Rikenella, and Odoribacter all significantly increased.

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Telmisartan induces a specific gut microbiota signature which may mediate its antiobesity effect

Cited by 7 publications

References 70 publications

The Role of the Gut Microbiome in Diabetes and Obesity-Related Kidney Disease

The Role of the Gut Microbiome in Diabetes and Obesity-Related Kidney Disease

The AT1 Receptor Blocker Telmisartan Reduces Intestinal Mucus Thickness in Obese Mice

Characteristics of gut microbiota in representative mice strains: Implications for biological research

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