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24 February 2026

16 Pages

Lacticaseibacillus paracasei MG5012 and Bifidobacterium animalis subsp. lactis MG741 Alleviate Metabolic Dysfunction-Associated Steatotic Liver Disease and Preserve Skeletal Muscle Integrity in High-Fat-Diet-Fed Mice

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and
1
Department of Food Technology and Nutrition, Inje University, Gimhae 50834, Republic of Korea
2
MEDIOGEN, Co., Ltd., Biovalley 1-ro, Jecheon 27159, Republic of Korea
*
Authors to whom correspondence should be addressed.
Nutrients2026, 18(5), 715;https://doi.org/10.3390/nu18050715
This article belongs to the Section Prebiotics, Probiotics and Postbiotics
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Abstract

Background/Objectives: This study investigated the systemic metabolic effects of two probiotic strains, Lacticaseibacillus paracasei MG5012 and Bifidobacterium animalis subsp. lactis MG741, on metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity-related muscle dysfunction in high-fat-diet (HFD)-induced obese mice. Methods: Obesity was induced in C57BL/6 mice via high-fat diet (HFD) feeding for 6 weeks. Subsequently, the mice were orally administered MG5012 or MG741 for 8 weeks. We assessed systemic metabolic parameters, including body weight, adiposity, and serum biomarkers. Additionally, histological and molecular analyses were performed to evaluate hepatic steatosis, intestinal barrier integrity, and muscle oxidative status. Results: Both strains significantly attenuated body weight gain and adiposity, reduced serum liver injury markers (γ-GTP, ALT, AST), and improved systemic metabolic parameters by restoring serum GLP-1 levels and reducing hyperinsulinemia. Crucially, MG5012 and MG741 strengthened intestinal barrier integrity by upregulating the tight junction proteins Occludin and Claudin-1. In the liver, histological analyses revealed reductions in hepatic steatosis and triglyceride content, accompanied by the downregulation of lipogenic genes (SREBP-1c, FAS). Furthermore, the probiotics preserved skeletal muscle integrity; while muscle weight remained unchanged, the strains increased muscle fiber cross-sectional area (CSA) and reduced serum markers of muscle damage (CPK, LDH). This protective effect was associated with significantly enhanced expression of antioxidant enzymes (SOD, CAT, GPx) in muscle tissue. Conclusions: These findings suggest that MG5012 and MG741 confer systemic metabolic benefits through the modulation of the gut–liver–muscle axis and may serve as promising functional food ingredients for the management of MASLD and obesity-associated muscle atrophy.

1. Introduction

Obesity is a major global public health issue that causes a wide spectrum of chronic diseases such as type 2 diabetes, cardiovascular disease, and certain cancers [1,2]. It is increasingly recognized as a systemic disease that not only drives metabolic complications but also involves chronic inflammation, hormonal imbalances, and adverse effects on skeletal muscle mass and function [3,4]. Thus, obesity is not merely excess fat accumulation but a complex pathological state that disrupts multiple organ systems and imposes a substantial healthcare burden.
Among the dietary contributors to obesity, chronic consumption of a high-fat diet (HFD) is strongly associated with the development of metabolic dysfunction-associated steatotic liver disease (MASLD) [5]. MASLD, especially when driven by excessive dietary fat rather than alcohol, can progress from simple steatosis to non-alcoholic steatohepatitis (NASH) and ultimately liver fibrosis [6,7]. Its pathogenesis involves dysregulated lipid metabolism, insulin resistance, and oxidative stress—hallmarks of the systemic metabolic dysfunction observed in obesity [8,9].
Skeletal muscle dysfunction is another critical concern in obesity. Obesity-associated muscle impairments, characterized by myosteatosis (ectopic fat accumulation) and oxidative stress, exacerbate insulin resistance and disrupt systemic metabolic homeostasis [10,11]. This highlights the urgent need for therapeutic strategies that address both adiposity reduction and the preservation of skeletal muscle integrity.
Probiotics have emerged as promising modulators of metabolic health by influencing the gut–liver–muscle axis, particularly under HFD-induced metabolic stress [12,13,14,15]. Previous studies using HFD-induced obese mouse models have shown that Lactobacillus plantarum MG5012 improves insulin resistance, while Bifidobacterium animalis ssp. lactis MG741 enhances intestinal barrier integrity, thereby ameliorating lipid metabolism and systemic inflammation [16,17]. Despite these metabolic benefits, the effects of MG5012 and MG741 on skeletal muscle mass and function remain poorly understood. Given the pivotal role of skeletal muscle in whole-body energy homeostasis, especially under obesogenic conditions, further investigation is needed. In addition, glucagon-like peptide-1 (GLP-1), a gut-derived incretin hormone, plays a key role in regulating energy balance during metabolic stress [18]. Emerging evidence also suggests that GLP-1 contributes to skeletal muscle remodeling via GLP-1 receptor-mediated signaling pathways [19].
Building on these insights, this study aimed to investigate the effects of MG5012 and MG741 on both MASLD and skeletal muscle health in an HFD-induced obese mouse model. Notably, to better capture the chronic and progressive nature of HFD-induced metabolic alterations, the dietary intervention period was extended from 12 to 14 weeks. This extended timeframe provides a more comprehensive basis for evaluating the systemic efficacy of MG5012 and MG741, particularly in terms of their roles in muscle preservation and metabolic regulation.

2. Materials and Methods

2.1. Preparation of Tested Sample

The L. paracasei MG5012 and B. animalis ssp. lactis MG741, isolated from breast milk and healthy infant feces, were produced by MEDIOGEN Co., Ltd. (Jecheon, Republic of Korea). These probiotics were cultured in Man Rogosa Sharpe broth (Difco, Sparks, MD, USA) at 37 °C for 18 h. The pellets of strains were centrifuged at 1500× g for 10 min, harvested and freeze-dried. The powdered samples were mixed with maltodextrin for dilution at a final concentration of 1 × 1011 CFU/g and stored at 4 °C until administration.

2.2. Animal Experiment

The seven-week-old C57BL/6 male mice (YOUNGBIO Co., Ltd., Seongnam, Republic of Korea) were housed in groups of 3–5 per cage under controlled conditions at 22 ± 3 °C and 50 ± 20% humidity, with a 12-h light–dark cycle and ad libitum access to food and water. The experimental animals were randomly divided into five groups using a random number generator, and all tested samples were administered orally (n = 7~9): (1) normal diet (ND; 1314, Altromin Spezialfutter GmbH & Co. KG, Lage, Germany), (2) 60% HFD (D12492, Research diets INC., New Brunswick, NJ, USA), (3) silymarin (200 mg/kg, S0292, Sigma-Aldrich, St. Louis, MA, USA) with HFD, (4) MG5012 (1 × 109 CFU/day) and (5) MG741 (1 × 109 CFU/day) with HFD. Prior to administration, the animals, except the ND group, were fed an HFD for 6 weeks and subsequently stratified into groups based on body weight. Silymarin and probiotics were suspended in sterile PBS and administered via oral gavage once daily for an additional 8 weeks. Body weight was recorded weekly for all animals throughout the experimental period. At the end of the experiment, the animals were anesthetized with isoflurane for blood collection, followed by the excision of the liver and quadriceps femoris muscle. All tissues were weighed, with a portion fixed in 10% neutral buffered formalin and the remaining tissues stored at −80 °C until subsequent analysis. To ensure blinding, distinct personnel were assigned to each experimental phase. Dedicated caretakers conducted animal husbandry, while a separate technical team performed dissections. All analytical procedures were carried out independently by investigators who were not involved in animal care or tissue collection. The animal study was approved by CentralBio Co., Ltd. (CBIACUC_CE24-0024EF).

2.3. Serum Biochemical Analysis

Blood samples were collected from the caudal vena cava and centrifuged at 3000 rpm for 20 min to isolate the serum. The obtained serum was analyzed using a biochemical analyzer (Hitachi 3500, HITACHI, Tokyo, Japan) to measure aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglycerides (TG), total cholesterol (TC), creatine phosphokinase (CPK), and lactate dehydrogenase (LDH). CPK and LDH levels were measured in all groups except the silymarin group.

2.4. Histological Analysis

Fixed liver tissues were processed using standard histological procedures, embedded in paraffin, sectioned at a thickness of 4 µm, and stained with hematoxylin and eosin (H&E). Hepatic steatosis was evaluated by assessing the stained liver tissue slides and quantifying the steatosis scores as follows: 0 (<5%), 1 (5% to <33%), 2 (33% to <66%), and 3 (>66%). For Oil Red O (ORO) staining, formalin-fixed liver tissues were saturated in a 30% sucrose solution and embedded in an optimal cutting temperature (OCT) compound. Frozen tissues were sectioned at a thickness of 8 µm and stained with ORO to visualize lipid droplets. To quantify the lipid accumulation, at least three randomly selected fields (200× magnification) per mouse were captured, and the ORO-positive area was analyzed using ImageJ software (ver. 1.8.0; NIH, Bethesda, MD, USA).
Fixed gastrocnemius muscle tissues were similarly processed, embedded in paraffin, sectioned at 4 µm, and stained with H&E. To evaluate muscle atrophy, histological images were captured from at least five randomly selected fields per mouse. The cross-sectional area (CSA) of individual muscle fibers was measured using ImageJ software.

2.5. Enzyme-Linked Immunosorbent Assay (ELISA)

The levels of ALT, AST, TG, and MDA were measured in liver tissue. Serum levels of insulin and glucagon-like peptide-1 (GLP-1) were assessed using a Mouse Insulin ELISA Kit. Specifically, a total GLP-1 ELISA kit was used to evaluate overall GLP-1 secretion. Additionally, gamma-glutamyl transferase (ɣ-GT) activity was measured in both serum and liver tissue using a ɣ-GT Activity Assay Kit. Detailed information regarding the specific kits used, including catalog numbers and manufacturers, is listed in Supplementary Table S1. All ELISA assays were performed according to the manufacturer’s instructions.

2.6. Western Blotting

The liver tissues were lysed using Tissue Extraction Reagent I (Invitrogen, Waltham, MA, USA). Proteins were separated on 4–20% SDS-PAGE gels (Bio-Rad, Hercules, CA, USA) and transferred onto 0.45 μm polyvinylidene fluoride membranes (Merck Millipore, Burlington, MA, USA). The membranes were blocked with 5% bovine serum albumin (GenDEPOT, Katy, TX, USA) for 1 h at room temperature and then incubated overnight at 4 °C with primary antibodies against SREBP-1, MnSOD, catalase, GPx, and actin (Santa Cruz Biotechnology, Dallas, TX, USA) and FAS (Cell Signaling Technology, Danvers, MA, USA). Detailed information regarding the primary antibodies used in this study, including catalog numbers and dilution ratios, is listed in Supplementary Table S2. After washing with TBS-T (tris-buffered saline − 0.1% Tween 20), the membranes were incubated with HRP-conjugated secondary antibodies (GenDEPOT) diluted at 1:5000 for 1 h at room temperature. Protein bands were visualized using WestGlow™ FEMTO ECL Chemiluminescent Substrate (Biomax Co. Ltd., Guri-Si, Republic of Korea) and detected with LuminoGraph III Lite imaging system (ATTO, Tokyo, Japan). The intensity of each band was quantified using ImageJ software (NIH, Bethesda, MD, USA).

2.7. Statistical Analysis

The results detected outliers using the interquartile range (IQR) statistical technique [20] and were analyzed using a one-way analysis of variance (ANOVA), followed by Dunnett’s multiple comparisons test to compare the treatment groups against the HFD group. All statistical analyses were performed using GraphPad Prism 10 (GraphPad Software Inc., Boston, MA, USA). The results were shown as the mean ± standard error (SE) of at least six replicates. Differences were considered statistically significant at p < 0.05.

3. Results

3.1. Effects of MG5012 and MG741 on Body Weight Regulation in HFD-Fed Mice

Compared to the ND group, the HFD group exhibited an approximately 150% increase in body weight, indicating that 14 weeks of HFD feeding effectively induced obesity (Figure 1B). Although the MG5012- and MG741-treated groups showed moderate reductions in body weight and weight gain compared to the HFD group, these differences were not statistically significant (p > 0.05) (Figure 1B,C). These findings suggest a potential anti-obesity effect of MG5012 and MG741. Meanwhile, food intake did not differ significantly among the four groups (p > 0.05), indicating that the observed body weight changes were independent of caloric intake (Figure 1D).
Figure 1. Effects of MG5012 and MG741 on body weight and food intake in HFD-fed mice. (A) Experimental design for the high-fat-diet-induced MASLD model in this study. (B) Body weight changes over the 14-week treatment period. (C) Weight gain during administration. (D) Average daily food intake per mouse during the experimental period. Data are presented as mean ± standard error (SE) (n ≥ 6). Statistical significance was determined using one-way ANOVA followed by Dunnett’s post hoc test. * and *** indicate p < 0.05 and p < 0.001, respectively. Outliers were identified and excluded using the interquartile range (IQR) method. ND: normal diet; HFD: high-fat diet; silymarin: HFD + silymarin; MG5012: HFD + MG5012; MG741: HFD + MG741.

3.2. MG5012 and MG741 Improve Serum Biomarkers of Hepatic and Metabolic Function in HFD-Fed Mice

In the MG5012- and MG741-treated groups, serum levels of key hepatic function biomarkers (γ-GTP, ALT, and AST) were significantly reduced compared to the HFD group (p < 0.01), indicating a protective effect against liver stress induced by HFD feeding (Figure 2A–C). Additionally, serum GLP-1 levels, a hormone involved in energy homeostasis, were markedly elevated in both MG5012- and MG741-treated groups (p < 0.001) (Figure 2D). Notably, these levels were significantly higher not only than those in the HFD group but also compared to the silymarin-treated positive control group. Furthermore, treatment with MG5012 and MG741 significantly reduced serum TG, TC, and insulin levels under HFD conditions (p < 0.05), suggesting that both probiotics exert beneficial effects on systemic energy metabolism (Figure 2E–G).
Figure 2. Effects of MG5012 and MG741 on serum biomarkers of hepatic and metabolic function in HFD-fed mice. (A) γ-Glutamyl transpeptidase (γ-GTP), (B) Alanine aminotransferase (ALT), (C) aspartate aminotransferase (AST), (D) glucagon-like peptide-1 (GLP-1), (E) triglycerides (TG), (F) total cholesterol (TC), and (G) insulin. Statistical significance was determined using one-way ANOVA followed by Dunnett’s post hoc test. *, **, and *** indicate p < 0.05, p < 0.01, and p < 0.001, respectively. Outliers were identified and excluded using the interquartile range (IQR) method. ND: normal diet; HFD: high-fat diet; silymarin: HFD + silymarin; MG5012: HFD + MG5012; MG741: HFD + MG741.

3.3. MG5012 and MG741 Attenuate Hepatic Dysfunction and Oxidative Stress in HFD-Fed Mice

Consistent with the results observed in serum, hepatic levels of key liver function biomarkers—γ-GTP, ALT, and AST—were significantly decreased in the MG5012- and MG741-treated groups compared to the HFD group, indicating a hepatoprotective effect against HFD-induced liver damage (Figure 3A–C). In addition, treatment with both probiotics significantly reduced HFD-induced MDA levels to a level comparable to that of the silymarin-treated group (p < 0.01) (Figure 3D).
Figure 3. Effects of MG5012 and MG741 on hepatic biomarkers of liver function and energy metabolism in HFD-fed mice. (A) γ-Glutamyl transpeptidase (γ-GTP), (B) alanine aminotransferase (ALT), (C) aspartate aminotransferase (AST), (D) malondialdehyde (MDA), and (E) glucagon-like peptide-1 (GLP-1). Statistical significance was determined using one-way ANOVA followed by Dunnett’s post hoc test. *, **, and *** indicate p < 0.05, p < 0.01, and p < 0.001, respectively. Outliers were identified and excluded using the interquartile range (IQR) method. ND: normal diet; HFD: high-fat diet; silymarin: HFD + silymarin; MG5012: HFD + MG5012; MG741: HFD + MG741.
For GLP-1, a hormone involved in the regulation of energy homeostasis, no significant change was observed in the silymarin-treated group relative to the HFD group. However, hepatic GLP-1 levels were significantly elevated in the MG5012-treated group (p < 0.05), suggesting a distinct metabolic benefit associated with this treatment (Figure 3E).

3.4. MG5012 and MG741 Reduce Hepatic Lipid Accumulation and Steatosis in HFD-Fed Mice

Histological analysis of liver tissue revealed that hepatic steatosis was significantly reduced in the MG5012- and MG741-treated groups compared to the HFD group (Figure 4A,B). Liver weight was also decreased in both treatment groups relative to the HFD group (p < 0.001) (Figure 4C).
Figure 4. Effects of MG5012 and MG741 on hepatic lipid accumulation and steatosis in HFD-fed mice. (A) Representative images of liver sections: upper panels stained with hematoxylin and eosin (H&E), and lower panels stained with Oil Red O (ORO). (B) Steatosis score. (C) Absolute liver weight. (D) Lipid droplet area quantified from ORO-stained sections. (E) Triglyceride (TG) content. (F) Western blot images of sterol regulatory element-binding protein 1c (SREBP-1c), fatty acid synthase (FAS), phosphorylated AMP-activated protein kinase (p-AMPK), and total AMPK. Quantification of (G) SREBP-1c, (H) FAS, and (I) the p-AMPK/AMPK ratio. Statistical significance was determined using one-way ANOVA followed by Dunnett’s post hoc test. *, **, and *** indicate p < 0.05, p < 0.01, and p < 0.001, respectively. ‘ns’ indicates not significant. Outliers were identified and excluded using the interquartile range (IQR) method. ND: normal diet; HFD: high-fat diet; silymarin: HFD + silymarin; MG5012: HFD + MG5012; MG741: HFD + MG741.
Oil Red O staining showed a marked reduction in lipid droplet accumulation in the MG5012-treated group relative to HFD controls (p < 0.001), further supporting the lipid-lowering effect (Figure 4D). Also, hepatic TG content was significantly lower in both MG5012- and MG741-treated mice than in HFD-fed controls (p < 0.05) (Figure 4E).
To elucidate the molecular mechanisms underlying this reduction in hepatic lipid accumulation, we examined the expression of proteins involved in lipid metabolism. Western blot analysis showed that although the phosphorylation of AMPK (p-AMPK) exhibited an increasing trend in the MG5012- and MG741-treated groups compared to the HFD group, this difference did not reach statistical significance (Figure 4F,I). Nevertheless, the expression levels of SREBP-1c and FAS, two key downstream mediators of hepatic lipid synthesis, were significantly decreased in both probiotic-treated groups (Figure 4F–H). These results suggest that the inhibition of hepatic lipid accumulation by MG5012 and MG741 is effectively mediated through the downregulation of lipogenic pathways involving SREBP-1c and FAS.

3.5. MG5012 and MG741 Suppress Adipocyte Hypertrophy in HFD-Fed Mice

Although the epididymal adipose tissue weight did not differ significantly between the HFD and probiotic-treated groups (Supplementary Figure S1), histological analysis revealed a marked improvement in adipose tissue morphology. Specifically, adipocyte size was significantly reduced in both the MG5012- and MG741-treated groups relative to HFD controls (Figure 5A,B; p < 0.01 and p < 0.05, respectively). This dissociation between fat mass and adipocyte size suggests that while the probiotics may not have drastically reduced total fat mass within the experimental period, they effectively attenuated adipocyte hypertrophy, thereby improving the storage capacity and metabolic health of white adipose tissue under high-fat-diet conditions.
Figure 5. Effects of MG5012 and MG741 on adipocyte hypertrophy in HFD-fed mice. (A) Epididymal adipose tissue stained with hematoxylin and eosin (H&E). (B) Quantification of adipocyte size. Statistical significance was determined using one-way ANOVA followed by Dunnett’s post hoc test. *, **, and *** indicate p < 0.05, p < 0.01, and p < 0.001, respectively. Outliers were identified and excluded using the interquartile range (IQR) method. ND: normal diet; HFD: high-fat diet; MG5012: HFD + MG5012; MG741: HFD + MG741.

3.6. MG5012 and MG741 Preserve Skeletal Muscle Integrity and Enhance Antioxidant Defense in HFD-Fed Mice

Despite no significant differences in gastrocnemius muscle weight among the four experimental groups, histological analysis revealed a notable increase in muscle fiber cross-sectional area (CSA) in the MG5012 and MG741 groups compared to the HFD control group (p < 0.05; Figure 6A–C). This dissociation between muscle mass and fiber size suggests that the probiotics improved muscle quality and attenuated myofiber atrophy, without significantly altering gross muscle weight. Additionally, serum creatine phosphokinase (CPK) levels were significantly reduced in both MG5012 and MG741 groups relative to the HFD group (p < 0.05 and p < 0.01, respectively), indicating an improvement in muscle function (Figure 6D).
Figure 6. Effects of MG5012 and MG741 on skeletal muscle morphology, injury markers, and antioxidant defense in HFD-fed mice. (A) Quadriceps muscle sections stained with hematoxylin and eosin (H&E). (B) Absolute muscle weight. (C) Quantification of muscle fiber cross-sectional area (CSA). (D) Serum creatine phosphokinase (CPK), (E) serum lactate dehydrogenase (LDH), (F) representative Western blot images of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Quantification of (G) SOD, (H) CAT, and (I) Gpx protein levels. Statistical significance was determined using one-way ANOVA followed by Dunnett’s post hoc test. * and *** indicate p < 0.05 and p < 0.001, respectively. Outliers were identified and excluded using the interquartile range (IQR) method. ND: normal diet; HFD: high-fat diet; MG5012: HFD + MG5012; MG741: HFD + MG741.
Moreover, serum lactate dehydrogenase (LDH) levels were significantly lower in the MG741 group compared to the HFD group (p < 0.05). While LDH is a general marker of cellular injury, its reduction, in conjunction with the decrease in muscle-specific CPK levels, suggests an alleviation of overall metabolic stress and tissue damage primarily driven by the high-fat diet (Figure 6E). Both MG5012 and MG741 supplementation increased the expression of antioxidant enzymes. Notably, in skeletal muscle tissue of the MG741 group, the expression levels of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (Gpx) were elevated by approximately 80%, 89%, and 25%, respectively, relative to the HFD control (Figure 6F–I). These results demonstrate that MG741, in particular, markedly enhanced the antioxidant defense system, which may contribute to improved antioxidative capacity in muscle tissue.

3.7. MG5012 and MG741 Improve Intestinal Barrier Integrity in HFD-Fed Mice

To investigate the effect of probiotics on gut barrier function, a key component of the gut–liver–muscle axis, we measured the expression of tight junction proteins in colonic tissue. The results revealed that HFD feeding significantly suppressed the expression of Occludin and Claudin-1 compared to the ND group. However, treatment with MG5012 and MG741 significantly restored the levels of these proteins (p < 0.05) (Figure 7), indicating that these strains effectively ameliorate HFD-induced intestinal barrier dysfunction.
Figure 7. Effects of MG5012 and MG741 on intestinal barrier integrity and tight junction protein expression in HFD-fed mice. Representative Western blot images of Occludin and Claudin-1 in colonic tissue. Quantification of (A) Occludin and (B) Claudin-1 protein levels. Statistical significance was determined using one-way ANOVA followed by Dunnett’s post hoc test. * and ** indicate p < 0.05 and p < 0.01, respectively. ‘ns’ indicates not significant. Outliers were identified and excluded using the interquartile range (IQR) method. ND: normal diet; HFD: high-fat diet; Silymarin: HFD + Silymarin; MG5012: HFD + MG5012; MG741: HFD + MG741.

4. Discussion

This study builds upon our previous findings using a 12-week HFD model, in which MG5012 and MG741 were shown to ameliorate hepatic steatosis via distinct mechanisms—MG5012 through modulation of insulin signaling and MG741 through improvement of gut barrier integrity [18,19]. While earlier results established the foundational efficacy of the strains in reducing hepatic lipid accumulation, the present study significantly extends the experimental scope and mechanistic understanding.
By extending the HFD duration to 14 weeks, we introduced a more prolonged metabolic challenge, allowing for a comprehensive assessment of the long-term therapeutic potential of MG5012 and MG741. Importantly, the present investigation extends beyond hepatic endpoints to explore additional metabolic pathways, including GLP-1–mediated signaling and the regulation of lipogenesis [21,22]. These expanded analyses provide deeper insight into the systemic mechanisms through which these strains exert their metabolic effects.
MASLD is a multifactorial metabolic disorder characterized by insulin resistance, which contributes to the dysregulation of lipid metabolism in both hepatic and adipose tissues, ultimately leading to chronic inflammation [23,24,25]. Numerous studies have demonstrated a strong association between insulin resistance and GLP-1 in MASLD [26]. GLP-1, a hormone secreted by enteroendocrine L-cells in the intestine, is primarily recognized for its role in maintaining glucose homeostasis through the modulation of insulin signaling [27]. However, emerging evidence suggests that GLP-1 also plays a significant role in lipid metabolism [28]. Previous studies have demonstrated that GLP-1 downregulates the expression of lipogenic genes in differentiated human adipocytes derived from obese individuals [21]. Conventionally, the metabolic benefits of GLP-1 are often attributed to its central action on appetite suppression, leading to reduced food intake and body weight [29]. However, in the current study, MG5012 and MG741 significantly ameliorated metabolic dysfunction and reduced body weight gain without altering daily food intake. This dissociation between food consumption and metabolic improvement suggests that the beneficial effects of GLP-1 in this model are likely mediated through peripheral mechanisms rather than central appetite regulation. In the present study, MG5012 and MG741 significantly restored serum GLP-1 levels in an HFD-induced MASLD model. Concurrently, the treatment significantly reduced fasting serum insulin levels, which were elevated in the HFD group. This reduction in hyperinsulinemia, coupled with restored GLP-1 levels, suggests an improvement in systemic metabolic regulation. Distinct from these metabolic parameters, both MG5012 and MG741 significantly reduced serum levels of AST, ALT, and γ-GTP. This finding suggests that these probiotic strains might exert hepatoprotective effects, potentially through the modulation of metabolic and inflammatory pathways involved in the progression of MASLD [30].
Notably, MG5012 and MG741 markedly reduced hepatic steatosis and regulated the expression of key lipogenic transcription factors, including SREBP-1c and FAS. Previous studies have reported that GLP-1 attenuates hepatic lipogenesis by modulating AMPK signaling pathways [22]. However, in our study, although the phosphorylation of AMPK showed an increasing trend in the probiotic-treated groups, it did not reach statistical significance. This suggests that the lipid-lowering effects of MG5012 and MG741 may be mediated, at least in part, through AMPK-independent mechanisms. One potential alternative pathway involves the cAMP/PKA signaling axis. GLP-1 receptor activation increases intracellular cAMP levels and activates Protein Kinase A (PKA), which has been shown to induce the degradation of nuclear SREBP-1c, thereby inhibiting lipogenesis independently of AMPK [31]. Alternatively, the marked reduction in hyperinsulinemia observed in the probiotic-treated groups may have directly reduced the insulin-mediated transcriptional induction of SREBP-1c, disrupting the vicious cycle of insulin resistance and de novo lipogenesis [32]. Based on these findings, it can be inferred that MG5012 and MG741 ameliorate lipid metabolic dysfunction in MASLD by downregulating SREBP-1c and FAS, consistent with the modulation of GLP-1 signaling pathways. However, further studies are warranted to elucidate the underlying molecular mechanisms and to clarify the direct relationship between GLP-1 regulation and the lipid-lowering effects of these probiotic strains in the context of MASLD.
Beyond their effects on the serum, liver, and adipose tissues, MG5012 and MG741 may exert broader systemic benefits by influencing peripheral tissues, such as skeletal muscle, thereby contributing to overall metabolic homeostasis. Although we did not directly measure GLP-1 receptor activation in skeletal muscle, previous studies have experimentally documented that circulating GLP-1 improves skeletal muscle glucose uptake and mitochondrial function [33]. Given that MG5012 and MG741 significantly restored serum GLP-1 levels in our study, it is plausible that these strains may also positively impact metabolic function in peripheral tissues. To test the potential impact on muscle health, we examined skeletal muscle structural and functional parameters. Our results demonstrated that both probiotic strains significantly increased the CSA of skeletal muscle and reduced serum markers of muscle damage (CPK, LDH). Furthermore, Western blot analysis of skeletal muscle tissue revealed that both probiotics significantly enhanced the expression of antioxidant enzymes (SOD, CAT, and GPx). Crucially, HFD-induced obesity is known to elevate oxidative stress, which promotes proteolysis and leads to muscle atrophy [34]. Therefore, the enhanced antioxidant defense observed in the probiotic groups likely mitigated this oxidative damage, thereby preserving muscle fiber integrity. This protective mechanism offers a plausible explanation for the maintained muscle fiber CSA and reduced tissue injury markers, suggesting that the probiotics attenuated obesity-induced myosteatosis rather than inducing hypertrophy through physical activity. This implies that the metabolic benefits of MG5012 and MG741 are not limited to the liver but extend to the preservation of skeletal muscle integrity, likely mediated through the attenuation of oxidative stress and improved systemic metabolic regulation [1].
In addition, to substantiate the ‘gut’ component of the proposed axis, we evaluated intestinal barrier function. Our results showed that MG5012 and MG741 significantly upregulated the expression of tight junction proteins, Occludin and Claudin-1, in colonic tissue. The restoration of gut barrier integrity is pivotal for preventing the translocation of luminal endotoxins (e.g., Lipopolysaccharide, LPS), which are known triggers of systemic inflammation and metabolic dysfunction [35,36]. Collectively, the simultaneous restoration of gut barrier integrity (Occludin and Claudin-1), serum GLP-1 levels, and muscle antioxidant defense supports the existence of a functional gut–liver–muscle axis.
It is well-established that the physiological effects of probiotics are highly strain-specific, meaning that even strains within the same species can exhibit different metabolic activities [16,17]. While numerous studies have reported the hepatoprotective effects of probiotics such as Lactiplantibacillus plantarum in MASLD models [37], fewer studies have simultaneously demonstrated beneficial effects on skeletal muscle integrity. Recently, the concept of the ‘gut–muscle axis’ has gained attention, with specific strains showing potential to alleviate muscle atrophy via anti-inflammatory or antioxidant pathways [38]. Uniquely, our study demonstrates that MG5012 and MG741 exert dual benefits by simultaneously targeting hepatic steatosis and skeletal muscle oxidative stress. This comprehensive efficacy suggests that these specific strains may offer superior therapeutic potential for managing complex metabolic syndromes where liver and muscle pathologies coexist, compared to probiotics that target a single organ system.
Taken together, our findings indicate that MG5012 and MG741 exert metabolic benefits not only in the liver but also in peripheral tissues such as skeletal muscle. These broad systemic effects may contribute to improved metabolic homeostasis and highlight the therapeutic potential of these probiotic strains in managing complex metabolic disorders, including MASLD. The human origin of L. paracasei MG5012 (from breast milk) and B. animalis ssp. lactis MG741 (from infant feces) provides important advantages, including enhanced safety, host adaptability, and colonization efficiency—critical features for effective probiotic interventions [39,40,41]. Given the pivotal role of the gut–liver axis in probiotic function, further investigations of alterations in gut microbiota and host metabolic interactions are warranted to clarify the mechanisms by which these strains modulate host metabolism [18,42]. Moreover, well-designed clinical studies are needed to validate the translational potential of MG5012 and MG741, particularly regarding their efficacy, safety, and host responses in clinical settings.

5. Conclusions

In conclusion, this study demonstrates that the probiotic strains Lacticaseibacillus paracasei MG5012 and Bifidobacterium animalis subsp. lactis MG741 exert beneficial effects on hepatic and muscular health in a high-fat-diet-induced mouse model of obesity. Crucially, both strains significantly restored intestinal barrier integrity by upregulating the tight junction proteins Occludin and Claudin-1, thereby reinforcing the first line of defense against metabolic stress. Concurrently, the strains alleviated hepatic steatosis and reduced liver injury markers—including ALT, AST, and γ-GTP. This is likely achieved by promoting the secretion of GLP-1 from intestinal L-cells, which subsequently leads to the downregulation of lipogenic transcription factors (SREBP-1c and FAS) and the improvement of systemic insulin sensitivity. In addition to their hepatoprotective effects, MG5012 and MG741 improved systemic metabolic parameters and reduced adipocyte hypertrophy. Notably, these strains preserved skeletal muscle integrity by increasing muscle fiber cross-sectional area, decreasing serum CPK and LDH levels, and upregulating antioxidant enzymes. Based on these findings, the proposed mechanism by which MG5012 and MG741 modulate the gut–liver–muscle axis is schematically summarized in Figure 8. Given their human origin and favorable safety profile, these strains hold strong potential as functional food ingredients or therapeutic probiotics for managing obesity-related metabolic disorders, including MASLD and obesity-associated muscle dysfunction. Further clinical studies are warranted to validate their efficacy and elucidate the underlying mechanisms in humans.
Figure 8. Proposed mechanism by which MG5012 and MG741 alleviate MASLD and preserve muscle integrity via the gut–liver–muscle axis in HFD-induced obese mice.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/nu18050715/s1, Table S1: List of antibodies used in this study; Table S2: List of ELISA kit used in this study; Figure S1: Effect of L. paracasei MG5012 and B. animalis subsp. lactis MG741 on epididymal adipose tissue weight in HFD-induced obese mice.

Author Contributions

Conceptualization, M.J., J.Y.L. and S.-I.C.; methodology, J.Y.L. and J.-Y.P.; formal analysis, J.Y.L., J.-Y.P. and S.-I.C.; investigation, J.Y.L., J.-Y.P. and S.-I.C.; resources, B.-K.K.; data curation, M.J., J.Y.L. and S.-I.C.; writing—original draft preparation, M.J.; writing—review and editing, M.J., J.Y.L. and S.-I.C.; visualization, J.Y.L. and J.-Y.P.; supervision, M.J., S.-I.C. and B.-K.K.; project administration, B.-K.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

The animal study was conducted in accordance with relevant institutional guidelines and regulations, and the protocol was approved by the Institutional Animal Care and Use Committee of CentralBio Co., Ltd. (approval number: CBIACUC_CE24-0024EF, 24 November 2025).

Data Availability Statement

The data that supports the findings of this study are available on request from the corresponding author upon reasonable request.

Conflicts of Interest

J.Y.L., J.-Y.P., S.-I.C. and B.-K.K.were employed by MEDIOGEN, Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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