Protective Role of Spermidine in Colitis and Colon Carcinogenesis

Gobert, Alain P.; Latour, Yvonne L.; Asim, Mohammad; Barry, Daniel P.; Allaman, Margaret M.; Finley, Jordan L.; Smith, Thaddeus M.; McNamara, Kara M.; Singh, Kshipra; Sierra, Johanna C.; Delgado, Alberto; Luis, Paula B.; Schneider, Claus; Washington, Mary Kay; Piazuelo, M. Blanca; Zhao, Shilin; Coburn, Lori A.; Wilson, Keith T.

doi:10.1053/j.gastro.2021.11.005

Cited by 65 publications

(37 citation statements)

References 63 publications

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“…These changes might explain the higher disease resistance of Min pigs compared with Yorkshire pigs. Additionally, the data on colonic metabolites that correlated negatively with disease activity showed that anileridine (spasmolytic action in the intestine [ 50 ]) and spermidine (protective role in colitis and colon carcinogenesis [ 51 ]) were decreased in Y-DSS pigs, suggesting an out-of-control state. Anileridine content was increased in M-DSS pigs, further supporting the ability of Min pigs to resist acute colitis.…”

Section: Discussionmentioning

confidence: 99%

Host-microbiota interaction-mediated resistance to inflammatory bowel disease in pigs

et al. 2022

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Background Disease resistance phenotypes are associated with immune regulatory functions and immune tolerance and have implications for both the livestock industry and human health. Microbiota plays an essential role in regulating immunity and autoimmunity in the host organism, but the influence of host-microbiota interactions on disease resistance phenotypes remains unclear. Here, multiomics analysis was performed to identify potential regulatory mechanisms of disease resistance at both the microbiome and host levels in two pig breeds. Results Acute colitis models were established in Min pigs and Yorkshire pigs, and control and diseased individuals were compared. Compared with Yorkshire pigs under the same nutritional and management conditions, Min pigs exhibited strong disease resistance, as indicated by a low disease activity index (DAI) and a low histological activity index (HAI). Microbiota sequencing analysis showed that potentially harmful microbes Desulfovibrio, Bacteroides and Streptococcus were enriched in diseased individuals of the two breeds. Notably, potentially beneficial microbes, such as Lactobacillus, Clostridia and Eubacterium, and several genera belonging to Ruminococcaceae and Christensenellaceae were enriched in diseased Min pigs and were found to be positively associated with the microbial metabolites related to intestinal barrier function. Specifically, the concentrations of indole derivatives and short-chain fatty acids were increased in diseased Min pigs, suggesting beneficial action in protecting intestinal barrier. In addition, lower concentrations of bile acid metabolites and short-chain fatty acids were observed in diseased Yorkshire pigs, which were associated with increased potentially harmful microbes, such as Bilophila and Alistipes. Concerning enrichment of the immune response, the increase in CD4+ T cells in the lamina propria improved supervision of the host immunity response in diseased Min pigs, contributing to the maintenance of Th2-type immune superiority and immune tolerance patterns and control of excessive inflammation with the help of potentially beneficial microbes. In diseased Yorkshire pigs, more terms belonging to biological processes of immunity were enriched, including Toll-like receptors signalling, NF-κB signalling and Th1 and Th17-type immune responses, along with the increases of potentially harmful microbes and damaged intestinal barrier. Conclusions Cumulatively, the results for the two pig breeds highlight that host-microbiota crosstalk promotes a disease resistance phenotype in three ways: by maintaining partial PRR nonactivation, maintaining Th2-type immune superiority and immunological tolerance patterns and recovering gut barrier function to protect against colonic diseases.

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Section: Discussionmentioning

confidence: 99%

Host-microbiota interaction-mediated resistance to inflammatory bowel disease in pigs

et al. 2022

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“…Over the last decades, polyamine research has continuously progressed, providing insight into the anabolic pathways and transport processes of polyamines. The effects of polyamines on cancer cells have also been explored in relation to different oncogenes and signaling pathways involved [1][2][3]. It has been demonstrated that oncogenes can affect the metabolism and function of polyamines by interfering with the expression and translation of key enzymes.…”

Section: Introductionmentioning

confidence: 99%

Nanospermidine in Combination with Nanofenretinide Induces Cell Death in Neuroblastoma Cell Lines

et al. 2022

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A new strategy to cause cell death in tumors might be the increase of intracellular polyamines at concentrations above their physiological values to trigger the production of oxidation metabolites at levels exceeding cell tolerance. To test this hypothesis, we prepared nanospermidine as a carrier for spermidine penetration into the cells, able to escape the polyamine transport system that strictly regulates intracellular polyamine levels. Nanospermidine was prepared by spermidine encapsulation in nanomicelles and was characterized by size, zeta potential, loading, dimensional stability to dilution, and stability to spermidine leakage. Antitumor activity, ROS production, and cell penetration ability were evaluated in vitro in two neuroblastoma cell lines (NLF and BR6). Nanospermidine was tested as a single agent and in combination with nanofenretinide. Free spermidine was also tested as a comparison. The results indicated that the nanomicelles successfully transported spermidine into the cells inducing cell death in a concentration range (150–200 μM) tenfold lower than that required to provide similar cytotoxicity with free spermidine (1500–2000 μM). Nanofenretinide provided a cytostatic effect in combination with the lowest nanospermidine concentrations evaluated and slightly improved nanospermidine cytotoxicity at the highest concentrations. These data suggest that nanospermidine has the potential to become a new approach in cancer treatment. At the cellular level, in fact, it exploits polyamine catabolism by means of biocompatible doses of spermidine and, in vivo settings, it can exploit the selective accumulation of nanomedicines at the tumor site. Nanofenretinide combination further improves its efficacy. Furthermore, the proven ability of spermidine to activate macrophages and lymphocytes suggests that nanospermidine could inhibit immunosuppression in the tumor environment.

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“…In line with our expectation, our results indicated that the amount of putrescine increased in the constipation group and dropped to a lesser extent after exposure to rhubarb. Spermidine was reported as being able to take part in maintaining a protective gut microbiota via reducing the expression of genes encoding for a-defensins (DEFAs) by means of transcriptomic and microbiome analyses (31). In contrast to putrescine, spermidine content in the constipation was lower than that in the control group.…”

Section: Results 6 Treatment Of Constipation With Rhubarb Caused Chan...mentioning

confidence: 99%

Underlying beneficial effects of Rhubarb on constipation-induced inflammation, disorder of gut microbiome and metabolism

Gao

Hua

et al. 2022

Preprint

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Background: Although constipation is a common syndrome and a worldwide health problem. Constipation patients are becoming younger with a 29.6% overall prevalence in the children, which has captured great attention because of its epigenetic rejuvenation and recurrent episodes. Despite the usage of rhubarb to relieve constipation, novel targets and genes involved in target-relevant pathways with remarkable functionalities should still be sought after. Materials and methods: We established a reliable constipation model in C57B/6N male mice using intragastric administration diphenoxylate and the eligible subjects received 600mg/25g rhubarb extraction to ameliorate constipation. Resultant constipation was morphological and genetically compared with the specimen from different groups. Results: The constipation mice exhibited thicker muscle layers, improved content of cytokines, including IL-17 and IL-23, and lower content of IL-22. The bacterial abundance and diversity varied tremendously. Notably, the alterations were reversed after rhubarb treatment. Additionally, SCFA and MLCFA were significantly influenced by constipation accompanied by enhanced expressions of SCFA receptors, GPR41 and GPR43. Conclusion: This thesis has provided an insight that rhubarb promoted the flexibility of collagen fiber, reduced pro-inflammatory cytokines and enhanced anti-inflammatory cytokines, and maintained intestinal microflora balance with potential effects on affecting the metabolism of fatty acids and polyamines.

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Protective Role of Spermidine in Colitis and Colon Carcinogenesis

Cited by 65 publications

References 63 publications

Host-microbiota interaction-mediated resistance to inflammatory bowel disease in pigs

Host-microbiota interaction-mediated resistance to inflammatory bowel disease in pigs

Nanospermidine in Combination with Nanofenretinide Induces Cell Death in Neuroblastoma Cell Lines

Underlying beneficial effects of Rhubarb on constipation-induced inflammation, disorder of gut microbiome and metabolism

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