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Host-specific effects of Eubacterium species on Rg3-mediated modulation of osteosarcopenia in a genetically diverse mouse population

Microbiome volume 12, Article number: 251 (2024) Cite this article

Abstract

Background

Osteosarcopenia, characterized by the simultaneous loss of bone and muscle mass, is a serious health problem in the aging population. This study investigated the interplay between host genetics, gut microbiota, and musculoskeletal health in a mouse model of osteosarcopenia, exploring the therapeutic potential of gut microbiota modulation.

Methods

We examined the effects of Rg3, a phytochemical, on osteosarcopenia and its interactions with host genetics and gut microbiota in six founder strains of the Collaborative Cross (CC) population. Subsequently, we evaluated the therapeutic potential of Eubacterium nodatum (EN) and Eubacterium ventriosum (EV), two gut microbes identified as significant correlates of Rg3-mediated osteosarcopenia improvement, in selected C57BL/6 J (B6) and 129S1/SvImJ (129S1) mouse strains.

Results

Rg3 treatment altered gut microbiota composition aligned with osteosarcopenia phenotypes, which response varied depending on host genetics. This finding enabled the identification of two microbes in the Eubacterium genus, potential mediator of Rg3 effect on osteosarcopenia. Oral administration of EN and EV differentially impacted bone density, muscle mass, exercise performance, and related gene expression in a mouse strain-specific manner. In 129S1 mice, EN and EV significantly improved these parameters, effectively reversing osteosarcopenic phenotypes. Mechanistic investigations revealed that these effects were mediated through the modulation of osteoblast differentiation and protein degradation pathways. In contrast, EN and EV did not significantly improve osteosarcopenic phenotypes in B6 mice, although they did modulate mitochondrial biogenesis and microbial diversity.

Conclusions

Our findings underscore the complex interplay between host genetics and the gut microbiota in osteosarcopenia and emphasize the need for personalized treatment strategies. EN and EV exhibit strain-specific therapeutic effects, suggesting that tailoring microbial interventions to individual genetic backgrounds may be crucial for optimizing treatment outcomes.

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Graphical Abstract

Background

Osteosarcopenia, characterized by a concurrent decline in muscle and bone mass with age, has emerged as a significant and escalating global public health concern. With rising life expectancy, the projected prevalence of osteosarcopenia is anticipated to increase dramatically, imposing a substantial burden on healthcare systems due to the elevated risk of falls, fractures, and limitations in functional mobility of patients [1]. However, there are currently no treatment options for osteosarcopenia approved by the Food and Drug Administration, highlighting the critical need to develop novel therapeutic strategies [2].

The etiology of osteosarcopenia likely involves a complex interplay between genetic and environmental factors. Genetic predisposition plays a significant role in osteosarcopenia, with specific gene variants conferring increased susceptibility to the syndrome [3, 4]. Methyltransferase like 21C, myocyte enhancer factor-2, and sterol regulatory element-binding transcription factor 1 have been well studied as candidate genes that are highly correlated with osteosarcopenia incidence [5,6,7]. Concurrently, environmental factors such as dietary patterns and gut microbiome composition also contribute to the disease process [8, 9]. Recent studies have highlighted a strong correlation between the gut microbiome and skeletal health [10,11,12], demonstrating that specific gut microbes or fecal microbiota transplantationcan influence both muscle [13, 14] function and bone integrity [14, 15, 16]. The environmental factors with the highest correlation with the disease were low potassium levels, alcohol consumption, low serum vitamin D levels, and immune factors [3]. However, dissecting the independent and interactive effects of these factors remains challenging.

Pharmacogenomics, a field dedicated to understanding how individual genetic variations influence drug responses, holds immense promise for the development of personalized treatment strategies for osteosarcopenia [17]. Traditional inbred mouse strains offer limited genetic variability, which hinders the generalizability of research findings in a broader human population [18]. To overcome this limitation, researchers are increasingly using genetically diverse mouse models, such as Collaborative Cross (CC) and Diversity Outbred populations. These genetically diverse mouse populations mirror the rich genetic heterogeneity found in humans, enabling a more comprehensive investigation of the complex interplay between genes and their environment [19, 20]. These models have proven valuable in studying the influence of genetic background on the response to various medications, including phytochemicals, in diseases such as obesity and diabetes [21,22,23,24]. Our previous research has elucidated the strain-dependent efficacy of Rg3 in osteosarcopenia models, highlighting the influence of host genetics on its therapeutic response [25]. Additionally, these models have been instrumental in identifying the influence of the genetic background on gut microbiota composition and homeostasis [26,27,28]. These findings highlight the importance of integrating pharmacogenomics with gut microbiome analyses in osteosarcopenia research. This combined approach holds promise for the development of personalized treatment strategies that consider both the genetic makeup and unique gut microbial composition of an individual.

Based on our previous research demonstrating the strain-dependent efficacy of Rg3, a phytochemical, in osteosarcopenia models [25], this study aimed to (1) investigate the mechanisms underlying the variable pharmacological effects of Rg3 across diverse genetic backgrounds, and (2) explore the therapeutic potential of gut microbiota modulation in osteosarcopenia. Leveraging the genetic diversity of CC founder strains, we examined the effects of Rg3, a well-characterized phytochemical with established pharmacological properties [29, 30], on osteosarcopenia and its interaction with host genetics, gut microbiota, and musculoskeletal health in six CC founder strains. This multifaceted approach led to the identification of Eubacterium nodatum (EN) and Eubacterium ventriosum (EV) as potential microbial targets. Subsequently, we evaluated the efficacy of EN and EV in reversing osteosarcopenia in selected mouse strains, aiming to elucidate the interplay between host genetics and gut microbiota in therapeutic responses.

Materials and methods

Bacterial media and cell culture conditions

Eubacterium nodatum (ATCC 33099; EN) and Eubacterium ventriosum (ATCC 27560; EV) were obtained from the American Type Culture Collection (ATCC, VA, USA) and cultivated in reinforced clostridial medium (RCM) under strict anaerobic conditions at 37 °C, per ATCC recommendations. After anaerobic cultivation, bacterial cultures were centrifuged, and the pellets were resuspended in sterile anaerobic phosphate-buffered saline for oral administration to mice.

Growth rate measurement

The growth rate of both bacteria was assessed in RCM under anaerobic conditions at 37 °C, both with and without Rg3 treatment. A 96-well plate reader (Multiskan SkyHigh; Thermo Fisher Scientific, MA, USA) was used for analysis. Each well was inoculated with a 1000-fold dilution of an overnight culture and subsequently treated with Rg3 in triplicate for each concentration. The cultures were incubated for 24 h with shaking at 200 rpm, and the optical density (OD) at 600 nm (OD600) was measured every 20 min. Exponential growth rates were calculated based on OD600 values between 0.02 and 0.1.

Animals: collaborative founder strains

The mouse experimental design is outlined in Fig. 1A. Five-week-old male mice (n = 8/strain) from six strains, namely A/J, C57BL/6 J, 129S1/SvImJ, NOD/ShiLtJ, NZO/EiJ, and PWK/PhJ (referred to here as AJ, B6, 129S1, NOD, NZO, and PWK) were obtained from the Jackson Laboratory (Bar Harbor, ME, USA). Mice were housed under standard laboratory conditions with a 12-h light/dark cycle, controlled temperature, and humidity. They were allowed to acclimate to their new environment for 2 weeks before the start of the experiment. Following acclimatization, the mice from each strain were randomly assigned to either the control or Rg3 group (n = 4/group). The control group received a vehicle control (0.5% CMC) orally, while the Rg3 group received Rg3 at a dose of 20 mg/kg/day via oral gavage for 6 weeks. After 2 weeks, all mice received intraperitoneal dexamethasone (DEX) injections (15 mg/kg/day) for 1 month to induce muscle atrophy and bone loss. Mice had ad libitum access to food and water throughout the study. After 6 weeks of Rg3 or vehicle administration and 16 h fasting, the mice were euthanized. Plasma, muscle (quadriceps, gastrocnemius, tibialis, and soleus), bone (femurs), spleen, cecum, and fecal samples were collected and stored at − 80 °C for further analysis. Muscle weight was measured using an analytical balance (Mettler Toledo, OH, USA), and the muscle-to-body weight ratio was calculated for atrophy assessment.

Fig. 1
figure 1

Experimental design for two independent studies. A Experimental design for the collaborative founder strain study. B Experimental design for the validation study using C57BL/6 J and 129S1/SvImJ strains

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Animals: validation of the two candidate bacteria in C57BL/6 J and 129S1/SvImJ strains

The mouse experimental design is outlined in Fig. 1B. A total of 100 male mice, 50 of each strain (C57BL/6 J and 129S1/SvImJ), were obtained from the Jackson Laboratory at 5 weeks of age. All animal experimental protocols were approved by the International Animal Care and Use Committee of the Korea Institute of Science and Technology (KIST-2021–091002) and adhered to the established guidelines and regulations. The mice were housed under controlled conditions (25 °C, 45% humidity, 12-h light/dark cycle) and fed a standard AIN-76A diet with ad libitum access to water. Following acclimatization, the mice from each strain were randomly assigned to five groups (n = 10/group): control, DEX, DEX + antibiotics, DEX + antibiotics + EN (DEX + EN), and DEX + antibiotics + EV (DEX + EV). Mice in the DEX + antibiotic groups received a 1-week broad-spectrum antibiotic cocktail [neomycin (1 g/L), ampicillin (1 g/L), vancomycin (0.5 g/L), metronidazole (0.5 g/L), imipenem (0.5 g/L), and ciprofloxacin (0.2 g/L)] in their drinking water before the administration of bacterial strains. EN and EV (1 × 109 CFU/mouse) were orally administered once daily for 4 weeks. All groups, except the control group, received intraperitoneal DEX injections for 2 weeks. Body weight was monitored every other day during DEX treatment. After 16 h of fasting, the quadriceps, gastrocnemius, soleus, and tibialis muscles were dissected, weighed (using an analytical balance with 0.01 mg sensitivity), and frozen in liquid nitrogen. The muscle-to-body weight ratio was used as the primary indicator of muscle atrophy.

Grip strength test and treadmill running exercise

The detailed mouse experimental design has been reported in our previous study [25]. Grip strength was measured using a Bioseb grip force meter (Pinellas Park, FL, USA), according to established protocols. Briefly, mice were placed on a grid and gently pulled by the tail in the opposite direction until their forelimbs were detached. The maximum force recorded during detachment was used as the grip strength score. Each mouse underwent three trials, with rest periods in between trials.

Endurance was assessed using a PanLab Touchscreen Treadmill (Harvard Apparatus, Holliston, MA, USA). Acclimatization involved a 15-min run at 10 m/min. The test started at 10 m/min and was gradually increased in increments of 1 m/min until exhaustion. A 20-V shock bar on the back of the treadmill deterred resting. The runtime and workload were recorded automatically. Exhaustion was defined as no movement for more than 10 s, and the total distance was calculated by multiplying the runtime and speed.

Histological analysis of skeletal muscle

Gastrocnemius muscles were immersed overnight in 4% formalin and subsequently embedded in paraffin. Tissue Sects. (5 µm) were stained with hematoxylin and eosin (H&E) using standard protocols. The muscle fiber cross-sectional area (CSA) was quantified using ImageJ software. For each muscle, five non-overlapping fields were randomly selected at 200 × magnification using a ZEISS microscope (Oberkochen, Germany). Within each field, the CSA of all muscle fibers was quantified using ImageJ software and expressed as a percentage of the mean of the control group.

ATP level measurement

ATP content in the tibialis muscle was assessed using a commercially available ATP content kit (DoGenBio, Seoul, Korea), following the manufacturer’s protocol. The protein contents of the samples were normalized to account for potential variability. The absorbance was measured at 570 nm using a microplate reader.

Muscle aconitase activity

Tibialis muscle samples were homogenized in cold radioimmunoprecipitation assay lysis buffer (500 μL/sample) using a homogenizer. Following homogenization, the samples were centrifuged at 13,000 rpm for 20 min. Aconitase activity in the supernatant was measured according to the manufacturer’s protocol (Abcam, Cambridge, UK). Absorbance was measured at 575 nm for 30 min at 37 °C using a spectrophotometer.

Tibialis muscle and femur mRNA analysis

Total RNA was isolated from the tibialis muscle and left femurs using the Hybrid-R RNA purification kit (GeneAll Biotechnology, Seoul, Korea). cDNA synthesis was performed using the Reverse Transcription Premix (ELPIS-Biotech, Daejeon, Korea). qRT-PCR was performed on a LightCycler 480 Real-Time PCR System (Roche, Basel, Switzerland) using PowerUpTM SYBRTM Green Master Mix (Thermo Fisher Scientific) and gene-specific primers. Mouse β-actin was used as the endogenous control. Relative gene expression was calculated using the 2−ΔΔCt method. The primer sequences are listed in Table 1.

Table 1 List of primers
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Micro-computed tomography

Distal right femurs were collected and fixed in 4% paraformaldehyde (PFA). Each fixed distal femur was scanned using a SkyScan 1172 (Bruker Micro CT Corp., Kontich, Belgium). An image was acquired under 142 µA of source current and 70 kV of source voltage. The scanned bones were analyzed using Nrecon and CTAn integrated software (Bruker Micro CT Corp.) to estimate bone mineral density (BMD), bone surface area/bone volume (BS/BV), trabecular thickness (Tb.Th), trabecular spacing (Tb.Sp), trabecular plate number (Tb.N), bone surface area/total volume (BS/TV), and bone volume/total volume (BV/TV).

Serum parameters of bone turnover

Blood samples were collected after an overnight fast. After centrifugation at 14,000 rpm for 30 min at 4 °C with the blood, 10 μL of serum was diluted 10 times and used. Serum osteocalcin (OCN) levels were measured using a Gla-type osteocalcin (Gla-OC) EIA Kit (TaKaRa Bio Inc., Japan). The absorbance was measured at 450 nm, and the analysis was performed as per the manufacturer’s instructions.

16s rRNA gene sequencing of fecal and cecal samples

Following animal sacrifice, the feces and cecum were immediately frozen at − 80 °C until DNA extraction. Bead-beating homogenization was used to disrupt the samples, followed by DNA isolation using the QIAamp® Fast DNA Stool Mini Kit (Qiagen, Hilden, Germany). The V3-V4 region of the 16S rRNA gene was amplified via PCR using the universal primers 341F and barcoded 806R. Gel electrophoresis confirmed the PCR product amplicons, which were then purified using AMPure XT beads and quantified using Qubit dsDNA reagent. Sequencing was performed on an Illumina MiSeq platform using a paired-end 2 × 300 bp reagent kit. Raw data analysis was performed using the QIIME2-DADA2 pipeline to generate amplicon sequence variants (ASVs). Taxonomic classification (phylum to genus) was performed using the QIIME 2 software. Alpha (Shannon, Faith’s PD, and observed ASVs) and beta (Unweighted Unifrac and Bray–Curtis) diversities were calculated using phyloseq and imported to R (v. 4.1.2) for analysis [30, 31]. Stacked bar plots depict taxon abundance at each classification level. ANCOM2.1 (significance threshold: ANCOM W > 0.7) was used for the differential abundance analysis of the genera.

Statistical analysis

R v4.1.2 (R Core Team) was used for all analyses. Differences between the control and Rg3 groups were evaluated using the Wilcoxon test. Efficacy data for EN and EV are presented as mean ± standard error of the mean (SEM). Group means were compared using one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test (α = 0.05). For each strain, a two-way ANOVA (α = 0.05) was used to assess the main effects (sample) and interactions (strain × sample) of muscle and bone health traits across all mice. This approach aimed to identify the influence of the genetic background on these traits. Spearman’s rank correlation (P-values adjusted via Benjamini-Hochberg) was used to explore the relationships between microbial taxa abundance and other variables. Correlations were visualized using the “heatmap” package [32]. The differential abundance of genera was analyzed using ANCOM 2.1 [33] (W > 0.7 considered significant). Beta diversity was assessed using the nonparametric permutational multivariate ANOVA test (McArdle and Anderson, 2001) in the “vegan” package [34].

Results

Host genotype modulates Rg3-mediated shifts in gut microbial diversity and composition

Expanding on our previously reported strain-specific effects of Rg3 on musculoskeletal health in six DEX-treated CC founder strains [25], we investigated its influence on gut microbiome composition. Fecal and cecal samples were analyzed using 16S rRNA gene amplicon sequencing to elucidate the potential interactions between the host genotype and the effects of Rg3 on the gut microbiota. Consistent with prior observations using CC founder strains, 16S rRNA gene amplicon sequencing of fecal and cecal samples revealed significant host genotype effects on the gut microbiota composition at the phylum level (Fig. 2A, Table S1 and S2). Notably, minimal differences were observed between the sample sites (feces vs. cecum) for each strain. The NOD strain displayed a lower abundance of Verrucomicrobiota, including Akkermansia muciniphila, than did the other strains (Fig. 2A). Interestingly, the NZO strain, which is predisposed to polygenic obesity, exhibited a markedly elevated abundance of Proteobacteria, including Escherichia-Shigella, specifically in fecal samples (Fig. 2A, Table S1). This suggests potential compartment-specific effects on the microbiota. Conversely, the wild-derived PWK strain harbored the highest abundance of Verrucomicrobiota in both feces and cecum (Fig. 2A). Rg3 treatment further modulated gut microbiota composition in a genotype-dependent manner. In the NZO strain, Rg3 treatment significantly reduced the abundance of Proteobacteria (Fig. 2A). Conversely, Rg3 treatment increased the abundance of Verrucomicrobiota in PWK (Fig. 2A). These findings suggest complex interactions between host genotype, Rg3 treatment, and the resulting gut microbial profile.

Fig. 2
figure 2

Rg3 treatment alters fecal microbiota composition in six Collaborative Cross (CC) founder strains. A Relative abundance of gut microbiota at the phylum level following Rg3 treatment in the six CC founder strains. B Strain-by-treatment interaction boxplots for three alpha diversity metrics (Shannon diversity, Faith’s PD, and observed ASV) following Rg3 treatment. C Comparison of alpha diversity metrics across the six founder strains with and without Rg3 treatment. Asterisks indicate statistically significant differences (*p < 0.05; **p < 0.01) as determined using Wilcoxon test. D Principal coordinate analysis (PCoA) plots depicting beta diversity of the gut microbiota in the six founder strains with and without Rg3 treatment. Symbols represent individual samples, and colors denote strain identity. E Proportion of differentially abundant taxa identified by Rg3 treatment within each strain. A/J (AJ); C57BL/6 J (B6); 129S1/SvImJ (129); NOD/ShiLtJ (NOD); NZO/HILtJ (NZO); and PWK/PhJ (PWK)

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Two-way ANOVA revealed significant effects of the strain and its interaction with the sample on alpha diversity indices (Shannon, Faith’s PD, and observed ASVs) in both feces and cecum (Fig. 2B and S1B, Table S3 and S4). The NOD strain displayed the highest alpha diversity, whereas the PWK strain displayed the lowest alpha diversity (Fig. S2A and 2B). Rg3 treatment significantly reduced alpha diversity in the cecum but not in the feces, with strain-specific responses observed (Fig. 2B, C, S1B, and S1C). Beta diversity analysis confirmed significant differences in the microbial community composition across strains following Rg3 treatment (Table 2, Fig. 3D, S1D, S2C-F). Notably, the NZO and PWK strains displayed distinct profiles, and Rg3 treatment induced significant shifts in these profiles compared with those of the control group (Table 2, Fig. 2D, S1D). Additionally, the proportion of differentially abundant taxa following Rg3 treatment varied with the strain (Fig. 2E and S1E). Collectively, these results suggest that the host genotype significantly influences the effect of Rg3 treatment on gut microbiota diversity and bacterial abundance profiles.

Table 2 Multivariate homogeneity of groups dispersions (betadisper) and permutational multivariate analysis of variance (ADONIS) analysis of the microbial beta diversity between strains or treatment groups (control vs. Rg3) in six CC founder strains. n = 44 (22 mice for control and 22 mice for Rg3-treated mice). A/J (AJ); C57BL/6 J (B6); 129S1/SvImJ (129); NOD/ShiLtJ (NOD); NZO/HILtJ (NZO); and PWK/PhJ (PWK)
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Fig. 3
figure 3

Abundance of EN and EV and their association with osteosarcopenic phenotypes in CC founder strains. A, B Association between osteosarcopenic traits and variance in Bray–Curtis distance of fecal (A) and cecal (B) microbiota composition in six CC founder strains. Significant associations (p-values) are included in the bar graph. C, D Differentially abundant genera between control and Rg3 treatment for fecal (C) and cecal (D) microbiota in six CC founder strains. Colors represent the strain and sample information. Asterisks indicate statistically significant differences (*p < 0.05; **p < 0.01) determined using ANCOM2.1 and Wilcoxon test. E, F Effect of Rg3 on the relative abundance of EN and EV from all mice (E) and individual strains (F). G, H Spearman correlation plots between grip strength and bacterial abundance of (G) EN in the feces and (H) EV in the cecum by sample treatment. A/J (AJ); C57BL/6 J (B6); 129S1/SvImJ (129); NOD/ShiLtJ (NOD); NZO/HILtJ (NZO); and PWK/PhJ (PWK)

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Gut microbiota diversity and Rg3-mediated genus-level changes correlate with muscle and bone phenotypes

Our previous study revealed that Rg3 exerted strain-dependent effects on muscle, bone, and immune functions [25]. In this study, we aimed to elucidate the potential contribution of gut microbiota to these Rg3-mediated phenotypes. Beta diversity analysis revealed that the fecal and cecal microbial community composition was significantly associated with muscle atrophy and bone loss-related phenotypes (Fig. 3A, B, and S3A). Notably, endurance capacity and bone mineral parameters showed the strongest correlations with alpha and beta diversity (Fig. S3B, S3C).

Next, we employed ANCOM to identify the differentially abundant bacterial genera in the feces and cecum following Rg3 treatment while controlling for strain effects. Rg3 treatment consistently decreased the abundance of Clostridia vadin BB60 and increased that of Lachnospiraceae bacterium A2 and Eubacterium in both compartments (Fig. 3C, D). Specific Eubacterium species, including EN and EV, exhibited significant changes in abundance across multiple strains after Rg3 treatment (Fig. 3E, F). For example, Rg3 administration increased EN in the feces of AJ and 129S1 strains, whereas it increased EV abundance in the cecum of 129S1, NOD, and PWK strains (Fig. 3F). These observations highlight the interplay between host genotype and Rg3 in shaping the abundance of specific bacterial genera.

Finally, we explored the correlation between Rg3-regulated genera and muscle atrophy/bone loss phenotypes. Among the identified genera (69 in feces and 54 in cecum), an abundance of Akkermansia, recognized for its muscle-protective properties [35], in both fecal and cecal samples, exhibited a positive correlation with grip strength, irrespective of Rg3 treatment (Fig. S4A, S4C, S4D). Conversely, Acetatifactor, a genus known to produce potentially deleterious lithocholic acid [36], was negatively correlated with grip strength in both compartments (Fig. S4B, S4C, S4D). This association was more pronounced after Rg3 treatment. Interestingly, EN and EV, whose abundance increased after Rg3 treatment, were significantly correlated with grip strength in the feces and cecum, respectively. Notably, Rg3 treatment modulated the strength of these correlations (Fig. 3G, H).

Strain-dependent amelioration of muscle atrophy by EN and EV through inhibition of protein degradation pathways

Building on the identified association between EN/EV abundance and muscle atrophy phenotypes, we investigated the effects of EN and EV on muscle function and morphology in a DEX-induced muscle atrophy model using B6 and 129S1 mice. We aimed to elucidate whether the observed increase in EN/EV abundance after Rg3 treatment in 129S1 mice translated to enhanced muscle health compared with that in the reference B6 strain. In vitro analysis confirmed the ability of Rg3 to promote the growth of both EN and EV at concentrations up to 25 μM (Fig. S5). In vivo, a targeted antibiotic regimen was employed to identify relevant bacterial modulators within the gut microbiota. DEX treatment and antibiotic administration resulted in a significant body weight reduction in both mouse strains. Notably, administration of neither EN nor EV led to body weight recovery (Fig. S6A). Interestingly, compared with the antibiotic pretreatment group, EN and EV selectively enhanced average myofiber CSA in the gastrocnemius muscle (Fig. 4A, B), grip strength (Fig. 4C), muscle mass (Fig. 4D–F) of 129S1 mice compared with those in B6 mice. This effect was more pronounced with EN treatment. Two-way ANOVA revealed a significant interaction between strain and groups for grip strength and muscle mass (Fig. S6B–G), suggesting a potential genetic influence on the efficacy of these bacterial interventions in ameliorating muscle atrophy.

Fig. 4
figure 4

Effect of EN and EV on muscle atrophy markers in DEX-treated B6 and 129S1 mice. A Representative hematoxylin and eosin (H&E) staining of the gastrocnemius muscle and (B) quantification of the average muscle fiber cross-sectional area. C Grip strength normalized to body weight (D–F) and muscle weight relative to body weight for gastrocnemius (D), tibialis (E), and soleus (F) muscles. G, H Effect of EN and EV on mRNA expression of protein degradation markers (Fbxo32 and Trim63) in DEX-treated B6 and 129S1 mice. Data are represented as mean ± SEM. Statistical significance was determined using one-way ANOVA followed by Tukey’s post hoc test. *p < 0.05, **p < 0.01, ns (not significant). C57BL/6 J (B6); 129S1/SvImJ (129S1)

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To explore the mechanisms underlying these strain-dependent phenotypic changes, we evaluated the expression of genes involved in protein degradation and myoblast differentiation. Similar to the observed muscle function and mass phenotypes, mRNA expression of the protein degradation markers Fbxo32, Mstn, and Trim63 was decreased upon EN or EV treatment to a greater extent in the 129S1 strain than that in the B6 strain (Figs. 4G, H, S7A). Conversely, the expression of myogenic markers (Myh2, Myod, Myog, Myf5, and Myf6) generally increased following EN or EV treatment in the B6 strain (Fig. S7B–F). These findings suggest that EN and EV may exert their effects through distinct mechanisms in the two strains, with a greater emphasis on the inhibition of protein degradation pathways in the 129S1 strain and modulation of myogenic pathways in the B6 strain.

EN and EV promote bone health through modulation of osteoblast differentiation in a strain-dependent manner

Building on the observed strain-dependent effects of EN and EV on muscle health, we investigated their effects on bone health in B6 and 129S1 mouse models with DEX-induced osteoporosis. This experiment aimed to determine whether the potential benefits of EN or EV are modulated by the genetic background of the host. Similar to muscle atrophy-related phenotypes, DEX and antibiotic treatment resulted in significant bone loss in the 129S1 strain, as evidenced by the decreased BMD, BV, serum osteocalcin, Tb.Th, and Tb.N. (Fig. 5A–F). Notably, treatment with EN or EV mitigated these DEX-induced bone loss effects in the 129S1 strain (Fig. 5A–F). Analysis of the combined data from both strains indicated that both EN and EV significantly increased BMD, BA, Tb.N, and serum osteocalcin (Fig. S6H–N). However, a two-way ANOVA revealed a significant effect of strain on all bone loss-related phenotypes highlighting the potential for genetic modulation of these responses.

Fig. 5
figure 5

Effect of EN and EV on bone microarchitecture markers in DEX-treated B6 and 129S1 mice. Microarchitecture was assessed using (A) micro-computed tomography in femur, B bone mineral density (BMD), C bone volume to total volume (BV/TV), D serum osteocalcin, E trabecular thickness (Tb.Th), F trabecular number (Tb.N), G and H mRNA expression of genes associated with osteoblast differentiation. Data are represented as the mean ± standard error of the mean (SEM). Statistical significance was determined using one-way ANOVA followed by Tukey’s post hoc test. Asterisks indicate significance levels: *p < 0.05, **p < 0.01, ***p < 0.001, ns (not significant). C57BL/6 J (B6); 129S1/SvImJ (129S1)

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To gain further insights into the underlying mechanisms, we evaluated the expression of key osteoblast differentiation markers, namely Alpl (alkaline phosphatase) and Tnfrsf11b (osteoprotegerin). The expression patterns of these markers generally mirrored the observed bone phenotype data (Fig. 5G, H), further supporting the potential influence of EN and EV on osteoblast differentiation. However, the data also suggest a differential effect of genetic background on the response of these markers to EN and EV administration (Fig. 5G, H). While EV increased the expression of Alpl and Tnfrsf11b in the 129S1 strain, its effects on these markers were less pronounced in the B6 strain. This further supports the notion that the efficacy of EN and EV in promoting bone health is influenced by the host's genetic background, potentially through their impact on osteoblast differentiation.

EN and EV enhance exercise performance in a strain-specific manner through modulation of mitochondrial biogenesis and gut microbiota

Prior observations indicated strain-specific influences of EN and EV on muscle atrophy and bone health-related traits. We investigated whether their effects on endurance performance and mitochondrial biogenesis in DEX-treated mice are influenced by the host genetic background. In contrast to the limited effects on grip strength and muscle mass in the B6 strain, both EN and EV treatments significantly increased the exercise performance during the treadmill running test in this strain (Fig. 6A). A significant strain effect was observed on the exercise performance (Fig. S6O and P), suggesting a possible genetic influence on endurance capacity. Next, we focused on mitochondrial biogenesis as a potential underlying mechanism for improved exercise performance. EV treatment significantly increased the mRNA expression of Ppargc1a (PGC-1α), a key transcriptional co-activator regulating mitochondrial biogenesis, in the tibialis muscle of the B6 strain (Fig. 6B). This upregulation was further reflected in the increased expression of downstream mitochondrial biogenesis markers, including Tfam, Tomm20, and Nrf1 (Figs. 6C, S7G, S7H). These findings suggest that EN and EV enhance endurance capacity in B6 mice by promoting mitochondrial biogenesis through PGC-1α signaling.

Fig. 6
figure 6

Effect of EN and EV on endurance-related markers and gut microbial diversity in DEX-treated mice. A Distance to exhaustion, B, C mRNA expression of (B) Ppargc1a, and (C) Tfam. D, E Relative abundance of bacterial taxa at the (D) phylum and (E) class levels is displayed in stack bar plot. F–H Alpha and beta diversity metrics are presented. F Observed generate amplicon sequence variants (ASVs), G Faith’s PD, and (H) PCoA plot depicting beta diversity (Bray–Curtis) are shown. I–K Abundance of specific bacterial genera is presented for (I) Romboutsia, J Rikenella, and (K) Lachnoclostridium. L–N Spearman correlation coefficients between the abundance of each bacteria genus and time to exhaustion are presented. Data are represented as the mean ± standard error of the mean (SEM). Statistical significance was determined by one-way ANOVA followed by Tukey’s post hoc test. Asterisks indicate significance levels: *p < 0.05, **p < 0.01, ***p < 0.001, ns (not significant). C57BL/6 J (B6); 129S1/SvImJ (129S1)

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Building on the observed improvements in exercise performance and mitochondrial biogenesis following EN and EV treatments in the B6 strain, we investigated their effects on the gut microbiome of DEX-treated mice using 16S rRNA gene amplicon sequencing of fecal samples. Given the established link between the gut microbiota and exercise performance in humans and genetically diverse mice [37,38,39], we hypothesized that EN and EV might exert their effects through gut microbial modulation. Compared with the control group, DEX and antibiotic pretreatment had a minimal impact on the gut microbiota composition in the 129S1 strain (phylum and class levels) (Fig. 6D and E). However, in the B6 strain, DEX and antibiotic pretreatment significantly increased the relative abundance of Gammaproteobacteria and decreased that of Clostridia compared with the control group. Notably, EN and EV treatments reversed these DEX-induced changes in the B6 strain (Fig. 6E). DEX and antibiotic pretreatment significantly reduced the alpha diversity indices (observed ASVs and Faith’s PD) in both strains (Fig. 6F and G). Interestingly, EV treatment significantly increased these alpha diversity indices in the B6 strain but not in the 129S1 strain (Fig. 6F and G). Additionally, EV treatment displayed a distinct beta diversity profile (Bray–Curtis distance, p = 0.059) compared to the DEX and antibiotic groups (Fig. 5H), indicating a shift in the overall gut microbial community composition in the B6 strain following EV administration.

We further explored the association between bacterial genera and exercise performance for each strain. Among the 41 genera identified in at least 10% of the samples, EN or EV treatment significantly increased the abundances of Romboutsia, Rikenella, and Lachnoclostridium specifically in the B6 strain, with minimal changes observed in 129S1 strain (Fig. 6I–K). Furthermore, these bacteria exhibited a significant correlation with endurance-related traits only in the B6 strain (Figs. 6L–N and S9). These findings suggest that EN and EV may enhance exercise performance in B6 mice, potentially through promoting the abundance of specific bacterial taxa, such as short-chain fatty acid (SCFA) producers.

Discussion

This study investigated the complex interplay between host genetics, gut microbiota, and the development of osteosarcopenia. Using a six-strain mouse model, we observed significant interactions between host genetics and gut microbiota, influencing disease phenotypes and responsiveness to Rg3, a phytochemical with potential therapeutic effects. Notably, Rg3 treatment modulated the abundance of specific gut microbes, particularly EN and EV, which were selected for further investigation. To evaluate the therapeutic potential of EN and EV, we conducted experiments involving oral administration to B6 and 129S1 mouse strains, representing Rg3-responsive and Rg3-unresponsive phenotypes, respectively. These strains were selected due to the observed differences in the effects of Rg3 on their gut microbiota composition. While both strains exhibited muscle atrophy and bone loss following treatment with DEX and antibiotics, oral administration of EN and EV only reversed osteosarcopenic phenotypes in the 129S1 strain. This recovery was evidenced by improvements in grip strength, muscle weight, muscle fiber width, and bone microstructure, suggesting that EN and EV may exert their effects through the modulation of osteoblast differentiation and protein degradation pathways in the 129S1 strain. Interestingly, in the B6 strain, EN and EV modulated mitochondrial biogenesis and microbial diversity but did not significantly improve osteosarcopenic phenotypes. This differential response highlights the complex interplay between host genetics and gut microbiota in determining treatment efficacy.

Consistent with previous reports, 16S rRNA gene amplicon sequencing confirmed substantial variation in the gut microbiota composition at the phylum level across the six CC founder strains [26, 27]. Notably, the abundance of Verrucomicrobiota differed significantly, with the wild-derived PWK strain showing the highest abundance and the NOD strain showing the lowest abundance. This observation aligns with our previous findings, in which the PWK strain exhibited superior grip strength, muscle mass, and exercise performance traits among the six strains [25]. In this study, the genus Akkermansia was identified as the sole member of the Verrucomicrobiota phylum in the mouse strains. Human studies have shown a positive association between Akkermansia abundance and bone health, muscle mass, and exercise performance [40, 41]. Additionally, oral administration of Akkermansia muciniphila has been shown to alleviate muscle atrophy in mouse models [35, 42]. Overall, these observations suggest that host genetics inherently influence the composition of the resident gut microbiota and that the high abundance of Akkermansia in the PWK strain may contribute to its improved osteosarcopenia phenotype.

The present study revealed a significant interaction between Rg3 treatment and host genotype in modulating gut microbiota composition. Notably, Rg3 treatment in the NZO strain, predisposed to obesity, led to a marked reduction in the abundance of Proteobacteria, a phylum associated with metabolic disorders and muscle atrophy due to the presence of taxa such as Escherichia-Shigella [42, 43]. Conversely, Rg3 treatment increased the abundance of Verrucomicrobiota in the PWK strain, likely because of its known ability to promote SCFA-producing bacteria such as Akkermansia [44]. These findings highlight the genotype-dependent effects of Rg3 on the gut microbiota composition, which in turn potentially influence its therapeutic efficacy. Beta diversity analysis corroborated these findings, demonstrating a distinct microbial community composition across strains following Rg3 treatment. These observations align with our previous data on the impact of Rg3 treatment on genetic diversity in osteosarcopenia [25] and underscore the intricate interplay between host genetics and treatment outcomes, reinforcing the importance of pharmacogenomics in developing personalized therapeutic strategies [45].

16S rRNA gene amplicon sequencing revealed significant alterations in the gut microbiota composition and diversity within the CC founder strains after Rg3 treatment, with these changes correlating with the osteosarcopenic phenotype. Emerging evidence suggests that alterations in the gut microbiota composition are associated with various disease states [25, 46,47,48]. Our findings contribute to this growing body of knowledge by shedding light on the intricate interplay between the gut microbiota composition and the modulation of muscle and bone phenotypes in osteosarcopenia. Among the identified microbial modulations, Akkermansia, a bacterial genus with documented therapeutic effects on obesity, osteoporosis, and muscle atrophy [35, 31, 49], exhibited a strong positive correlation with Rg3 treatment and improved osteosarcopenic markers in this study. Conversely, the abundance of Acetatifactor, a bacterium associated with diabetes, obesity, and inflammatory bowel disease [50,51,52,53,54], was negatively correlated with Rg3 treatment. Acetatifactor produces lithocholic acid, a secondary bile acid that has been implicated in various metabolic and inflammatory disorders [55, 56]. The observed decrease in Acetatifactor abundance following Rg3 administration suggests a potential suppressive effect on the production of deleterious bile acids, which could contribute to the observed improvements in osteosarcopenia. However, further investigation is needed to confirm this hypothesis and elucidate the specific mechanisms involved. Our differential abundance analysis using ANCOM identified EN and EV as the bacterial genera consistently modulated by Rg3 treatment across all CC founder strains, independent of the host genotype. Rg3 administration increased the abundance of EN and EV in the fecal and cecal samples, with strain-specific variations. We observed significant positive correlations between EN abundance in fecal samples and grip strength, whereas EV abundance in cecal samples was correlated with grip strength. In addition, the therapeutic potential of EN and EV was shown through the alteration of gene expression and muscle function in B6 and 129S1 mouse strains with DEX- and antibiotic-induced osteosarcopenia. Oral administration of EN and EV modulated the expression of genes associated with protein degradation, myoblast differentiation, and osteoblast differentiation in both strains. These changes subsequently led to the improvement of osteosarcopenic outcomes including muscle mass, grip strength, and bone density. Eubacterium is a beneficial bacterial genus known to produce butyrate, an SCFA that contributes to energy metabolism and immune function [57]. Previous studies have reported the enrichment of Eubacterium in individuals with regular exercise habits. Conversely, its abundance is diminished in elderly individuals with physical frailty and sarcopenia [58,59,60,61]. Furthermore, Eubacterium supplementation improves muscle mass, myofiber area, and exercise performance in animal models of muscle atrophy [62, 63]. Interestingly, the abundance of Eubacterium has also been linked to both obesity and diabetes, potentially through the activation of PGC-1α signaling [64]. Within the Eubacterium genus, EV has been specifically associated with muscle health. Depletion of EV has been observed in patients with muscle atrophy, whereas higher EV abundance has been correlated with greater muscle mass and improved patient survival rates [65,66,67]. Our findings demonstrated a positive correlation among EN and EV abundance, Rg3 treatment, and the subsequent suppression of osteosarcopenic traits. The results suggest that the suppressive effects of Rg3 on osteosarcopenia may be mediated, at least in part, by the modulation of the gut microbiota, with EN and EV playing key roles.

However, these changes by EN and EV were more pronounced in the 129S1 strain, which also exhibited significant improvements in grip strength, muscle weight, muscle fiber width, and bone microstructure. Interestingly, while the B6 strain showed greater improvement in exercise capacity following EN and EV treatment, this did not correlate with significant improvements in other osteosarcopenic phenotypes. This discrepancy between gene expression changes and phenotypic outcomes, particularly in the B6 strain, highlights the complex interplay between host genetics, gut microbiota, and therapeutic responses. Recent studies have demonstrated that host genetic background can significantly influence the composition and function of the gut microbiota, leading to variations in drug metabolism, nutrient absorption, and immune response [68,69,70,71]. For instance, B6 and 129S1 strains exhibit differences in their susceptibility to various diseases and their responses to therapeutic interventions due to variations in their genetic makeup [72,73,74]. These genetic differences may influence their response to EN and EV, contributing to the observed strain-specific effects. It suggests that while EN and EV may influence certain pathways, their ability to fully reverse osteosarcopenia may be limited by factors specific to the host’s genetic background. This underscores the need for further investigation into the mechanisms underlying these strain-specific responses, including a deeper exploration of the pathways involved and the potential influence of other factors, such as host immune response or microbiome composition.

Further analysis revealed that the observed improvement in exercise capacity in the B6 strain may be linked to the modulation of mitochondrial biogenesis. Oral administration of both EN and EV significantly increased PGC-1α mRNA expression, leading to enhanced mitochondrial development [75]. This effect was most pronounced in the B6 strain, mirroring the observed recovery of exercise capacity and gut microbial diversity without the improvement of muscle-related phenotypes. PGC-1α plays a critical role in various metabolic processes, including mitochondrial biogenesis and oxidative metabolism in skeletal muscle [76], contributing to improved mobility and potentially offering a preventive effect against sarcopenia [77, 78]. While the precise relationship between PGC-1α and gut microbiota remains unclear, our findings demonstrate a clear association. Decreased PGC-1α expression has been observed in the intestinal epithelium of patients with inflammatory bowel disease exhibiting gut microbiota abnormalities [79]. Similarly, germ-free and fecal microbiota transplant piglets exhibited downregulated PGC-1α expression in their muscles compared with normal piglets [80]. This suggests that alterations in gut microbiota composition can influence PGC-1α expression and mitochondrial function in various tissues, including skeletal muscle. Furthermore, antibiotic treatment has been shown to decrease exercise capacity in both humans and DO mice [81]. In this study, antibiotic-induced dysbiosis specifically reduced exercise capacity and PGC-1α expression in the B6 strain. Conversely, EN and EV treatment restored intestinal microbiota in the B6 strain, leading to increased exercise capacity and PGC-1α expression. This suggests that EN and EV may promote mitochondrial biogenesis and enhance exercise capacity, at least in part, by modulating the gut microbiota and restoring microbial diversity. However, further research is needed to elucidate the precise mechanisms underlying these interactions and determine whether similar effects are observed in other genetic backgrounds. Our investigation demonstrates that oral administration of EN and EV alleviates artificially induced osteosarcopenic phenotypes, potentially through upregulation of PGC-1α expression and mitochondrial biogenesis, a mechanism consistent with findings from previous research [82]. However, this effect was primarily observed in the B6 strain, while the 129S1 strain exhibited improvements in muscle and bone health through the modulation of protein degradation and osteoblast differentiation. This further highlights the strain-specific nature of the therapeutic responses to EN and EV.

Our investigation revealed intriguing strain-dependent responses to EN and EV administration in B6 and 129S1 mice, highlighting the complex interplay between host genetics, gut microbiota, and therapeutic responses in osteosarcopenia. While these bacterial strains improved osteosarcopenia-related traits in 129S1 mice, they primarily impacted exercise performance and gut microbiota composition in B6 mice, potentially through the modulation of mitochondrial biogenesis and microbial diversity. This differential response underscores the need for personalized treatment strategies and further research to elucidate the underlying mechanisms. Future studies should investigate the ADME profiles of EN and EV metabolites, examine genetic polymorphisms in relevant pathways, and employ deep metagenomic analysis to better understand the strain-specific effects [83]. Additionally, investigating the host immune response to EN and EV administration in both strains could reveal differences in immune signaling pathways or inflammatory responses that may contribute to the observed strain-specific effects. While this study provides valuable insights, it is important to acknowledge the limitations, such as the use of 16S rRNA sequencing and a mouse model. Future studies should focus on validating these findings in human clinical trials and exploring the specific mechanisms by which EN and EV exert their effects in different genetic backgrounds, including their interactions with host cells and other microbial communities. Overall, this study contributes to our understanding of the complex interplay between host genetics, gut microbiota, and therapeutic responses in osteosarcopenia, paving the way for the development of personalized treatment strategies that consider individual variability in both genetic makeup and gut microbial composition.

Data availability

All sequencing files have been deposited in the NCBI short-read sequence archive (https://www.ncbi.nlm.nih.gov/sra) under BioProject number PRJNA1100731.

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Acknowledgements

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Funding

This research was supported by the Korea Institute of Science and Technology intramural research grants, and a National Research Foundation of Korea (NRF) grant funded by the Korean government (No. NRF-2022R1A6A3A01085975).

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Author notes

  1. Soyeon Hong and Bao Ngoc Nguyen contributed equally to this work.

Authors and Affiliations

  1. Smart Farm Research Center, Korea Institute of Science and Technology (KIST), Gangneung Institute of Natural Products, Gangneung, Gangwon-Do, 25451, Republic of Korea

    Soyeon Hong & GyHye Yoo

  2. College of Dentistry, Gangneung Wonju National University, Gangneung, Gangwon-Do, Republic of Korea

    Bao Ngoc Nguyen

  3. Center for Natural Product Efficacy Optimization, Korea Institute of Science and Technology (KIST), Gangneung Institute of Natural Products, 679 Saimdang-Ro, Gangneung, Gangwon-Do, 210-340, Republic of Korea

    Bao Ngoc Nguyen, Huitae Min, Hye-Young Youn, Sowoon Choi, Young Tae Park & Myungsuk Kim

  4. Center for Natural Product Systems Biology, Korea Institute of Science and Technology (KIST) Gangneung Institute, Gangneung, 25451, Republic of Korea

    Emmanuel Hitayezu, Kwang-Hyun Cha & Choong-Gu Lee

  5. Department of Natural Product Applied Science, University of Science and Technology (UST), Daejeon, 34113, Republic of Korea

    Kwang-Hyun Cha, Young Tae Park, Choong-Gu Lee, GyHye Yoo & Myungsuk Kim

  6. Department of Convergence Medicine, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-Do, Republic of Korea

    Kwang-Hyun Cha, Choong-Gu Lee & Myungsuk Kim

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Contributions

Concept and design: Choong-Gu Lee, GyHye Yoo, Myungsuk Kim; Supervision: Kwang-Hyun Cha, Young Tae Park, GyHye Yoo, Myungsuk Kim; Resource and material: Soyeon Hong, Bao Ngoc Nguyen, Huitae Min; Data collection and processing: Soyeon Hong, Bao Ngoc Nguyen, Huitae Min, Hye-Young Youn; Analysis/interpretation: Soyeon Hong, Bao Ngoc Nguyen, Myungsuk Kim; Literature search: Soyeon Hong, Bao Ngoc Nguyen, Hye-Young Youn, Myungsuk Kim; Writing: Soyeon Hong, Bao Ngoc Nguyen, Myungsuk Kim. All the authors discussed the results and reviewed the manuscript.

Corresponding authors

Correspondence to GyHye Yoo or Myungsuk Kim.

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All animal experiments were approved by the International Animal Care and Use Committee of the Korea Institute of Science and Technology (Approval no.: KIST-2021–091002; Date of approval: December 30, 2021).

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Hong, S., Nguyen, B.N., Min, H. et al. Host-specific effects of Eubacterium species on Rg3-mediated modulation of osteosarcopenia in a genetically diverse mouse population. Microbiome 12, 251 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40168-024-01971-1

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