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. 2023 Oct;14(5):2168-2183.
doi: 10.1002/jcsm.13294. Epub 2023 Jul 13.

Faecal microbiota transplantation from young rats attenuates age-related sarcopenia revealed by multiomics analysis

Xiaoxing Mo  1 , Lihui Shen  1 , Ruijie Cheng  1 , Pei Wang  1 , Lin Wen  1 , Yunhong Sun  1 , Qiang Wang  1 , Juan Chen  1 , Shan Lin  1 , Yuxiao Liao  1 , Wei Yang  1 , Hong Yan  2 , Liegang Liu  1
Affiliations

Faecal microbiota transplantation from young rats attenuates age-related sarcopenia revealed by multiomics analysis

Xiaoxing Mo et al. J Cachexia Sarcopenia Muscle. 2023 Oct.

Abstract

Background: Gut microbiota plays a key role in the development of sarcopenia via the 'gut-muscle' axis, and probiotics-based therapy might be a strategy for sarcopenia. Fecal microbiota transplantation from young donors (yFMT) has attracted much attention because of its probiotic function. However, whether or not yFMT is effective for sarcopenia in old recipients is largely unknown. Thus, we aimed to investigate the effect and mechanism of yFMT on age-related sarcopenia.

Methods: The fecal microbiota of either young (12 weeks) or old (88 weeks) donor rats was transplanted into aged recipient rats for 8 weeks. Then, muscle mass, muscle strength, muscle function, muscle atrophy, and muscle regeneration capacity were measured. Analysis of fecal 16 s rRNA, serum non-targeted metabolomic, gut barrier integrity, and muscle transcriptome was conducted to elucidate the interaction between gut microbiota and skeletal muscles.

Results: As evaluated by magnetic resonance imaging examination, grip strength test (P < 0.01), rotarod test (P < 0.05), and exhaustive running test (P < 0.05), we found that yFMT mitigated muscle mass loss, muscle strength weakness, and muscle function impairment in aged rats. yFMT also countered age-related atrophy and poor regeneration capacity in fast- and slow-switch muscles, which were manifested by the decrease in slow-switch myofibres (both P < 0.01) and muscle interstitial fibrosis (both P < 0.05) and the increase in the cross-section area of myofibres (both P < 0.001), fast-switch myofibres (both P < 0.01), and muscle satellite cells (both P < 0.001). In addition, yFMT ameliorated age-related dysbiosis of gut microbiota and metabolites by promoting the production of beneficial bacteria and metabolites-Akkermansia, Lactococcus, Lactobacillus, γ-glutamyltyrosine, 3R-hydroxy-butanoic acid, and methoxyacetic acid and inhibiting the production of deleterious bacteria and metabolites-Family_XIII_AD3011_group, Collinsella, indoxyl sulfate, indole-3-carboxilic acid-O-sulphate, and trimethylamine N-oxide. Also, yFMT prevented age-related destruction of gut barrier integrity by increasing the density of goblet cells (P < 0.0001) and the expression levels of mucin-2 (P < 0.0001) and tight junctional proteins (all P < 0.05). Meanwhile, yFMT attenuated age-related impairment of mitochondrial biogenesis and function in fast- and slow-switch muscles. Correlation analysis revealed that yFMT-induced alterations of gut microbiota and metabolites might be closely related to mitochondria-related genes and sarcopenia-related phenotypes.

Conclusions: yFMT could reshape the dysbiosis of gut microbiota and metabolites, maintain gut barrier integrity, and improve muscle mitochondrial dysfunction, eventually alleviating sarcopenia in aged rats. yFMT might be a new therapeutic strategy for age-related sarcopenia.

Keywords: Fecal microbiota transplantation; Gut microbiota; Metabolites; Mitochondrial dysfunction; Muscle; Sarcopenia.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
yFMT attenuates age‐related muscle mass loss, muscle strength weakness, and poor muscle function in aged rats. (A) Representative magnetic resonance imaging (MRI) scans of gastrocnemius (GC), tibialis anterior (TA), extensor digitorum longus (EDL), and soleus (SOL) muscles. The areas outlined in red, green, purple, and blue represented GC, TA, EDL, and SOL muscles, respectively. (B) Grip strength (n = 8). (C) Mean time in the rotarod test (n = 8). (D) Mean speed in the rotarod test (n = 8). (E) Distance to exhaustion in the exhaustive running test (n = 8). (F) Time to exhaustion in the exhaustive running test (n = 8). Data were analysed by t‐test (n = 8) or Mann–Whitney U‐test (n = 4). Young versus Aged, *P < 0.05, **P < 0.01, and ***P < 0.001; Aged yFMT versus Aged oFMT, # P < 0.05, ## P < 0.01, and ### P < 0.001.
Figure 2
Figure 2
yFMT increases the CSA of myofibres in the muscles of aged rats. (A) H&E staining of GC muscle (scale bar, 50 μm). (B) H&E staining of SOL muscle (scale bar, 50 μm). (C) The cross‐sectional area (CSA) of myofibres in GC muscle (n = 4). (D) The CSA of myofibres in SOL muscle (n = 4). Data were analysed by Mann–Whitney U‐test. Young versus Aged, ***P < 0.001; Aged yFMT versus Aged oFMT, ### P < 0.001.
Figure 3
Figure 3
The effects of yFMT on the myofibre types of muscles in aged rats. (A) Immunohistochemical staining of fast‐ and slow‐switch myofibres in GC muscle (scale bar, 50 μm). (B) Immunohistochemical staining of fast‐ and slow‐switch myofibres in SOL muscle (scale bar, 50 μm). (C) Quantification of fast‐ and slow‐switch myofibres in GC muscle (n = 4). (D) Quantification of fast‐ and slow‐switch myofibres in SOL muscle (n = 4). Data were analysed by Mann–Whitney U‐test. Young versus Aged, ***P < 0.001 and****P < 0.0001; Aged yFMT versus Aged oFMT, ## P < 0.01 and ### P < 0.001.
Figure 4
Figure 4
yFMT modulates gut dysbiosis in aged rats. (A) Principal component analysis (PCA) of gut microbiota using unweighted UniFrac method (n = 8). (B) Bar plot of gut microbiota at the phylum level (n = 8). (C) Bar plot of gut microbiota at the genus level (n = 8). (D) Significant changes in gut microbiota at the genus level (n = 8). Data were analysed by t‐test. Young versus Aged, *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001; Aged yFMT versus Aged oFMT, # P < 0.05, ## P < 0.01, ### P < 0.001, and #### P < 0.0001.
Figure 5
Figure 5
yFMT shapes serum metabolites in aged rats. (A) Partial least squares discriminant analysis (PLS‐DA) analysis of serum metabolite profiles (n = 8). (B) Venn diagram showing different serum metabolites among groups (n = 8). (C) Heatmap of significantly different serum metabolites that could be restored by FMT treatment (n = 8). (D) Violin plots representing different serum metabolites regulated by gut microbiota (n = 8). Data were analysed by t‐test. Young versus Aged, *P < 0.05, **P < 0.01, and ***P < 0.001; Aged yFMT versus Aged oFMT, # P < 0.05, ## P < 0.01, and ### P < 0.001. ns, not significant.
Figure 6
Figure 6
yFMT restores age‐related gut mucosal barrier damage. (A) Alcian blue staining of the colon (scale bar, 50 μm). (B) Representative immunofluorescence images of mucin‐2 (Muc‐2) in the colon (scale bar, 50 μm). (C) The number of goblet cells in the colon (n = 4). (D) Quantification of Muc‐2 fluorescence intensity (n = 4). Data were analysed by Mann–Whitney U‐test. Young versus Aged, ****P < 0.0001; Aged yFMT versus Aged oFMT, #### P < 0.0001.
Figure 7
Figure 7
yFMT recovers age‐related gut mechanical barrier impairment. (A) Representative immunofluorescence images of zonula occluden‐1 (Zo‐1) in the colon (scale bar, 50 μm). (B) Quantification of Zo‐1 fluorescence intensity (n = 4). (C) Western blot analysis of Zo‐1, occluding, and claudin‐1 in the colon. (D) Quantification of Zo‐1, occluding, and claudin‐1 protein levels (n = 3). (E) Serum levels of LPS. Data were analysed by Mann–Whitney U‐test. Young versus Aged, *P < 0.05 and ****P < 0.0001; Aged yFMT versus Aged oFMT, # P < 0.05 and #### P < 0.0001.
Figure 8
Figure 8
yFMT affects the expression levels of mitochondrial‐related genes in aged muscles. (A) Heatmap of mitochondrial‐related genes in GC muscle (n = 8). (B) Heatmap of mitochondrial‐related genes in SOL muscle (n = 8). (C) JC‐1 of mitochondria in GC and SOL muscles (n = 4). (D) Western blot analysis of peroxisome proliferator‐activated receptor‐γ coactivator (PGC)‐1α and TFAM in GC and SOL muscles. (E) Quantification of PGC‐1α and TFAM protein levels (n = 3). Data were analysed by t‐test (n = 8) or Mann–Whitney U‐test (n = 4). Aged yFMT versus Aged oFMT, # P < 0.05 and ## P < 0.01.
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