To the Editor: Metabolic syndrome (MetS), defined as a pathologic condition characterized by obesity, hypertension, hyperlipidemia, and insulin resistance, could increase the risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease.[1] The pathogenesis of MetS is complex, involving various factors such as genetics, gut microbes, diet, and lifestyle. It has been recognized as one of the major threats to human health. Animal studies have described that probiotics, including Lactobacillus and Bifidobacterium, may play significant roles in modulating the host's metabolic abnormalities by shaping gut microbes and increasing the production of signal molecules, such as short-chain fatty acids (SCFAs).
Establishing appropriate experimental animal models that mimic the disease state in humans is critical for exploring the pathophysiology and treatment of MetS. Rodents, including rats and mice, are the most common animal models that are used to investigate the MetS. Approaches used to induce MetS in rodents include dietary manipulation, genetic modification, and drug interventions. Diet is considered to be the main driving factor for the induction of metabolic defects in humans. The disease state of MetS in diet-induced obesity (DIO) models is extremely similar to that observed in human patients because the diets fed to animals properly simulate the diverse dietary habits of humans.[2] Rodent models appear to have certain analogous characteristics of MetS in humans after feeding with high-sugar high-fat diets, such as impaired glucose tolerance, increased blood glucose, abnormal lipid metabolism, insulin resistance, and epididymal fat deposition.
Along with DIO models, genetic models of MetS are also immensely prominent and are commonly used to investigate the pathogenesis of MetS caused by genetic factors. It significantly shortens the process of inducing MetS in animals. Compared with DIO models, genetic models have more explicit pathogenesis, more stable and severe MetS symptoms, and more obvious effects in drug research.[2] Zucker fatty (ZF) rats, Zucker Diabetic Fatty (ZDF) rats, Koletsky rats, DahlS Z-Leprfa/Leprfa (DS/obese) rats, and Wistar Ottawa Karlsburg W (WOKW) rats are suitable animal models of MetS with disease characteristics comparable to those of humans. All genetic models above commonly exhibit comprehensive MetS symptoms, such as obesity, insulin resistance, hypertension, dyslipidemia, hyperinsulinemia, and impaired glucose tolerance.
Antihypertensive agents (beta-blockers and diuretics), endocrine agents (corticosteroids, danazol, growth hormone, and oral contraceptives), psychiatric drugs (antipsychotics, antidepressants, and antiepileptic drugs), and other drugs (immunosuppressants, niacin, protease inhibitors, and retinoids) are commonly used to induce MetS in animals. Drug-induced models are suitable for exploring drug-related MetS in humans, and while their creation is inexpensive, it is time-consuming. Studies have shown that mice fed corticosterone manifested typical MetS characteristics, including obesity, dyslipidemia, hypertension, glucose intolerance, and insulin resistance, and all adverse effects can be reversed after ceasing corticosterone supplementation.
Animal models of MetS, besides typical rodent models, also include non-human primates, companion animals (e.g., cats and dogs), and pigs. Non-human primates are particularly valuable for the study of MetS, since the metabolic defects in monkeys tend to occur late due to overeating and are similar to those occurring in humans. Thus, the experimental results can be better inferred from humans. Common companion animals, such as cats and dogs, can also be used to explore MetS in humans because of the same environmental risk factors as humans, such as high-sugar high-fat diets and physical inactivity. Pigs are considered suitable models for the study of obesity and MetS owing to similarities with humans in anatomical structure, physiology, diet, and propensity to be overweight, although they are large and expensive to manage.[2]
Multiple animal studies have shown that probiotic interventions can significantly ameliorate MetS. The selection of proper markers that can intuitively reflect the disease state of MetS and validly evaluate the effects of probiotics on MetS is crucial for properly exploring the relationship between probiotics and MetS. As previously indicated, the alterations of gut microbes were considered as one of the pathogenesis of MetS. The beneficial effects of probiotics on the dysbiosis of gut microbes in animal models have been demonstrated in numerous studies. The gut microbes of DIO mice commonly manifested as increased Firmicutes and decreased Bacteroides; Thus, an increased ratio of Firmicutes to Bacteroides (F/B) in the intestinal tract was observed, all of which could be reversed after interventions with probiotics.[3]
Markers related to metabolism, including blood glucose, triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and fasting insulin, are crucial for properly appraising the beneficial effects of probiotics on MetS. The abnormal glycolipid metabolism of mice with MetS was significantly improved by interventions with Lactobacillus, which was characterized by decreased fasting blood glucose, TG, and TC.[3] Along with Lactobacillus, Bifidobacterium has also been shown to ameliorate metabolic abnormalities in rats with MetS by improving insulin resistance and reducing blood glucose and TG levels. Moreover, a retrospective analysis of hospital patients indicated that the serum uric acid to HDL-C ratio was a strong predictor of MetS in T2DM.[4]
Multiple studies have shown that chronic low-grade inflammation, induced by abnormal gut microbial composition and increased gut permeability, plays a crucial role in the pathogenesis of MetS. Increased SCFAs promote the secretion of glucagon-like peptide-1 (GLP-1) in mice with MetS following the probiotic intervention, which can increase the production of anti-inflammatory cytokines and reduce the generation of pro-inflammatory cytokines. Simultaneously, the amelioration of intestinal barrier integrity regulated by SCFAs is beneficial to recover from bacteremia and endotoxemia. The inflammation and intestinal barrier integrity of rodent models with MetS were ameliorated under the interventions with probiotics such as Lactobacillus, manifested by decreased pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), and increased expression of tight junction genes Zonula occludens-1 (ZO-1) and synthesis of tight junction proteins.[3] Lactobacillus (L.) rhamnosus has been proven to reverse ethanolamine-induced and MSD-induced gut permeability, inflammation, and glucose metabolic dysfunctions in obese/diabetic mice.[5]
The global MetS epidemic has necessitated the elucidation of more categorical disease mechanisms to pave the way for more efficacious interventions and therapeutics. Numerous animal studies have demonstrated the beneficial effects of probiotics on MetS. However, most of these studies were based on limited and common probiotic species, and translating the consequences from animals to humans may be challenging. Therefore, exhaustive elucidation of the mechanisms and beneficial effects of interventions with existing probiotics on MetS and the discovery of novel probiotics in further studies are fundamental.
Furthermore, several markers can be selected to evaluate the beneficial effects of probiotics on MetS and to monitor the pathophysiological variations of the disease. Nevertheless, restricted markers cannot completely reflect the disease state of MetS because of its complex pathogenesis and diverse pathophysiological phenomena. Therefore, it is necessary to define more comprehensive and representative markers to properly evaluate and monitor the disease.
In conclusion, the use of animal models continues to be of great importance for the study of MetS, as they are capable of monitoring pathophysiological variations in the disease. Subsequent studies are encouraged to develop more appropriate and ideal animal models of MetS aimed at achieving maximum similarity with what occurs in human patients. Moreover, it is essential to identify beneficial gut microbes and microbial metabolites associated with MetS via multi-omics methods, such as intestinal metagenomics, macro-transcriptomics, and advanced metabolomics, to properly explore the relationships among gut microbes, probiotics, and MetS, as well as to pursue feasible prevention and treatment strategies for MetS.
Funding
The study was supported by the Science and Technology Poverty Alleviation Project, Department of Science and Technology, Sichuan Province (No. 2021ZHFP0162).
Conflicts of interest
None.
Footnotes
How to cite this article: He PG, Qu QY, Zhong ZJ, Zeng PB. Animal models for probiotics intervention on metabolic syndrome. Chin Med J 2023;136:2771–2772. doi: 10.1097/CM9.0000000000002749
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