Abstract
Probiotics are considered to play an crucial role in the treatment of high-fat diet (HFD)-induced lipid metabolic diseases, including metabolic syndrome (MS). This study aimed to investigate the effects of Lactobacillus plantarum S9 on MS in HFD-fed rats, and to explore the underlying role of probiotics in the treatment of MS. Sprague-Dawley rats were fed with HFD for 8 weeks, followed by the treatment of L. plantarum S9 for 6 weeks, and The body weight and blood glucose level of rats were detected on time. The results showed that L. plantarum S9 significantly decreased the body weight gain, Lee’s index, and liver index. Additionally, L. plantarum S9 reduced the levels of serum lipids and insulin resistance. L. plantarum S9 also decreased the levels of alanine aminotransferase (ALT) and aspartate transaminase (AST) in liver. Moreover, the serum levels of MS-related inflammatory signaling molecules, including lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF-α), were significantly elevated. Western blot analysis showed that L. plantarum S9 inhibited the activation of nuclear factor-κB (NF-κB) pathway, decreased the expression level of Toll-like receptor 4 (TLR4), suppressed the activation of inflammatory signaling pathways, and reduced the expression levels of inflammatory factors in HFD-fed rats. Moreover, it further decreased the ratios of p-IκBα/IκBα, p-p65/NF-κB p65, and p-p38/p38. In summary, L. plantarum S9, as a potential functional strain, prevents or can prevent onset of MS.
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Introduction
Metabolic syndrome (MS), as a lifestyle-related disease, affects about 20% of the global population, and it was considered by the World Health Organization (WHO) as one of the metabolic disorders that seriously affect human health1. Clinically, the main manifestations of MS are obesity, hyperglycemia, hypertension, and hyperlipidemia2. To date, several studies have presented different views on the pathogenesis of MS, including insulin resistance, oxidative damage, and metabolic disorders related to triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C), while the specific mechanism has still remained elusive3,4. Of note, some studies demonstrated that a high-energy diet and reduced exercise are the main reasons for the occurrence of MS5. High-fat intake may destroy the homeostasis of intestinal microflora, reduce the diversity of intestinal microorganisms, and lead to the increased intestinal permeability, oxidative damage, and inflammatory expression, thereby accelerating the pathogenesis of MS, which is mainly characterized by lipid metabolism disorders6. Therefore, the development of intestinal microbial targeted strategies, including probiotics or probiotic dietary fiber preparations is of great significance for the treatment of MS7.
Probiotics are defined as “living microorganisms that are beneficial for the health of the host when ingested in a certain dose”, which promotes the health of the body by maintaining intestinal homeostasis, improving autoimmunity, resisting oxidative damage, and inflammatory expression8. In recent years, probiotic supplements have been used as an adjuvant therapy for lipid metabolism disorders, which was called “intestinal interference therapy” in clinic9. As reported by Khanna et al., probiotics can regulate gut microbiota and glucose and lipid metabolism in Sprague Dawley (SD) rats by high-fat diet (HFD)-induced metabolic complications, thereby improving obesity-related parameters and biochemical indexes of MS10.
As widely used probiotics, Lactobacillus plantarum and Bifidobacterium have recently attracted attention of researchers for their potential benefits against a variety of diseases (e.g., MS)11,12. L. plantarum can improve gut microbiota imbalance and promote the production of short-chain fatty acids (SCFAs) and other metabolites, thereby regulating intestinal inflammation and body health13. It was reported that L. gasseri SBT2055 inhibited adipose tissue inflammation and intestinal permeability in rats fed with HFD14. Recently, several probiotics, including L. paracasei HII01 and NL41, have been reported to interact with inflammatory intestinal tissues to inhibit the expression levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), thereby resisting increased systemic inflammation in patients with MS14,15. In addition, L. helveticus intake improved renal dysfunction caused by MS via reducing the expression levels of inflammatory markers and upregulating the insulin resistance pathway16. Therefore, L. plantarum may be a new therapeutic strategy for the prevention and treatment of metabolic diseases related to diet, inflammation, and intestinal microorganisms17,18.
Our previous studies have confirmed that L. plantarum could improve acute liver injury in mice induced by lipopolysaccharide (LPS) combined with d-galactosamine and non-alcoholic fatty liver disease (NAFLD) caused by HFD, which was related to the inhibition of the nuclear factor-κB (NF-κB) pathway19,20. Hence, the present study aimed to investigate the ameliorative effects of L. plantarum S9 on HFD-induced MS rats, and to determine whether the underlying mechanism could be related to the inhibition of the NF-κB pathway.
Results
L. plantarum S9 decreased weight gain, liver index and Lee’s index in HFD-induced MS rats
The weight gain, liver index, and Lee’s index in each group are shown in Fig. 1. Compared with the control group, the body weight, liver index, and Lee’s index in HFD group significantly increased after 8 weeks of HFD. However, the administration of L. plantarum S9 slowed down the weight gain in rats fed with HFD, which was 23.35% lower than that of the HFD group (P < 0.01). In addition, the L. plantarum S9 treatment decreased the liver index and Lee’s index in MS rats (all P < 0.05). The above-mentioned results indicated that L. plantarum S9 intervention could delay the process of fat accumulation in MS rats fed with HFD.
L. plantarum S9 alleviated the glucose metabolism disorders in HFD-induced MS rats
As illustrated in Fig. 2, rats in the HFD group had higher values of fasting blood glucose, fasting insulin, and HOMA-IR index compared with those in the control group (all P < 0.01), indicating that there was a significant insulin resistance in MS rats. However, L. plantarum S9 reversed the increase of fasting blood glucose, fasting insulin, and HOMA-IR index in MS rats fed with HFD (P < 0.01, P < 0.01, P < 0.05). Moreover, HOMA-B index in the model group was significantly higher than that in the control group (P < 0.01), but there was no significant difference in HOMA-B index after L. plantarum S9 treatment (P > 0.05). These results revealed that MS rats that received L. plantarum S9 had a better glucose tolerance and a higher insulin sensitivity.
L. plantarum S9 improved serum biochemical parameters in HFD-induced MS rats
As displayed in Fig. 3, the levels of TC, TG, and LDL-C in serum of rats in HFD group significantly increased compared with the control group (all P < 0.01), while the level of HDL-C significantly decreased (P < 0.05). Of note, the administration of L. plantarum S9 significantly reversed the above-mentioned changes, in which significantly decreased the levels of TC, TG, and LDL-C (P < 0.05, P < 0.01, P < 0.01), while significantly increased the level of HDL-C (P < 0.05). In addition, the L. plantarum S9 also downregulated the expression levels of AST and ALT by 50.57% and 37.19% compared with the HFD group, respectively (all P < 0.01). These results suggested that L. plantarum S9 could improve lipid metabolism disorders and liver injury in MS rats fed with HFD.
L. plantarum S9 reduced the levels of proinflammatory cytokines in serum of HFD-induced MS rats
As illustrated in Fig. 4, HFD significantly increased the levels of LPS and TNF-α in serum of MS rats, which indicated that HFD could induce a high level of proinflammatory response in MS rats. However, compared with HFD group, the L. plantarum S9 significantly decreased the levels of LPS and TNF-α in serum (62.42 ± 2.54 vs. 89.77 ± 4.01, P < 0.01; 35.47 ± 1.27 vs. 38.35 ± 1.45, P < 0.05), which further revealed that L. plantarum S9 had a significant anti-inflammatory activity.
L. plantarum S9 improved pathological changes in HFD-induced MS rats
The results of H&E staining (Fig. 5) showed that the liver cells in the HFD group were blurred and obvious fat droplets appeared. After administration of L. plantarum S9, the injury of liver cells was significantly reduced and tended to a normal cellular morphology. In addition, the results of oil-red O staining also showed that oral administration of L. plantarum S9 could reduce the fatty degeneration of liver tissues caused by HFD-induced fat accumulation to some extent.
L. plantarum S9 inhibited the levels of inflammatory in HFD-induced MS rats via regulating TLR4/NF-κB p65 pathway
In order to further explore the effects of L. plantarum S9 on inflammatory expression in MS rats, we detected the expression levels of the TLR4/NF-κB p65 pathway-related proteins (Fig. 6). Compared with the control group, the HFD induction upregulated the level of Toll-like receptor 4 (TLR4) (P < 0.01) and promoted the phosphorylation of downstream proteins (IκBα, NF-κB p65 and p38) (all P < 0.01), which showed a high level of inflammation response, while L. plantarum S9 intervention significantly inhibited the expression level of TLR4 and further decreased the ratios of p-IκBα/IκBα, p-p65/NF-κB p65, and p-p38/p38. These results also indicated that L. plantarum S9 treatment could modulate the inflammatory expression by HFD induction.
Discussion
MS is a major disease that includes obesity, hyperlipidemia, and insulin resistance21. Recently, studies have confirmed that probiotic intervention is a novel strategy for alleviating MS22. Supplementation of probiotics in patients with MS, particularly those containing Lactobacillus or Bifidobacterium, appears to be a promising strategy for the prevention and treatment of MS23.
The regulatory effects of probiotics on lipid profile of host have been extensively studied. A recent study showed that lactobacillus strains significantly reduced serum levels of TC, TG, and LDL-C, while increased serum HDL-C level in rats fed with HFD24. Similarly, the results of the current study also showed that L. plantarum S9 not only reduced body weight gain, Lee’s index, and liver index in rats fed with HFD, but also decreased serum levels of TC, TG, and LDL-C. Furthermore, L. plantarum S9 treatment significantly increased serum HDL-C level. Nallala et al. reported similar results related to the influence of L. plantarum VJC38 on the increase of HDL concentration in Wistar albino rats25. It was reported that L. fermentum CQPC0 increased the level of HDL-C in both serum samples and liver tissue of obese rats fed with HFD26. One proposed mechanism to explain HDL increase after probiotic treatment was that the decrease of serum TG level might indirectly lead to the increase of serum HDL level. However, another study demonstrated that some strains or their fermented milk did not appear to affect HDL concentration27. These results suggested that probiotics could improve metabolic disorders related to strain specificity. However, these findings need to be further confirmed to clarify the role and mechanism of probiotics in improving metabolic disorders. In addition, liver is an organ of detoxification and lipid metabolism, and ALT and AST levels are important markers of liver injury. L. plantarum S9 could significantly reduce the ALT and AST levels, suggesting that L. Plantarum S9 has a protective effect on liver injury induced by HFD. Long et al. also reported that L. plantarum KFY04 mitigated HFD-induced increase of ALT and AST levels28.
Insulin resistance is a key factor in MS, and secondary hyperinsulinemia can induce a variety of metabolic disorders and cardiovascular diseases29. Recent studies showed that probiotics could effectively reduce insulin resistance and improve insulin sensitivity, which is an important strategy for improving MS. For instance, the administration of L. acidophilus combined with curcumin significantly improved insulin level and reduced insulin resistance in high-fructose-induced metabolic complex rats30. Another study demonstrated that oral administration of L. fermentum CQPC06 significantly decreased the blood glucose level and serum insulin level in NAFLD mice31. Similarly, Musso et al. reported that L. fermentum CRL1446 improved the HOMA index in mice with MS32. In the present study, it was found that after administration of L. plantarum S9 for 6 weeks, glucose metabolism of rats with MS was significantly improved, and glucose and insulin levels were significantly reduced, suggesting that L. plantarum S9 could effectively restore glucose metabolism and insulin resistance of rats with MS. The results of the current study are consistent with those reported previously, indicating that different strains of probiotics can reduce insulin resistance caused by various metabolic disorders in humans and animals.
MS is typically associated with systemic low-grade inflammation, which is characterized by activation of certain pro-inflammatory signaling pathways and increased levels of pro-inflammatory cytokines, such as LPS, IL-1β, IL-6, and TNF-α33. In the present study, the levels of LPS and TNF-α were significantly upregulated in HFD rats, indicating that the HFD model was in a low-grade inflammatory state. However, L. plantarum S9 significantly reduced the LPS and TNF-α levels, suggesting that L. plantarum S9 could reduce the inflammatory response in HFD-induced MS rats. It has been reported that the elevated levels of LPS and TNF-α, as well as the release of pro-inflammatory cytokines are important triggers of diseases associated with metabolic disorders. L. pentosus S-PT84 prevents HFD/LPS-induced systemic inflammation by reducing the secretion of TNF-α and monocyte chemoattractant protein-1 (MCP-1)34. The TLR4/NF-κB signaling pathway regulates the production of inflammatory cytokines. TLR4 is the receptor of bacterial LPS, which can rapidly transmit the signal of LPS transduction pathway into the nucleus and activate NF-κB located at the downstream hub35. The activated NF-κB enters the nucleus to promote the synthesis and release of inflammatory cytokines36. A previous study have found that the expression level of TLR4 in the central nervous system was continuously elevated throughout the MS37. The results of the current study showed that the expression levels of TLR4 and NF-κB p65 significantly increased in the HFD model group. The expression level of NF-κB p65 increased, and the TNF-α content of NF-κB downstream inflammatory factor was elevated, suggesting that the activation of the TLR4/NF-κB signaling pathway might be involved in the pathogenesis of MS. Inhibition of the TLR4/NF-κB signaling pathway is an effective method to ameliorate inflammation associated with MS. In the present study, the expression levels of TLR4 and NF-κB p65 were significantly downregulated in HFD rats after receiving probiotics, and the nuclear expression of NF-κB p65 decreased, suggesting that L. plantarum S9 could inhibit the activation of the TLR4/NF-κB signaling pathway. Other probiotics, such as L. casei Lbs, L. freuteri V3401, L. rhamnosus GG, and Bifidobacterium bifidum have also been reported to ameliorate inflammation in MS patients38,39.
In summary, oral administration of L. plantarum S9 could reduce weight gain, and ameliorate lipid metabolism and insulin resistance. L. plantarum S9 was also shown to mitigate MS-associated inflammatory responses. L. plantarum S9 decreased the expression levels of pro-inflammatory cytokines through suppressing the TLR4/NF-κB pathway, which alleviated MS in rats fed with HFD (Fig. 7). Therefore, L. plantarum S9 could alleviate HFD-induced MS by reducing hyperlipidemia, insulin resistance, and inflammation.
Materials and methods
Preparation of L. plantarum S9
L. plantarum S9 is a new strain of lactic acid bacteria (LAB) isolated from sauerkraut and deposited in China Center for Type Culture Collection (Wuhan, China; Accession No. M208150). The strain was cultured in de Man Rogosa Sharpe (MRS) broth at 37 °C for 17 h. The pellets were harvested via centrifugation at 2000g for 10 min, and twice washed with phosphate-buffered saline (PBS, pH = 7.4), then, the live bacteria were re-suspended in physiological saline, and the concentration was adjusted to 1.0 × 109 CFU/ml for oral administration in mice.
Animals and groups
Healthy male Sprague-Dawley (SD) rats (body weight, 220–240 g; n = 30) were purchased from Changchun Yisi Experimental Animal Technology Co., Ltd. (Changchun, Jilin). Before beginning the experiment, rats were fed adaptively for a week under specific-pathogen-free (SPF) conditions (12/12 h light/dark cycle) at controllable temperature (22 ± 1 °C) and humidity (50 ± 1%), and all rats had free access to drinking water and food. All animal experiments were approved by the Animal Ethics Committee of Jilin Academy of Agricultural Sciences (approval number: SCXK2020-0001, Jilin, China).
After one week of adaptation, 30 rats were randomly divided into three groups (n = 10 per group): control group, HFD group and HFD + S9 group. Rats in control group fed with normal diet containing 10% fat, while HFD group and HFD + S9 group were fed with HFD containing 60% fat for 8 weeks40. Then, HFD + S9 group was orally administered 2 ml L. plantarum S9, and control group and HFD group were given the same dose of normal saline (once daily for 6 weeks). The nutritional composition of the diet was shown in Table 1. The body weight and blood glucose level of rats in each group were recorded every week. After administration, all rats were fasted for 12 h and anesthetized by intraperitoneal injection of 5% pentobarbital sodium, and blood samples were collected through cardiac puncture and serum was obtained after centrifugation at 4000g for 10 min at 4 °C. Then, rats were sacrificed by cervical dislocation, and the serum and liver were collected. Moreover, part of the liver was placed in 10% paraformaldehyde for pathological staining, and the remaining liver tissue was snap-frozen in liquid nitrogen and stored at − 80 °C for further analysis41.
Determination of related parameters
The final weight and length of rats were recorded 1 day prior to sacrifice, weight gain of each group was calculated according to the defined formula [final weight (g) − initial body weight (g)], and the Lee’s index was calculated using the following formula: Lee’s index = the cube root of final weight (g)/naso-anal length (cm). When rats were sacrificed, the liver was immediately removed, the weight of the liver was recorded, and the liver index was calculated using the following formula: Liver index = (liver weight/final body weight) × 100. The body weight and body length of rats in each group were averaged.
Serum biochemical parameters analysis
In accordance with the manufacturers’ protocols, the levels of insulin, total cholesterol (TC), TG, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in serum were detected using a kit purchased from Nanjing Jiancheng Bioengineering Institute (Nanjing, China), and the contents of lipopolysaccharide (LPS), tumor necrosis factor-α (TNF-α), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were determined by an ELISA kit (Shanghai Jianglai Biotechnology Co., Ltd., Shanghai, China). Therefore, the fasting blood glucose level of rats was measured using an ACCU-CHEK active blood glucose meter (Roche Diabetes Care GmbH, Mannheim, Germany), and homeostasis model assessment-insulin resistance (HOMA-IR) index and beta cell function percent (HOMA-B) index were calculated as follows: HOMA-IR = fasting blood glucose (mmol/L) × fasting insulin concentration (mU/L)/22.5; HOMA-B = 20 × fasting insulin concentration (mIU/L)/[fasting blood glucose (mmol/L) − 3.5].
Histological analysis
According to a previous study42, the liver tissue was fixed in 10% neutral paraformaldehyde (pH = 7.0), then, embedded into paraffin, and 4-μm paraffin-embedded sections were prepared and placed on clean glass microscope slides for hematoxylin and eosin (H&E) staining and oil-red O staining. Afterwards, images were visually analyzed using an optical microscope (Eclipse E100; Nikon, Tokyo, Japan), and the pathological changes of liver in each group were observed via the Image J software (National Institutes of Health, Bethesda, MD, USA).
Western blot analysis
The total protein of rat liver was extracted by a RIPA kit (ComWin Biotech Co., Ltd., Beijing, China) according to the method of Wang et al.43, and the liver extract was centrifuged at 10,000g for 10 min at 4 °C and separated to harvest the protein extract. Then, the protein content in the supernatant was detected using a BCA kit (Wanleibio Co., Ltd., Shenyang, China), adjusted to the uniform concentration, fully mixed with the buffer solution [60 mM Tris–HCl, 2% sodium dodecyl sulfate (SDS), and 2% β-mercaptoethanol, pH = 7.2], and denatured for 10 min in boiling water. Then, the protein samples were separated by 10% SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred onto polyvinylidene fluoride (PVDF) membranes. The protein samples were sealed with Tris-buffered saline with 0.05% Tween-20 (TBST) solution, containing 3% bovine serum albumin (BSA) at room temperature for 60 min. Finally, incubation was performed with rabbit anti-TLR4 (1:1000, bs-20379R, Bioss, China), rabbit anti-p38 (1:1000, bs-0637R, Bioss, China), rabbit anti-p-p38 (Thr180, 1:1000, bs-5476R, Bioss, China), rabbit anti-IκBα (1:1500, bs-1287R, Bioss, China), rabbit anti-p-IκBα (Ser 36, 1:1000, bs-18129R, Bioss, China), rabbit anti-NFκB p65 (1:1500, bsm-52305R, Bioss, China), rabbit anti-p-p65 (Ser 281, 1:1500, bs-17502R, Bioss, China), and rabbit anti-β-actin (1:1000, bs-0061R, Bioss, China) at 4 °C for 12 h, followed by incubation with horseradish peroxidase (HRP)-conjugated secondary antibody at 37 °C for 60 min. β-actin served as a loading control, and the target band optical density was quantified using Image Quant LAS 4000 (Fuji Film, Tokyo, Japan) (Supplementary Figures).
Statistical analysis
All experimental results were expressed as mean ± standard deviation. SPSS 20.0 software (IBM, Armonk, NY, USA) was used to analyze the inter-group variations using one-way analysis of variance (ANOVA), followed by the Tukey’s post-hoc test. P < 0.05 was considered statistically significant.
Ethics declarations
All animal experiments were approved and guided by the Animal Care Committee of Jilin Academy of Agricultural Sciences (approval number: SCXK2020-0001).
IACUC approval
All animal studies (including the rat euthanasia procedure) were conducted according to the AAALAC and the IACUC guidelines.
ARRIVE guidelines
All the research methods contained in the manuscript are carried out in accordance with the requirements of ARRIVE.
Data availability
All datasets generated for this study were included in the manuscript and available on request from the corresponding author.
Abbreviations
- MS:
-
Metabolic syndrome
- HFD:
-
High-fat diet
- ALT:
-
Alanine aminotransferase
- AST:
-
Aspartate transaminase
- LPS:
-
Lipopolysaccharide
- TNF-α:
-
Tumor necrosis factor-α
- IL-6:
-
Interleukin-6
- NF-κB:
-
Nuclear factor-κB
- TLR4:
-
Toll-like receptor 4
- WHO:
-
World Health Organization
- HDL-C:
-
High-density lipoprotein cholesterol
- LDL-C:
-
Low-density lipoprotein cholesterol
- TC:
-
Total cholesterol
- TG:
-
Triglyceride
- SCFAs:
-
Short-chain fatty acids
- NAFLD:
-
Non-alcoholic fatty liver disease
- LAB:
-
Lactic acid bacteria
- MRS:
-
De Man Rogosa Sharpe
- SPF:
-
Specific-pathogen-free
- HOMA-IR:
-
Homeostasis model assessment-insulin resistance
- SDS:
-
Sodium dodecyl sulfate
- PVDF:
-
Polyvinylidene fluoride
- BSA:
-
Bovine serum albumin
- HRP:
-
Horseradish peroxidase
- ANOVA:
-
Analysis of variance
- MCP-1:
-
Monocyte chemoattractant protein-1
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Acknowledgements
This work was funded by China Agriculture Research System of MOF and MARA and 2021 Jilin Province Science and Technology Development Plan (20210101424JC).
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L.Z.: methodology, software, formal analysis, investigation and editing. Y.S. and Y.W.: methodology, supervision, writing-review and editing. L.W.: project administration and data curation. L.Z.: methodology and project administration. Z.Z.: formal analysis, investigation, writing-review and editing. S.L.: conceptualization, methodology, project administration, resources, formal analysis, investigation, writing-original draft and supervision. All the co-authors approved the final version of the manuscript and agreed to submit it to Scientific Reports.
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Zhao, L., Shen, Y., Wang, Y. et al. Lactobacillus plantarum S9 alleviates lipid profile, insulin resistance, and inflammation in high-fat diet-induced metabolic syndrome rats. Sci Rep 12, 15490 (2022). https://doi.org/10.1038/s41598-022-19839-5
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DOI: https://doi.org/10.1038/s41598-022-19839-5
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