TIMI 2158 No.

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Review

Gut microbiota–bile acid–skeletal muscle axis

Laura Mancin , 1,2,* Gary D. Wu, 3 and Antonio Paoli 1,2,4

The gut microbiota represents a ‘metabolic organ’ that can regulate human Highlights
metabolism. Intact gut microbiota contributes to host homeostasis, whereas com- The microbiota plays a central role in the
positional perturbations, termed dysbiosis, are associated with a wide range of host’s health and development. A
dysbiotic microbiota, which is defined
diseases. Recent evidence demonstrates that dysbiosis, and the accompanying
as low microbial diversity and an unsta-
loss of microbiota-derived metabolites, results in a substantial alteration of skele- ble composition over time, is associated
tal muscle metabolism. As an example, bile acids, produced in the liver and further with an alteration of skeletal muscle me-
metabolized by intestinal microbiota, are of considerable interest since they reg- tabolism and functionality.

ulate several host metabolic pathways by activating nuclear receptors, including

Bile acids, which are synthesized in the
the farnesoid X receptor (FXR). Indeed, alteration of gut microbiota may lead to liver as primary bile acid, and trans-
skeletal muscle atrophy via a bile acid–FXR pathway. This Review aims to suggest formed by the intestinal microbiota into
a new pathway that connects different mechanisms, involving the gut–muscle a variety of metabolically active metabo-
lites, act as ligands for the farnesoid X
axis, that are often seen as unrelated, and, starting from preclinical studies, we hy- receptor (FXR) and influence skeletal
pothesize new strategies aimed at optimizing skeletal muscle functionality. muscle physiology.

Manipulation of the gut microbiota by

probiotics may represent an emerging
The impact of intestinal microbiota on bile acid and human metabolism and promising strategy to prevent and/
or treat a wide range of conditions such
The gut microbiota, with a biomass of ~1.5–2.0 kg, comprises over 100 trillion bacterial cells and
as age-associated sarcopenia.
3 million genes harboring the human gastrointestinal tract [1]. Thanks to the new molecular
techniques and advanced bioinformatics platforms [2] (Box 1), the impact of the gut microbiota Targeting gut microbiota and FXR signal-
on human metabolic and immunological health is being increasingly recognized, suggesting ing by specific probiotics and diet com-
ponents (i.e., protein and amino acids)
an intimate connection between gut microbiota, host metabolism, immunity, and the central may improve host microbiota function
nervous system [3]. The gut microbiota, is by now recognized as a ‘central metabolic and skeletal muscle phenotype in elderly
organ’ (see Glossary) because of its ability to produce bioactive compounds influencing people.
human health in a series of host–microbe metabolic axes [4]. These microbial metabolites – such
Monitoring and managing the intesti-
as serotonin, histamine, γ-aminobutyric acid (GABA), branched-chain amino acids (BCAAs), and nal microbiota may represent a next-
short-chain fatty acids (SCFAs) – enter the systemic circulation and signal to distant organs, generation medicine able to tackle or
thereby influencing host physiology [5] and pathophysiology [6]. More recently, a novel class of reduce the litany of chronic diseases
and a pivotal component of personal-
bioactive compounds, the microbiota-derived bile acids, have emerged as important cell-signaling
ized medicine.
molecules involved in host metabolism [7].

Notably, the microbiota residing in the distal small intestine and colon can change the structure, 1
Department of Biomedical Sciences,
bioavailability, and bioactivities of bile acids, thus consequently influencing the bile acid metabolism University of Padua, Padua, Italy
2
and its impact on host metabolic homeostasis [7]. Human Inspired Technology Research
Center HIT, University of Padua,
Padua, Italy
3
In this Review we discuss the potential role of microbially derived bile acids in influencing skeletal Division of Gastroenterology, Perelman
muscle metabolism via FXR signaling. We also explore different causal mechanisms through School of Medicine, University of
Pennsylvania, Philadelphia, PA 19104,
which the gut microbiota potentially regulates bile acids and skeletal muscle functionality. We USA
4
believe that knowledge of the gut–muscle axis requires an understanding of the underlying Research Center for High Performance
interactions between the gut microbiota, bile acids, and skeletal muscle mass as well as the Sport, UCAM, Catholic University of
Murcia, Murcia, Spain
inter-relationships among them. Moreover, understanding novel insights that control the complex
network regulating muscle mass may provide potential therapeutic strategies for the prevention and
treatment of muscle wasting and weakness in many clinical conditions such as age-associated *Correspondence:
sarcopenia. laura.mancin@phd.unipd.it (L. Mancin).

Trends in Microbiology, Month 2022, Vol. xx, No. xx https://doi.org/10.1016/j.tim.2022.10.003 1

© 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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Box 1. High-throughput sequencing technologies for gut microbiome research

Glossary
Computational biology coupled with microbiome bioinformatics have increased our understanding of the complex net- Anabolic resistance: blunted
work between polymicrobial communities, their internal interactions, and their interactions with human health and disease stimulation of muscle protein synthesis
[73]. (MPS) to common anabolic stimuli in
skeletal muscle (i.e., exercise and protein
While, initially, gut microbiome research has focused on the ‘composition’ of the gut ecosystem ‘who are they?’, to date, feeding).
the researchers are moving towards the determination of the ‘functionality’ of gut microbes, that is, ‘what are they really Central metabolic organ: the gut
doing?’, in order to understand the functional potential of microbial communities and how these processes may affect microbiota can be defined as a central
the host’s physiology. metabolic organ because of its capacity,
on interacting with the host, to produce
Indeed, the standard high-throughput approach, such as 16S rRNA, which is performed by the isolation of specific pieces several metabolites (microbiota-derived
of DNA from a sample, PCR amplification of single marker genes, and further sequencing of these amplicons, does not metabolites) that are implicated in both
target the whole genomic content of a sample and it does not translate the taxonomic characterization into functionality. health and disease.
Moreover, since many species of microbes are similar along the full length of the 16S rRNA gene, it is impossible for the Dysbiosis: any change in the
16S rRNA method to distinguish all bacteria at strain level. composition and function of resident
commensal bacteria. The imbalance in
Differently, methods such as the ‘untargeted’ whole-genome shotgun (WGS) sequencing allow the identification of all the gut microbiota community is usually
(‘meta-’) microbial gene content present in a sample, the identification of DNA viruses, and an in-depth taxonomic associated with disease.
resolution at strain level. In addition, shotgun metagenomics provides additional information about the functionality of Farnesoid X receptor (FXR): a nuclear
the microbial community by comparing the identified genes and predicted protein to specific databases such as the Kyoto receptor activated by bile acids. It
Encyclopedia of Genes and Genomes (KEGG [74]). Thus, shotgun metagenomics has the potential to be the foremost and regulates bile acid synthesis, conjugation,
preferred method to be used in clinical research settings [75]. and transport, as well as various aspects
of lipid and glucose metabolism.
Fibroblast growth factors (FGFs): a
Gut microbiota and bile acid-activated receptors family of cell signaling proteins that
generally act as systemic circulating
Bile acids, the end product of cholesterol metabolism, are amphipathic molecules that function as
molecules of extracellular origin that
detergents, thus facilitating the digestion and absorption of dietary lipids and fat-soluble vitamins activate specific cell-surface receptors.
[8]. Moreover, in addition to their role in lipid absorption, they function as endocrine modulators Inflammaging: the long-term result of
which interact with different host nuclear receptors [8]. Indeed, bile acid signaling activity is the chronic physiological stimulation of
the innate immune system which
primarily driven by its ability to activate different nuclear receptors, such as FXR, pregnane C
become damaging during ageing.
receptor (PXR), vitamin D receptor (VDR), and a G protein-coupled receptor (TGR5), which regulate Muscle protein breakdown (MPB): a
both bile acid synthesis and several host metabolic processes, including glucose homeostasis, metabolic process of muscle
energy expenditure, and liver metabolism [9]. remodeling, adaptation to training, and
increasing muscle mass. Protein
balance is defined as the difference
Among these nuclear receptors, one of particular interest is FXR, which is expressed mainly in the liver between MPS and MPB.
and the distal ileum. Bile-acid-dependent activation of FXR induces the expression of fibroblast Muscle protein synthesis (MPS): a
growth factor (FGF) 15 (FGF15) in mice, and its ortholog FGF19, in humans (generally referred to metabolic process in which amino acids
are incorporated into skeletal muscle
FGF15/19) [10]. FGF15/19, once released into the enterohepatic circulation, reaches the liver proteins. It is the process of new muscle
where it binds to FGF receptor 4/β-klotho (FGFR4/KLB) complex to regulate bile acid synthesis. protein synthesis.
Myokines: a panel of cytokines and
In the liver, FGF15 suppresses the expression of cholesterol 7α-hydroxylase (CYP7A1), the proteins secreted by skeletal muscle.
Myokines regulate muscle metabolism
rate-limiting enzyme, and it reduces bile acid synthesis. Interestingly, since the gut microbiota (autocrine function) as well as distant
can change the bile acid structure and pool composition, it indirectly regulates the influence of organs (paracrine/endocrine).
bile acids on the expression of FXR-FGF15 and CYP7A1. Thus, in this way, bile acid synthesis Probiotic: live microorganisms which,
when administered in adequate
is under gut microbiota–liver feedback control [10] (Figure 1).
amounts, confer a health benefit on the
host.
To date, studies on gut microbiota, bile acids, and FXR pathways had focused primarily on their role in Proteostasis: the process that
several tissues, such as liver, intestine, and adipose tissue [9,11–13], while, only a few studies regulates protein within the cell. It is a
complex process that functions to
investigated the relationship with skeletal muscle metabolism [14,15]. However, recently, and
maintain all the proteins within and
concurrently with the growing interest in the gut–muscle axis [16–19], research began to focus on around the cell (proteome).
the intestinal crosstalk between gut microbiota, bile acids, and skeletal muscle mass. Indeed, Sarcopenia: a condition characterized
preclinical studies demonstrated that bile acids, FXR signaling, and FGF15/19 expression may by a progressive loss of skeletal muscle
mass and function. It is correlated with
influence host skeletal muscle metabolism by promoting skeletal muscle growth while blunting
physical disability, poor quality of life, and
skeletal muscle wasting [14,20,21]. These pioneering studies [14,20,21] suggest that gut death.
microbiota–bile acids–FXR-FGF15/19 signaling might represent a key component involved in

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the gut–skeletal muscle axis; however, human and murine bile acids have different signaling
properties that may hamper a proper translational conclusion [8].

Bile acid and gut microbial metabolism

The principal human bile acids are the primary bile acids, chenodeoxycholic acid (CDCA), cholic
acid (CA), deoxycholic acid (DCA), and lithocholic acid (LCA). Humans generate CDCA and CA,
while mice produce CA and muricholic acids (MCAs), predominantly beta-MCA (βMCA). Primary
bile acids are produced in the liver, subsequently conjugated to glycine (predominantly in
humans) or taurine (rodents), and then secreted into the small intestine. In the intestine, primary
conjugated bile acids are deconjugated by microorganisms harboring bile salt hydrolase (BSH)
activity and then metabolized into secondary bile acids, by the distal intestinal microbiota.
These chemical modifications include first deconjugation (the removal of amino acid residues)
and further metabolization by removal of hydroxyl groups (dihydroxylation), oxidation

(A)

(B)

Trends in Microbiology

Figure 1. (A) Metabolic conversion of primary conjugated bile acids into secondary deconjugated bile acids. Representation of metabolic conversion of 24 carbon bile
acids and secondary bile acids by gut microbiota. The table (pink) summarizes representative bile acid species and related metabolic conversion. The orientation of the hydroxyls is also
indicated. (B) Enteropathic circulation and regulation of bile acid synthesis by repression of cholesterol 7α-hydroxylase (CYP7A1). Fibroblast growth factor 19 (FGF19) is expressed in
the small intestine under the transcriptional control of the bile acid-activated farnesoid X receptor (FXR) pathway. Release of intestinal FGF15/19 into enteropathic circulation followed by
binding of FGF15/19 to hepatic FGFR4/β-klotho leads to the repression of hepatic CYP7A1 that inhibits bile acid synthesis. FGF19 also binds the gallbladder receptors FGFR3/β-
klotho and induces the dilation of the gallbladder while filling with bile. More details can be found in the text. Abbreviations: KLB, β-klotho; RXR, retinoid X receptor.

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(dehydrogenation), or epimerization [7]. This microbial deconjugation of bile acids prevents the
active re-uptake from the small intestine via the apical sodium dependent bile acid transporter
(ASBT). The intestinal absorption of bile acids is approximately 95%, which indicates that about
5% of the bile acid pool (~0.3–0.6 g of bile acid per day) escapes absorption and may undergo
several modifications by the distal gut microbiota [7].

This resulting fraction of bile acid, which eludes the enterohepatic circulation, can be excreted via
feces or reach the systemic circulation. In the intestine, the metabolism of primary bile acids is
largely controlled by the intestinal microbiota [8]; indeed, by modulating bile acid metabolism,
the microbial community plays an essential role in modulating systemic host metabolism [8]. Systemic
circulation allows the microbially metabolized bile acid to act as endocrine molecules, activating
bile-acid-mediated pathways and thus regulating host metabolic processes, including lipid and
glucose metabolism, energy expenditure, and systemic inflammation [9,12].

The detailed classification of the common bile acid species and the related microbial metabolism
are beyond the aim of this Review but are deeply discussed in two excellent reviews by
Wahlström et al. and de Aguiar Vallim et al. [7,8].

Microbial regulation of bile acid metabolism and associated FXR signaling

Bile acids are composed of four steroid rings forming a hydrocarbon lattice with a convex
hydrophobic face, a concave hydrophobic face containing hydroxylic groups, and a short five-
carbon acid side chain that is subsequently amidated with taurine and glycine. The rank order from
hydrophobic to hydrophilic property is LCA > DCA > CDCA > CA > MCA; these differences in bile
acid structure provide different effects on the specific activation of bile acid nuclear receptors [22].
Two different pathways are involved in the synthesis of bile acids: the classical or ‘neutral’ pathway,
which accounts for at least 75% of bile acid production, and generates both CDCA and CA, and
the alternative pathways or ‘acidic’ pathway, which predominantly generates CDCA. The classical
pathway is regulated by the cholesterol 7α-hydroxylase (CYP7A1), a cytochrome P450 enzyme
that converts cholesterol into 7α hydroxycholesterol. CYP7A1 represents the rate-limiting enzyme
which determines the amount of bile acids produced. The alternative pathway involves several reac-
tion steps but essentially depends upon the oxidation of the cholesterol side chain 27 by sterol-27-
hydroxylase (CYP27A1) and the consequent oxysterol 7α-hydroxylase (CYP7B) enzyme [22].

Interestingly, the presence of gut microbiota regulates bile acid synthesis by alleviating FXR inhi-
bition in the small intestine and consequently by regulating the expression of hepatic enzymes
(CYP7A1, CYP7B1, and CYP27A1) through an FGF15-dependent mechanism [10].

Before excretion from hepatocytes into the gallbladder, and further passage to the duodenum,
bile acids are amidated (‘conjugated’) with amino acids glycine and taurine. Then, the presence
of dietary fat in the duodenum causes secretion of cholecystokinin CCK from the intestinal
mucosa – which promotes contraction of the gallbladder and relaxation of the sphincter of
Oddi, thus allowing the passage of bile into the duodenum, where ~95% of biliary secreted bile
acids are actively reabsorbed. In the distal intestinal tract, primary conjugated bile acids can be
deconjugated and 7α-dehydroxylated by the intestinal microbiota to form secondary bile acids,
thus increasing the heterogeneity of the bile acid pool. Given that the conversion of primary bile
acids into secondary bile acids relies on the presence of a microbial community, germ-free (GF)
animals develop bile acid dysmetabolism [10]. As a matter of fact, in GF mice or antibiotic-
treated mice, the absence of gut microbiota leads to a bile acid pool consisting of mainly primary
conjugated bile acids, such as TβMCA [10]. Sayin and colleagues [10], demonstrated that GF
mice, compared to conventionally raised (CONV-R) mice, have reduced levels of bile acids in the

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cecum and colon, compensated by the increased bile acid level in the gallbladder and small intestine,
leading to an overall increase in the bile acid pool. By contrast, in the presence of gut microbiota, bile
acid levels were reduced in the gallbladder and small intestine, and the total bile acid pool was
reduced by 71% ± 2% [10].

Bile acids were also more chemically diverse in CONV-R mice (higher prevalence of secondary bile
acid) especially in the cecum, colon, and feces, thus indicating that the primary microbial effects of
bile acid composition were in compartments with the highest number of bacteria. In addition, no
secondary bile acids were evident in GM mice [10].

Further analyses conducted in different intestinal segments revealed that the bile acid profile in
CONV-R mice was dominated by conjugated TCA in the proximal intestine and deconjugated CA
in the distal small intestine, suggesting an efficient microbial BSH activity in the small intestine that
is necessary for the consequent microbial metabolism into secondary bile acids [10]. Conversely,
the small intestine of GF mice contained exclusively the primary bile acids TβMCA and TCA.

Lastly, different microbial modifications of the bile acid pool were evident in the distal tract of
CONV-R mice, which was dominated by secondary bile acids DCA and ωMCA, while depleted
of conjugated bile acids [10]. Interestingly, the reduced synthesis of the primary bile acid, and
FXR antagonist, TβMCA [10], promoted the activation of intestinal FXR signaling and the
consequent production of FGF15 [10].

The authors demonstrated that the presence of gut microbiota reduced the total amount of
conjugated and unconjugated metabolites of βMCA in the entire enterohepatic system by
approximately 71% ± 3% [10].

Similarly, the importance of intestinal microbiota on bile acid metabolism and systemic gene
expression has been also demonstrated by Joyce et al. [23]. In their study, gnotobiotic mouse
models colonized by Escherichia coli (EC) strains to express BSH activity (ECBSH), showed a
decreased concentration of plasma tauro-conjugated BAs, when compared to GF mice
colonized with BSH-negative EC. These results demonstrated the effect of in vivo deconjugation
of bile acids. Particularly, the authors revealed a reduction in the level of the potent FXR antagonist
TβMCA relative to levels in EC-colonized mice because of in situ BSH activity. Furthermore,
gastrointestinal BSH activity reduced the expression of cyp7a1 in the liver, thus reducing de novo
synthesis of bile acids [23].

In line with previous findings, Li and colleagues [24] demonstrated that the antioxidant Tempol, by
modifying the gut microbiota composition in mice (reducing numbers of bacteria of the genus
Lactobacillus, which represents the main source of BSH activity), led to the accumulation of
FXR antagonists, such as TβMCA, and inhibited the intestinal FXR signaling [24].

Interestingly, based on preclinical evidence, human studies demonstrated that human gut micro-
biota may also be involved in the metabolism of bile acid and related FXR-FGF19 signaling
[25]. As a matter of fact, it has been demonstrated that the gut microbiota in cirrhotic patients
showed dysbiosis, with a lower prevalence of 7α-dehydroxylating bacteria (Lachnospiraceae,
Ruminococcaceae, and Blautia) and a higher abundance of potentially pathogenic bacteria
(Enterobacteriaceae), compared to controls [26]. The authors revealed that these changes
were associated with a decreased conversion of primary bile acids into secondary fecal bile
acids (reduction of the secondary:primary bile acid ratio), thus hypothesizing the contribution of
gut microbiota function to perform 7α-dehydroxylation of bile acids. Additionally, to further explore

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the mechanism, the authors provided a broad-spectrum antibiotic, rifaximin, that is known to
change the functional activity of microbes. In line with the hypothesis, rifaximin reduced the
secondary:primary bile acid ratio without a significant change in bacterial abundance. The result
indicated that a change in microbiota function was likely associated with the decreased conversion
of primary bile acids to secondary bile acids [26].

Similarly, a randomized controlled clinical trial [27] demonstrated that 7 days of oral vancomycin
administration in male subjects with metabolic syndrome, reduced the amount of Gram-positive
intestinal bacteria, especially those belonging to the phylum Firmicutes (Clostridium cluster IV,
Lactobacillus plantarum, and various butyrate-producing bacteria, including F. prauszniitzii
Faecalibacterium prausnitzii and Eubacterium hallii), which are mainly involved in human bile acid
dehydroxylation. Concomitantly, vancomycin treatment was associated with a decreased excretion
of secondary bile acids DCA, LCA, and iso-LCA, and an increased amount of primary bile acids
CA and CDCA. In addition, given that intestinal bile acids regulate expression of FGF19, the plasma
level of FGF19 (basal and post prandial) significantly decreased after vancomycin treatment [27].

Skeletal muscle mass: the gut–muscle axis

Skeletal muscle represents ~40–50% of the total body weight and it is also a reservoir of amino
acids stored as protein [28]. Skeletal muscle, with its marked plasticity, is capable of adaptation
throughout life in response to a variety of signals including neural activation, mechanical loading,
growth factors, and nutritional status [29,30]. Skeletal muscle, in turn, similar to gut microbiota,
exerts a signaling function through the secretion of various myokines [31]. The discovery of mus-
cle crosstalk with other organs and tissues in the body opens several lines of research aiming to
uncover novel important links between the gut microbiota and skeletal muscle [32].

Skeletal muscle proteins are constantly and simultaneously synthesized and degraded. Net protein
balance is defined as the difference between skeletal muscle protein synthesis (MPS) and
muscle protein breakdown (MPB). The balance between MPS and MPB is crucial for muscle
mass and functions [33]. Indeed, protein balance does not function as a simplistic binary
operation (e.g., synthesis or degradation) but instead as a summation of multiple processes
that dynamically operate in an interconnected network [34].

Skeletal muscle atrophy is a morphological adaptation that is characterized by the narrowing of

myofibers, the reduction in muscle mass, protein content, force production, and by fiber type
changes [35,36]. Understanding the molecular mechanisms and signaling pathways behind
muscle atrophy is important to develop countermeasures to prevent muscle wasting and preserve
its physiological function. In addition to many well know factors that influence muscle protein
balance, such as nutrition, exercise, hormones, inflammation, and innervation [37], the gut micro-
biota also exerts nonautologous signals with the capacity to influence pathways involved in protein
homeostasis, or proteostasis [16,17,38].

GF mice lacking gut microbiota exhibited muscle atrophy, a reduced expression of insulin-like
growth factor (IGF), and a decreased transcription of genes associated with skeletal muscle
growth and mitochondrial function [38]. Conversely, fecal transplant from pathogen-free mice
into GF mice resulted in an increase in skeletal muscle mass, a reduction in skeletal atrophy
markers, and an improved oxidative metabolic capacity of the muscle [38].

Interestingly, in humans, a recent study adopting a severe hypoactivity model of dry immersion
(DI), has investigated the relationship between muscle atrophy, induced by DI, and human gut
microbiota composition [39]. The authors demonstrated that a short period of severe physical

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inactivity was able to induce muscle atrophy, with a significant effect on leg lean mass (–2.5%)
measured by dual X-ray absorptiometry, (DEXA), and a significant alteration in operational tax-
onomic unit(s) (OTUs) associated with the order Clostridiales and the family Lachnospiraceae
[39]. To note, the family Lachnospiraceae can produce SCFAs and convert primary to secondary
bile acids [40]. In this study, the higher abundance of Lachnospiraceae has been interpreted as a
positive adaptation to hypoactivity because its reduction is associated with negative health implica-
tion [39,40]. Moreover, an increased Lachnospiraceae abundance has been observed in the hind-
limb unloading mouse model of hypoactivity [41] and in mice after 37 days in the International
Space Station [42]. These results may reveal that the family Lachnospiraceae is generally sensitive
to hypoactivity and might play a key role in the hypoactivity–gut microbiota axis [39].

In support of such findings, preclinical studies demonstrated that the presence of gut microbiota
and microbially derived metabolites, including SCFAs and bile acids, may be involved in the
mechanism regulating skeletal muscle metabolism [14,16,17,38].

More specifically, it has been shown that the absence of gut microbiota or antibiotic-induced
dysbiosis influences the expression of muscle atrophy markers (FoxO, Atrogin-1, Murf-1, and
MyoD), the transcription of genes associated with skeletal muscle growth [extracellular signal-
regulated kinase (ERK) 1/2, p90 ribosomal S6 kinase p90RSK, ribosomal protein S6 RPS6]
and genes related to mitochondrial function (peroxisome proliferator-activated receptor
coactivator-1α, AMP-activated protein kinase AMPK) [14,16,17,38].

In GF mice, the lack of gut microbiota exhibited a greater decline in skeletal muscle mass,
decreased expression of insulin-like growth factor 1, and reduced transcription of a gene
associated with skeletal muscle growth, compared to pathogen-free mice. Moreover, the absence
of gut microbial ecosystem upregulated the expression of forkhead box O3 (FoxO3), Atrogin-1,
and MuRF-1 and reduced the expression of the myosin heavy-chain genes [38]. The muscle-
specific ubiquitin ligases atrogin-1 and Muscle RING finger 1 (MuRF1), are commonly upregulated
in different models of atrophying muscle and are responsible for the increased protein degradation
through the ubiquitin–proteasomes system [37]. MuRF1 is involved in the breakdown of myofibrillar
proteins (actin and myosin heavy chain), whereas Atrogin-1 controls the protein synthesis [43].

However, novel and emerging pathways that regulate the complex network of muscle atrophy,
such as the FXR–FGF15/19-ERK pathway, may be of potential interest, although their specific
role in human muscle wasting must be elucidated [34].

For example, Qui and colleagues [14] demonstrated that an antibiotic-induced gut dysbiosis pro-
moted skeletal muscle atrophy in mice, resulting in reduced muscle mass and smaller myofiber
size in a mechanism involving the intestinal FXR–FGF15-ERK 1/2 signaling pathway [14].

Taken together, these results suggest a possible, intriguing link between the gut microbiota, bile
acids, and skeletal muscle mass. However, although animal models are mostly adopted because
their genome is similar to that of humans, and the advantages of studying a similar molecular
mechanism [44], further human clinical trials are warranted for potential clinical translation.

Gut microbiota, bile acid, and fibroblast growth factor 19: the gut–muscle atrophy
axis
FGFs contain >20 signaling molecules with different pleiotropic functions (Box 2) [45]. Specifically,
the new subfamily of gut-derived FGF15/19, namely endocrine FGFs, have recently stimulated
the attention in biomedical research since its intrinsic capacity to act as hormones. Indeed,

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Box 2. Fibroblast growth factors as metabolic messengers

FGFs constitute a large family of 22 proteins involved in several biological functions. FGFs exploit their activity in human
development and metabolism by binding and activating four membrane tyrosine kinase FGF receptors (FGFRs 1–4).

Based on sequence homology, FGF ligands are clustered into five subfamilies which act autocrinally and/or paracrinally
(FGFs 1, 4, 7, 8, 9) and one endocrine subfamily, the FGF19. This ‘endocrine-acting’ FGF19 subfamily comprises FGFs
19, 21, and 23 [46].

If, on one side, most FGF ligands act by binding heparan sulfate glycosaminoglycans (HSGAGs), on the other, the subclass
of FGF19 shows low affinity towards heparan sulfate (HS), allowing its diffusion away from their site of production [46].

For this reason, FGF19 and its mouse ortholog FGF15 (together denoted FGF15/19) are considered transversal metabolic
messengers which regulate a plethora of human physiological function such as bile acid homeostasis [10], hepatic protein
and glycogen synthesis [76], nutrient partitioning [76], skeletal muscle growth [21], and whole-body energy [77].

Endocrine FGF19 signaling involves binding to FGFR4 and requires the activation of the coreceptor β-klotho (KLB) in order
to exert the majority of physiological functions [78]. Klotho proteins are single-pass transmembrane proteins with an
extracellular domain consisting of two tandem glycosidase-like domains, termed KL1 and KL2 [79].

The binding of FGF19 to the FGFR4–β-klotho complex results in receptor dimerization, activation, and autophosphorylation
of the small guanosine triphosphate Ras and extracellular signal-regulated protein kinase (ERK) signaling pathway. More
specifically, in vitro studies involving different cell lines such as HEK293, L6, C2C12, and Caco-2, demonstrate that
FGF19 induces the phosphorylation of FGFR substrate 2α (FRS2α) and ERK 1/2 [46]. In addition, FGF19 induces the
expression of the mammalian target of the rapamycin complex 1-p70S6K, ERK-p90RSK signaling pathway and increase
the small heterodimer partner (SHP) stability by inhibiting its ubiquitination and proteasomal degradation [80].

FGF15/19 is expressed mainly in the ileum, secreted from the intestinal epithelial cells surrounding the intestinal villi and
tightly regulated by the nuclear bile acid receptor farnesoid X receptor (FXR). Once it reaches the portal circulation,
FGF19 regulates bile acid synthesis (downregulation of CYP7A1, the rate-limiting enzyme of bile salt synthesis) via a
negative feed-back loop, acting on both hepatic synthesis and gallbladder filling [8].

However, since mouse FGF15 and human FGF19 exhibit differences in terms of molecular structure and biological actions,
there is the necessity to imply an appropriate interpretation of preclinical data originating from the use of FGF19 in rodents.

The development of FGF19 analogs [81] or the identification of an alternative pathway able to increase its systemic
availability (e.g., modulation of microbiome [10]) might represent a promising strategy for ameliorating human health, but
further exploration is needed.

FGF19 can regulate several host metabolic processes, including whole-body energy, increase in
fatty acid oxidation, glucose metabolism, and BAs synthesis. Recently, the treatment with
FGF15/19 has become a therapeutic target for metabolic diseases such as obesity, type 2 dia-
betes (T2D) and non-alcoholic fatty liver disease (NAFLD) [46]. In addition, some evidence re-
ported a novel function of FGF19 in regulating skeletal muscle protein balance via binding and
activation of FGF receptor 4 (FGFR4) and the coreceptor β-klotho complex [14,20,21]. Interest-
ingly, in humans, an ongoing clinical triali, involving 170 patients (18–70 years old) with chronic
kidney disease, has been designed to assess the relationship between the concentration of
FGF19, skeletal muscle mass and function, and fecal microbiota. The researchers hypothesized
that a decreased plasma concentration of FGF19 might be associated with a decreased muscle
mass and function, in a mechanism involving, at least in part, the gut microbiota. Moreover, Qui
et al. [15] demonstrated that intestinal FXR-FGF15/19 signaling was downregulated in aged
men (≥60 years) and that this result positively correlated with a decreased plasma FGF19 con-
centration and relative appendicular skeletal muscle mass. Indeed, the authors [15] found that
changes in intestinal FXR expression were in line with changes in skeletal muscle mass, grip
strength, and microbial diversity of aged men, suggesting that the pathogenesis of age-
associated muscle wasting might be related to gut dysbiosis and consequent dysregulation of
FXR-FGF15/19 signaling.

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Indeed, to deeply investigate whether skeletal muscle atrophy might be mechanistically

caused by the gut microbiota (dys)regulation of the bile acids (BAs)–FXR pathway, the
same research group [14] treated 10-week-old male mice with a cocktail of antibiotics for
4 weeks with the aim of depleting the gut microbiota and perturbing the gut microbial bile
acid metabolism. The authors demonstrated that skeletal muscle mass, myofiber size, and
grip strength were reduced in antibiotic-treated mice. To note, the authors provided evidence
that, as a result of dysbiosis, the microbial metabolism function of bile acid was downregu-
lated so that conjugated primary bile acids, including the FXR antagonist TβMCA [10],
increased [14]. Thus, in consequence, the intestinal FXR signaling was inhibited because of
the accumulation of the FXR antagonist TβMCA [14]. Hence, to verify whether MPS was
changed in skeletal muscle of treated mice, and whether the change of MPS was related to
decreased circulating FGF15, the researchers assessed the level of gene expression of
FGF15/19 receptor complex FGFR4/KLB in skeletal muscle. According to the lowered
plasma level of FGF15, the level of β-klotho (KLB) was decreased, together with an ERK
signaling pathway downregulation, leading to lowered MPS [14]. In support of such a physi-
ological role for FGF19, Benoit et al. found that FGF19 is able to preserve and enhance
skeletal muscle mass in different mouse models [21].

Indeed, the authors demonstrated that FGF19 may reduce muscle wasting through an ERK 1/2
mechanism and its downstream effector, mechanistic target of rapamycin (mTOR). The scientists
found that mice provided with a daily administration of recombinant human FGF19 for 7 days
showed an increased skeletal muscle mass and strength compared with vehicle-treated mice.
Indeed, FGF19 increased (i) the phosphorylation of ERK 1/2 and its downstream targets
p90RSK, and (ii) the phosphorylation of S6 kinase (S6K), the downstream target of mTOR. The
receptors for FGF19 in mice (FGFR1, FGFR4, and β-klotho) are expressed in skeletal muscle,
suggesting that FGF19 could act through these receptors in skeletal muscle tissue. In support
–
of this hypothesis, FGF19 did not affect the muscle mass of Kl–/ mice, which encodes β-klotho.
Additionally, the authors then investigated the role of FGF19 in different pathogenic conditions of
muscle wasting, including obesity and aging. In mice aged 25 months, a time at which sarcopenia
is evident, 1 week of FGF19 treatment increased skeletal muscle mass, the myofiber size, and grip
strength [21].

Lastly, and more recently, Guo and colleagues demonstrated both in vivo and in vitro that FGF19 was
able to protect skeletal muscle against obesity-induced muscle atrophy by inhibiting the protein
expression of muscle atrophy marker and enhancing the expression of myogenic differentiation-
related molecules [20].

Overall, these findings [14,20,21] suggest that the enterokine FGF19 may be a novel factor
implicated in the regulation of skeletal muscle metabolism, including the protection from skeletal
muscle wasting. This mechanism is in line with previous studies involving the FGFs–KLB–FGFR4
complex in myogenesis [47,48] (Figure 2).

However, although the mechanisms have been elucidated in different mice models, there are still
many challenges ahead in grasping the full complexity of bile acid signaling and its specific role in
human metabolism. For example, given that there are significant differences between the bile acid
profiles of mice and humans [7], further studies will be necessary to determine the relevance of
those results in humans. It would be of importance to understand whether the gut microbiota
modulation of bile acid–FXR signaling may represent one potential mechanism able to increase
the skeletal muscle availability of FGF19 in humans, and thus treat and/or prevent different path-
ological diseases associated with muscle wasting.

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Trends in Microbiology

Figure 2. A proposed molecular mechanism of crosstalk between gut microbiota and skeletal muscle via FXR–FGF15/19. On the left, the molecular signaling
pathways of gut microbiota and skeletal muscle: the unbalanced gut microbiota (lacking BSH-harboring bacteria) and the consequent accumulation of primary bile acid T(β)
MCA, induce a reduction in skeletal muscle mass. The accumulation of the FXR antagonist, T(β)MCA, causes muscle atrophy by inhibiting the ileal FXR–FGF15/19 signaling.
Consequently, ERK signaling cascades were downregulated so that the muscle synthetic response is impaired because of the diminished circulating FGF15/19. In addition, the
dysbiotic gut microbiota influences the expression of muscle-atroph- related markers by upregulating Atrogin-1 and Murf-1. On the right, the molecular signaling pathways of
gut microbiota and skeletal muscle: the balanced gut microbiota (containing BSH-harboring bacteria) and the decreased amount of primary bile acid (including T(β)MCA) induce
an increase in skeletal muscle mass. The healthy gut microbiota stimulates the expression of FGF15/19 by deconjugating T(β)MCA into CA (alleviating FXR antagonism) and
activates FXR–FGF15/19 signaling. FGF15/19 increases the phosphorylation of ERK 1/2 and of its downstream target RSK/P90. FGF15/19 also increases the activity of RPS6;
the main downstream target of mTOR. Abbreviations: BSH, bile salt hydrolase; ERK, extracellular signal-regulated protein kinase; FXR, farnesoid X receptor; mTOR, mechanistic
target of rapamycin; RPS6, Ribosomal protein S6 ;RSK/p90, p90 ribosomal S6 kinases.

Gut microbiota, probiotics, and skeletal muscle mass in aging

The hypothesis of ‘gut–muscle axis’, and the fact that alteration in gut microbiota coincides with
alteration in skeletal muscle metabolism (e.g., skeletal muscle catabolism), led the research to
focus on novel strategies capable of regulating and optimizing muscle performance by targeting
the composition of the gut microbiota [49].

Indeed, from a feasibility standpoint, the ability to influence skeletal muscle by modulating the gut
microbiota may be very attractive, and has therefore been proposed [50,51] for ameliorating
some conditions, such as age-associated sarcopenia.

Indeed, age-associated sarcopenia represents one potential disease that may benefit, at least in
part, from the positive effect of probiotic administration [50–52]. In alignment with current
knowledge, generally, probiotic interventions aiming to modulate gut microbiota demonstrated
beneficial effects on protein synthesis and degradation through: (i) the regulation of sensitivity of

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skeletal muscle to different anabolic stimuli; (ii) modulation of inflammation; (iii) improvement in
available energy; and (iv) improvement in glucose and lipid metabolism [50–52].

This explains why recent studies have developed different nutritional strategies, including
probiotic supplementation, to target muscle mass and function [53,54]. Probiotics are
nonpathogenic living organisms that have beneficial effects on host health and disease prevention
when ingested in adequate amounts [55]. To date, probiotic supplementation has been proven to
be efficient for improving muscle mass and function in rodents [50]. As a matter of fact, selected
strains of probiotics, such as lactobacilli and bifidobacteria, have been demonstrated to be useful
for the prevention of age-related muscle loss in different models of aged mice [56,57]; however,
when translating these results to humans, the picture becomes less clear because of the scarcity
of studies and the difficulties in measuring accurately and repeatedly muscle mass and function in
elder people [51].

Preclinical animal studies

Animal studies provide a valid model for studying human physiology and disease, and preclinical
trials remain essential to understand the molecular mechanisms underlying the onset of many
diseases, such as those correlated with impairments of skeletal muscle mass [44,58,59].

One of the first pioneering studies that investigated the gut microbiota as a means to affect lean
tissue mass was conducted by Bindels et al. in leukemic mouse models, because of their
cachectic phenotype [19]. Microbial profiling in these mice revealed the presence of gut dysbiosis
characterized by a selective reduction of Lactobacillus reuteri and Lactobacillus gasseri/johnsonii.
To counteract the drop in the level of lactobacilli, the leukemic mice were given, for 2 weeks, a
selected probiotic administration containing the missing live bacteria. This supplementation
was able to decrease the expression of atrophy-related genes (MuRF1 and Atrogin-1) as well
as the serum levels of inflammatory cytokines (interleukin 6, monocyte, monocyte chemoattrac-
tant protein-1, and interleukin 4). The authors reported that restoring the gut microbiota, by
adding specific strains, such reduction in the relative abundance of L. reuteri and L. gasseri/
johnsonii, reduced the inflammation, and this effect correlated with the reduction of markers related
to ubiquitin–proteasome pathways. Of note, the positive effect of probiotics on skeletal muscle
mass has been shown to be strain-specific since 2 weeks of supplementation with Lactobacillus
acidophilus NCFM did not reduce the skeletal muscle atrophy markers [19].

Similarly, 10-month-old mice significantly increased muscle mass (gastrocnemius muscle weight)
and muscle functionality (muscle strength) after 12 weeks supplementation with Lactobacillus
casei LC122 or Bifidobacterium longum BL986, compared to aged-matched controls [57].
However, although Lactobacillus and Bifidobacterium treatment conferred a similar anti-aging
effect, these two bacterial species seemed to act through different cellular pathways [57].

Lastly, a recent study demonstrated that 12-week administration of Lactobacillus casei Shirota
(LcS), by altering the composition of the gut microbiota, was able to reduce the age-related
declines in muscle mass and strength in senescence-accelerated mouse prone-8 (SAMP8)
mice [56].

Thus, up to now, these preclinical results suggest that some alterations in gut microbiota may be
harmful to muscle growth and that interventions meant to deplete gut pathogens, such as antibiotic
treatment, may have unintended consequences for the host muscle phenotypes. Conversely,
probiotic supplementation substantially protects the microbial ecosystem with a consequent
improvement in skeletal muscle mass and function.

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Human clinical studies

In humans, the use of probiotics has begun to be considered, in association with other nutritional
strategies, as a very promising tool to maintain muscle mass and function in elderly population [60].
Indeed, in the case of elderly people, probiotic supplementation may become essential since the
analysis of intestinal microbiota showed an alteration in microbial composition as a function of
age and health status [61,62]. As a matter of fact, the gut microbiota of frail or sarcopenic people
is more altered (e.g., enriched in proinflammatory commensals at the expense of beneficial
microbes) compared with people of the same age who are better in health [61,63,64].

Further, individuals with high frailty scores revealed a significant reduction in the relative abundance of
lactobacilli, F. prausnitzii species, and the Bacteroides/Prevotella ratio, and an increased level of
potentially pathogenic bacteria such as Enterobacteriaceae [50]. However, although these

Trends in Microbiology

Figure 3. Probiotic and adequate protein intake for the maintenance of skeletal muscle health. On one side, adequate daily energy–protein intake improves
musculoskeletal health. Protein digestion and amino acid absorption represent the sequential mechanism by which ingested proteins provide amino acids available for the
organism. Once ingested, amino acids are released and taken up across the gut mucosa, where many of them are released into the systemic circulation to be transported and
taken up by skeletal muscle. On the other side, probiotics may act synergically. Specific probiotics positively modulate the gut microbiota (by preventing and/or treating gut
dysbiosis) while promoting the growth of beneficial bacteria (i.e., increasing the relative abundance of BSH-containing bacteria). Beneficial bacteria consequently metabolize
conjugated bile acids, which can upregulate the FXR-FGF15/19 signaling. FGF15/19, once released into the systemic circulation, can be transported and taken up by skeletal
muscle which expresses the receptors for FGF15/19 (FGFR4/β-klotho). FGF15/19 increases muscle mass, myofiber size, and muscle strength. Abbreviations: BSH, bile salt
hydrolase; ERK, extracellular signal-regulated protein kinase; FXR, farnesoid X receptor; RPS6, ribosomal protein S6; RSK/p90,p90 ribosomal S6 kinases.

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observational studies reveal a relationship between gut microbiota and sarcopenia, to prove the Outstanding questions
causal effect of bacteria on host skeletal muscle, human clinical trials adopting interventions Does alteration of the gut microbiota,
(i.e., supplementation with prebiotics and/or probiotics) should be primarily considered. also termed dysbiosis, cause a decline
in skeletal muscle mass and function?

In this context, only two studies provided bacterial supplementation in elderly people [65,66]. Can the gut microbiota become a
potential therapeutic target for the
Buigues et al. performed a randomized placebo-controlled trial in which they demonstrated that prevention and/or treatment of muscle
wasting and associated conditions?
the supplementation with prebiotic Darmocare Pre®, composed of fructooligosaccharides and
inulin (that also targets microbiota), improved two criteria of frailty syndrome: time to exhaustion Does intestinal dysbiosis cause a
and grip strength in a cohort of 60 older participants aged 65 years and over [65]. dysregulation of the bile acid–FXR–
skeletal muscle axis?

Conversely, the study of Valentini and colleagues [66] did not identify differences in physical Do probiotics regulate and optimize
performance, measured by grip strength, between placebo and symbiotic groups. age-related muscle loss through bile
acid–FXR signaling?
Overall, the literature arising from animal studies [19,56,57] shows that specific probiotic strains,
What specific probiotics do we need
lactobacilli and bifidobacteria, can influence the skeletal muscle metabolism and restore age- to target sarcopenia through the bile
related muscle loss. However, in humans, the role of the intestinal microbiota in the development acid–FXR axis?
of age-associated muscle loss is a critical area that requires further research before translating to
Will the use of probiotic supplementation
patients. [51]. By contrast, animal models allowed us to understand that probiotics may influence become a common practice in the
skeletal muscle balance between protein synthesis and degradation through different potential development of personalized treatments
mechanisms such as the different pathways involved in mitochondrial function and energy for age-associated muscle disorders?
metabolism [50]. Whether other potential signaling pathways, such as BA–FXR signaling, are
Can gut microbiota profiling become
involved, has not yet been tested. an additional biomarker for the early
detection of sarcopenia among older
We may speculate that probiotic supplementation, by regulating gut microbiota [50] and adults?
consequent bile acid synthesis and metabolism [8], might foster greater BA–FXR signaling
and availability of FGF19, but studies investigating this molecular pathway are warranted.
Future studies may also investigate the potential combination of probiotic strains with other
nutritional strategies that target both microbiota (i.e., polyphenols, prebiotics) and muscle
(protein, amino acids) [50] to improve host microbiota function and skeletal muscle phenotype
in elderly people (Figure 3).

Ultimately, although we decided to focus this analysis on skeletal muscle mass, it should be kept
in mind that probiotic supplementation may also be considered for its positive impact on muscle
functionality, including the regulation of inflammation, nutrient metabolism, insulin resistance, and
oxidative stress [50]. As such, probiotic supplementation may couple existing strategies, such as
regular physical activity and proper nutrition, to promote the abundance of intestinal bacteria
that could drive beneficial metabolic changes in the human host and prevent or treat different
diseases, including sarcopenia [50,67,68].

Concluding remarks
Over the past decades, considerable progress has been achieved in the field of ‘gut–muscle axis’.

The mechanisms underneath intestinal microbiota and skeletal muscle metabolism have
attracted researchers from diverse scientific background due to their relevance in various fields
of study such as inflammaging [69], cancer-related cachexia [70], and sports medicine [18].
From the recent findings, a new scenario emerges that considers the gut microbiota as a con-
tributor to skeletal muscle growth and performance [14,16,17]. Indeed, preclinical studies have
revealed a novel and promising pathway that may connect gut microbiota, bile acids, and skel-
etal muscle mass [14,15]. These findings may offer exciting perspectives to this novel field of

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research and introduce stimulating questions which should identify gut microbiota as a new
therapeutic target.

Current research gives us important clues about how the gut microbiota may exert its effect on
skeletal muscle mass [14,15,20,21]; however, the causality of age-related gut microbiota
dysbiosis and skeletal muscle wasting has not yet been demonstrated in humans. In vivo studies
and human clinical trials investigating the effects of probiotics in the elderly population and on
sarcopenia, are very limited and this area needs further investigation.

We believe that, in line with the current available evidence, harboring a ‘metabolically favorable’
microbiota may be fundamental for maintaining a normal muscle protein synthesis rate in specific
conditions of anabolic resistance, such as aging. Moreover, targeting the network between
microbiota, bile acid, and FXR signaling seems to evolve a promising avenue for the treatment
of age-associated skeletal muscle loss, and we hope that this Review will stimulate a debate
and new research on this matter.

Even though the gut microbiota represents ‘a piece of a whole’, we need to continually
understand it and, as technology advances, it will become even easier to investigate the mecha-
nisms by which microorganisms actively communicate with host skeletal muscle metabolism,
similarly to other human organs.

The gut microbiota, as its centrality to human health, will continue to attract the scientific commu-
nity, while the technology advancements will continue to provide innovative tools aimed to reveal
the role of the gut microbiota as a target for personalized medicine [71,72]. We are only just
beginning to elucidate the complex but promising relevance of the microbiota to human health
and disease (see Outstanding questions).

Declaration of interests
No interests are declared.

Resources
i
https://clinicaltrials.gov/ct2/show/NCT04896047?term=fgf19+muscle&draw=2&rank=1

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