Abstract
Skeletal muscle wasting is affected by the gut microbiota dysbiosis through multiple pathways, including inflammatory process, defected immune system, and anabolic resistance. We aimed to systematically review the studies investigating the gut microbiota composition in sarcopenic and cachexic humans and animals.
We carried out a comprehensively systematic search using relevant keywords on PubMed, Web of Science, and Scopus databases until July 2021. Original human observational research and animal studies related to our research topics published in English were selected.
Seven human studies and five animal studies were included. Three human studies were case-control, whereas the other four were cross-sectional studies that investigated three different conditions, including age-related sarcopenia, as well as liver cirrhosis and cancer cachexia. The principal alteration in age-related sarcopenia and liver cirrhosis-induced sarcopenia was a reduction in short-chain fatty acids (SCFAs) -producing bacteria. Lachnospiraceae family, consisting of Lachnospira, Fusicatenibacter, Roseburia, and Lachnoclostridium, significantly decreased in age-related sarcopenia, while in liver cirrhosis-induced sarcopenia, the alpha diversity of gut microbiota decreased compared with the control group. Moreover, Enterobacteriaceae, which has a pro-inflammatory effect increased in muscle-wasted animals.
This systematic review presents associations between the gut microbiota alterations and skeletal muscle wasting as a consequence of various pathologies, including aging sarcopenia, renal failure, and cancer cachexia in both human and animal studies.
Clarifying the associations between the alterations of the gut microbiota composition and sarcopenia and identifying the role of gut dysbiosis in these complications will provide novel approaches to prevent or halt muscle wasting.
- Abbreviations
- CHF
Chronic heart failure
- CKD
Chronic kidney disease
- COPD
Chronic obstructive pulmonary disease
- IL
Interleukin
- LPS
Lipopolysaccharides
- NOS
Newcastle–Ottawa Assessment Scale
- PRISMA
Preferred Reporting Items for Systematic reviews and Meta-Analyses
- SCFAs
Short-Chain Fatty Acids
- SYRCLE
Systematic Review Centre for Laboratory animal Experimentation
- TLR4
Toll-like receptor 4
Introduction
Skeletal muscle wasting is a common complication of various pathologies, including both chronic events, ranging from aging sarcopenia to renal and cardiac failure, and acute diseases, such as cancer cachexia (Robinson et al. 2020, Schoch et al. 2020). All of these conditions are characterized by significant derangement in muscle fibers’ size and number, the protein content, myonuclear number, and muscle strength (Sakuma and Yamaguchi 2018). Cachexia is a multifactorial syndrome defined by unceasing loss of skeletal muscle mass leading to progressive functional impairment associated with cancer and other severe chronic illnesses, including AIDS, cirrhosis, chronic heart failure (CHF), chronic kidney disease (CKD) , and chronic obstructive pulmonary disease (COPD) (Fearon et al. 2011, Argilés et al. 2014, Graul et al. 2016). Muscle loss also occurs in sarcopenia, defined as the age-related loss of muscle mass, strength, and physical performance (Chen et al. 2020). The loss of muscle mass begins at age 40 by losing ∼8% of muscle mass per decade, which accelerated to 15% over the age of 70 and is continued until death (Marzetti et al. 2017). Skeletal muscle wasting is a common condition among older adults and is associated with several adverse health outcomes. The prevalence of sarcopenia ranges from 5% to 13% in the 60–70 years old population and 11% to 50% in those ≥80 years (Peterson and Braunschweig 2016, Sayers et al. 2019). The estimated prevalence of cachexia due to any disease is around 1% of the patient population and affects 50–80% of cancer patients (von Haehling and Anker 2014). The accompanying loss of strength can contribute to morbidity and mortality as well as reduced quality of life (Ebner et al. 2015). Recent studies demonstrate that cancer cachexia may account for up to 20% of cancer deaths, while sarcopenia imposes a substantial economic burden on society by causing a series of adverse economic and social impacts, such as falls, fractures, hospitalization, and death (Argilés et al. 2014, Liguori et al. 2018, Chiappalupi et al. 2020). Many factors contributing to the loss of muscle mass and strength have been suggested, while inadequate nutrition and physical inactivity are central components of sarcopenia physiopathology in the elderly. On the other hand, in many muscle pathologies (e.g. cancer cachexia), systemic inflammation and anabolic resistance play a crucial pathophysiological role in the origin of muscle wasting (Holeček 2017, Furrer and Handschin 2019). The gut microbiota is being increasingly recognized as a modulator of inflammatory response and anabolic balance. The gut microbiota refers to the microorganisms inhabiting the human gastro-intestinal tract and living in symbiosis with the host (Nishida et al. 2018). Microbiota encompasses a diverse community of microbes, mainly bacteria and also viruses, fungi, protozoa, and archaea, that carry out various functions influencing the regulation of host metabolism (Schoeler and Caesar 2019). Dysbiosis in gut microbiota may contribute to unhealthy aging and trigger inflammation and anabolic resistance (Kim and Jazwinski 2018). This condition is particularly widespread in older individuals, while chronic diseases, such as cancer and CKD cachexia, can also contribute to the enhancement of dysbiosis (Herremans et al. 2019). Alteration in gut microbiota is associated with a surge in pro-inflammatory cytokine levels affecting muscles compared to healthy adults. The gut microbiota influences skeletal muscle cells by producing or modifying a variety of compounds (e.g. vitamin B12) and amino acids (e.g. tryptophan) representing the elemental substrates for muscle protein anabolism (Ticinesi et al. 2017, Manickam et al. 2020, Qiu et al. 2021). Hence, the “gut–muscle axis” has emerged as a new field to study the underlying pathophysiological mechanisms of muscle wasting (Ticinesi et al. 2019, Przewłócka et al. 2020). Investigation in the field of gut microbiota will open new doors to the novel therapeutic targets in muscle wasting. This study was designed to comprehensively review the human and animal studies that investigated the composition and function of the gut microbiota in sarcopenic and cachexic patients.
Methods
Search strategy
A comprehensively systematic search was carried out through PubMed, Web of Science, and Scopus databases for all relevant studies focused on the gut microbiota composition in muscle wasting documented up to July 2021. We included the final search entry [C] for this systematic review.
[Cachexia] (Title/Abstract) OR [“muscle wasting”] (Title/Abstract) OR [Sarcopenia] (Title/Abstract) OR [“Muscular atrophy”] (Title/Abstract)
[“microbial profile”] (Title/Abstract) OR [microflora] (Title/Abstract) OR [“bacterial flora”] (Title/Abstract) OR [“gut microbial composition”] (Title/Abstract) OR [“faecal microbial composition”] (Title/Abstract) OR [“intestinal microbial composition”] (Title/Abstract) OR [“bacterial composition”] (Title/Abstract) OR [Microbiota] (Title/Abstract) OR [“Microbial Community”] (Title/Abstract) OR [“Community, Microbial”] (Title/Abstract)] OR [Microbiome] (Title/Abstract) OR [“Human Microbiome”] (Title/Abstract) OR [Dysbiosis] (Title/Abstract)
[A] AND [B]
The search results were imported in EndNote Reference Manager X20 and duplicates were removed by the software function “remove duplicates” and manually by two independent authors.
Eligibility criteria and selection of studies
Two independent investigators screened and selected the articles through the most relevant titles and abstracts. Then, the full text of retrieved publications was reviewed, and based on inclusion and exclusion criteria, the pertinent papers were selected. The inclusion criterion was original human observational research and animal studies related to our research topics published in English. The exclusion criteria consist of: (1) clinical trials; (2) nonoriginal articles, including review articles, editorials, commentaries, opinions, or any studies with no original data; and (3) duplicated results.
The present study was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) , and the process of study selection is demonstrated in the PRISMA flow diagram (Moher et al. 2015).
Data extraction
Data extracted from the full text articles include first author’s surname, publication date, country of origin, study design (e.g. case control, cross sectional, …), participants’ characteristics (sample size, age, sex, and underlying disorder), and findings regarding microbiota alterations (including the methodology used for the microbiota sequencing and the altered bacteria).
Quality assessment
The quality of the included human studies was assessed using the Newcastle-Ottawa Assessment Scale (NOS). The quality of human studies was classified as high quality for scores 8–10, moderate quality for scores 5–7, and low quality for scores <5. Moreover, the quality of the included animal studies was determined according to the Systematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk-of-bias tool, which asks nine questions that are scored as “low risk”, “high risk”, or “unclear”. We defined score 2 for “low risk” answers, score 1 for “unclear” answers, and score 0 for “high risk” answers. The quality of animal studies was considered as high quality for scores 13–18, moderate quality for scores 12–6, and low quality for scores <6. The results of the quality assessment of articles are presented in Supplementary Tables S1–S3.
Results
Study selection
By searching the online databases, 596 results were yielded, of which 243 were duplicate records. Of the remaining articles (353), 338 articles were removed after the title/abstract screening process, and 15 articles remained to assess their full text. Among these articles, 3 articles did not fulfill the inclusion and exclusion criteria, and 12 articles were ultimately met eligibility criteria and included in this systematic review. Fig. 1 shows the process of selecting included articles in this systematic review.
Flow diagram or search result.
Study characteristics
This systematic review contains 12 articles, includes of 7 human studies (Picca et al. 2019, Ticinesi et al. 2020, Kang et al. 2021, Margiotta et al. 2021, Ni et al. 2021, Ponziani et al. 2021, Ren et al. 2021) and 5 animal studies (Siddharth et al. 2017, Bindels et al. 2018, Pötgens et al. 2018, Chen et al. 2020, Pötgens et al. 2021). Three human studies were case-control (Kang et al. 2021, Ponziani et al. 2021, Ren et al. 2021), and the other four human studies were cross-sectional studies (Picca et al. 2019, Ticinesi et al. 2020, Margiotta et al. 2021, Ni et al. 2021). Sample size in human studies ranged from 35 to 90. Three human studies investigated the effect of age-related sarcopenia on the gut microbiota composition (Picca et al. 2019, Ticinesi et al. 2020, Kang et al. 2021), whereas two human studies explored the microbiota composition in muscle-wasting patients affected with liver cirrhosis (Ponziani et al. 2021, Ren et al. 2021). Two remained human studies were about muscle wasting in cachectic patients due to lung cancer and CKD (Margiotta et al. 2021, Ni et al. 2021). Among five animal studies, three studies were conducted on CD2F1 mice (Pötgens et al. 2018, Chen et al. 2020, Pötgens et al. 2021), while the other two studies were implemented on rats using Sprague-Dawley rats (Chen et al. 2020) and Wistar rats (Siddharth et al. 2017). Four animal studies investigated the effect of the induced cachexia on the gut microbiota (Bindels et al. 2018, Pötgens et al. 2018, Chen et al. 2020, Pötgens et al. 2021), and only one study was about age-related sarcopenia (Siddharth et al. 2017). The microbiota assessment method used in all the studies was 16S rRNA sequencing (Table 1 and Table 2).
Characteristics of included human studies.
| Study | Country | Predisposing disease | Diagnosis method of muscle wasting | Population characteristics | Study design | Microbiota assessment method | Bacterial detected significantly higher abundance | Bacterial detected significantly lower abundance | Quality assessment score |
|---|---|---|---|---|---|---|---|---|---|
| Ren et al. (2021) | China | liver cirrhosis | Muscle-wasting according to L3 SMI index | Numbers: Case: Patients with liver cirrhosis and muscle wasting (n = 30) | Case-control | 16S rRNA sequencing | Genus: Weissella unclassified | Family: Lachnospiraceae bacterium, Erysipelotrichaceae bacterium | 9 |
| Control: Liver cirrhosis without muscle wasting (n = 30) | Species: Peptostreptococcus stomatis, Escherichia coli, Bacteroides coprocola, Bacteroides caccae, Eubacterium infirmum, and Bacteroides faecis | Genus: Granulicella unclassified, Eggerthella unclassified | |||||||
| Healthy controls (n = 30) | Species: Bacteroides uniformis, Clostridium clostridioforme, Clostridium asparagiforme, Ruminococcus flavefaciens, Anaerostipes hadrus, and Bifidobacterium catenulatum | ||||||||
| Age: Case (Patients with liver cirrhosis and muscle wasting) : 45.50 ± 12.74 | |||||||||
| Control (Liver cirrhosis without muscle wasting) : 42.21 ± 12.40 | |||||||||
| Sex: Case: Women = 10 (33.3%) | |||||||||
| Control: Women = 14 (46.7%) | |||||||||
| Ponziani et al. (2021) | Italy | liver cirrhosis | Sarcopenia according to FNIH | Numbers: Case: Cirrhosis Sarcopenia (n = 19) | Case-control | 16S rRNA sequencing | Genus: Eggerthella | Phylum: Proteobacteria, Euryarchaeota | 9 |
| Control: Cirrhosis no Sarcopenia (n = 31) | Family: Methanobrevibaceae, prevotellaceae | ||||||||
| Controls: Sarcopenia (n = 14) | Genus: Akkermansia, Methanobrevibacter, Prevotella, and Verrcumicrobiaceae | ||||||||
| Controls no Sarcopenia (n = 36) | |||||||||
| Age: Case: Cirrhosis Sarcopenia: 70 (63–74) | |||||||||
| Control: Cirrhosis no Sarcopenia: 66 (58.5–76.5) | |||||||||
| Controls: Sarcopenia: 75.5 (72–77.25) | |||||||||
| Controls no Sarcopenia: 72.5 (58.25–75.25) | |||||||||
| Sex: Case: Cirrhosis Sarcopenia: women = 7 (36.84%) | |||||||||
| Control: Cirrhosis no Sarcopenia: women = 8 (25.81%) | |||||||||
| Controls: Sarcopenia: women = 6 (42.86%) | |||||||||
| Controls no Sarcopenia: women = 15 (41.67%) | |||||||||
| Kang et al. (2021) | China | Advanced age | Sarcopenia or possible sarcopenia according to AWGS | Numbers: Case: Sarcopenic: (n = 11) | Case-control | 16S rRNA sequencing | Family: Porphyromonadaceae, Lactobacillaceae | Phylum: Firmicutes | 8 |
| preCase: possibly sarcopenic: (n = 16) | Genus: Lactobacillus | Genus: Lachnospira, Fusicatenibacter, Roseburia, Eubacterium, and Lachnoclostridium | |||||||
| Control: Healthy: (n = 60) | |||||||||
| Age: Case: Sarcopenic: (76.45 ± 8.58) | |||||||||
| preCase: possibly sarcopenic: (74.00 ± 6.94) | |||||||||
| Control: Healthy: (68.38 ± 5.79) | |||||||||
| Sex: Case: Sarcopenic: women = 7 (63.64%) | |||||||||
| preCase: possibly sarcopenic: women = 11 (68.75%) | |||||||||
| Control: Healthy: women = 33 (55.00%) | |||||||||
| Margiotta et al. (2021) | Italy | Stage IIIb-IV CKD + Advanced age | Sarcopenia according to EWGSOP2 | Numbers: Sarcopenic (n = 18) | Cross-sectional | 16S rRNA sequencing | Family: Micrococcaceae, Verrucomicrobiaceae | Family: Veillonellaceae, gemellaceae | 10 |
| Not Sarcopenic (n = 45) | Genus: Megasphaera, Veillonella, Rothia, Coprobacillu, and Akkermansia | Genus: Acidaminococcus, Gemella | |||||||
| Age: Sarcopenic (83.1 ± 5.7) | |||||||||
| Not Sarcopenic (79.7 ± 6.2) | |||||||||
| Sex: Sarcopenic: women = 2 (11%) | |||||||||
| Not Sarcopenic: women = 17 (28%) | |||||||||
| Ni et al. (2021) | Hungry | Lung cancer | Cachexia according to aPG-SGA | Numbers: Cachexic lung cancer (n = 12) | Cross-sectional | 16S rRNA sequencing | Species: Klebsiella oxytoca | Species: Prevotella copri, Faecalibacterium prausnitzii, and Lactobacillus gasseri | 8 |
| Non-Cachexic lung cancer (n = 19) | |||||||||
| Age: Cachexic lung cancer (64.25 ± 4.16) | |||||||||
| Non-Cachexic lung cancer (64.11 ± 7.86) | |||||||||
| Sex: Cachexic lung cancer: women = 7 (58.3%) | |||||||||
| Non-Cachexic lung cancer: women = 5 (26.3%) | |||||||||
| Ticinesi et al. (2020) | Italy | Frailty according to SPPB | Sarcopenia according to SMI/height2 | Numbers: Sarcopenic Subjects (n = 5) | Cross-sectional | 16S rRNA sequencing | Species: Faecalibacterium prausnitzii, Roseburia inulinivorans, and Alistipes shahii | 8 | |
| Non-Sarcopenic Controls: (n = 12) | |||||||||
| Age: Sarcopenic Subjects (77 (75.5–86) ) | |||||||||
| Non-Sarcopenic Controls: (71.5 (70–75) ) | |||||||||
| Sex: Sarcopenic Subjects: women = 4 (80%) | |||||||||
| Non-Sarcopenic Controls: women = 10 (83.3%) | |||||||||
| Picca et al. (2019) | Italy | Frailty according to SPPB | Sarcopenia according to FNIH | Numbers: Frail and Sarcopenic (n = 18) | Cross-sectional | 16S rRNA sequencing | Family: Peptostreptococcaceae, Bifidobacteriaceae | Genus: Slackia, Eubacterium | 9 |
| Nonsarcopenic Nonfrail (n = 17) | Genus: Dialister, Pyramidobacter, and Eggerthella | ||||||||
| Age: Frail and Sarcopenic (75.5 ± 3.9) | |||||||||
| Nonsarcopenic Nonfrail (73.9 ± 3.2) | |||||||||
| Sex: Frail and Sarcopenic: women = 10 (56%) | |||||||||
| Nonsarcopenic Nonfrail: women = 5 (29%) |
| Study | Country | Predisposing disease | Diagnosis method of muscle wasting | Population characteristics | Study design | Microbiota assessment method | Bacterial detected significantly higher abundance | Bacterial detected significantly lower abundance | Quality assessment score |
|---|---|---|---|---|---|---|---|---|---|
| Ren et al. (2021) | China | liver cirrhosis | Muscle-wasting according to L3 SMI index | Numbers: Case: Patients with liver cirrhosis and muscle wasting (n = 30) | Case-control | 16S rRNA sequencing | Genus: Weissella unclassified | Family: Lachnospiraceae bacterium, Erysipelotrichaceae bacterium | 9 |
| Control: Liver cirrhosis without muscle wasting (n = 30) | Species: Peptostreptococcus stomatis, Escherichia coli, Bacteroides coprocola, Bacteroides caccae, Eubacterium infirmum, and Bacteroides faecis | Genus: Granulicella unclassified, Eggerthella unclassified | |||||||
| Healthy controls (n = 30) | Species: Bacteroides uniformis, Clostridium clostridioforme, Clostridium asparagiforme, Ruminococcus flavefaciens, Anaerostipes hadrus, and Bifidobacterium catenulatum | ||||||||
| Age: Case (Patients with liver cirrhosis and muscle wasting) : 45.50 ± 12.74 | |||||||||
| Control (Liver cirrhosis without muscle wasting) : 42.21 ± 12.40 | |||||||||
| Sex: Case: Women = 10 (33.3%) | |||||||||
| Control: Women = 14 (46.7%) | |||||||||
| Ponziani et al. (2021) | Italy | liver cirrhosis | Sarcopenia according to FNIH | Numbers: Case: Cirrhosis Sarcopenia (n = 19) | Case-control | 16S rRNA sequencing | Genus: Eggerthella | Phylum: Proteobacteria, Euryarchaeota | 9 |
| Control: Cirrhosis no Sarcopenia (n = 31) | Family: Methanobrevibaceae, prevotellaceae | ||||||||
| Controls: Sarcopenia (n = 14) | Genus: Akkermansia, Methanobrevibacter, Prevotella, and Verrcumicrobiaceae | ||||||||
| Controls no Sarcopenia (n = 36) | |||||||||
| Age: Case: Cirrhosis Sarcopenia: 70 (63–74) | |||||||||
| Control: Cirrhosis no Sarcopenia: 66 (58.5–76.5) | |||||||||
| Controls: Sarcopenia: 75.5 (72–77.25) | |||||||||
| Controls no Sarcopenia: 72.5 (58.25–75.25) | |||||||||
| Sex: Case: Cirrhosis Sarcopenia: women = 7 (36.84%) | |||||||||
| Control: Cirrhosis no Sarcopenia: women = 8 (25.81%) | |||||||||
| Controls: Sarcopenia: women = 6 (42.86%) | |||||||||
| Controls no Sarcopenia: women = 15 (41.67%) | |||||||||
| Kang et al. (2021) | China | Advanced age | Sarcopenia or possible sarcopenia according to AWGS | Numbers: Case: Sarcopenic: (n = 11) | Case-control | 16S rRNA sequencing | Family: Porphyromonadaceae, Lactobacillaceae | Phylum: Firmicutes | 8 |
| preCase: possibly sarcopenic: (n = 16) | Genus: Lactobacillus | Genus: Lachnospira, Fusicatenibacter, Roseburia, Eubacterium, and Lachnoclostridium | |||||||
| Control: Healthy: (n = 60) | |||||||||
| Age: Case: Sarcopenic: (76.45 ± 8.58) | |||||||||
| preCase: possibly sarcopenic: (74.00 ± 6.94) | |||||||||
| Control: Healthy: (68.38 ± 5.79) | |||||||||
| Sex: Case: Sarcopenic: women = 7 (63.64%) | |||||||||
| preCase: possibly sarcopenic: women = 11 (68.75%) | |||||||||
| Control: Healthy: women = 33 (55.00%) | |||||||||
| Margiotta et al. (2021) | Italy | Stage IIIb-IV CKD + Advanced age | Sarcopenia according to EWGSOP2 | Numbers: Sarcopenic (n = 18) | Cross-sectional | 16S rRNA sequencing | Family: Micrococcaceae, Verrucomicrobiaceae | Family: Veillonellaceae, gemellaceae | 10 |
| Not Sarcopenic (n = 45) | Genus: Megasphaera, Veillonella, Rothia, Coprobacillu, and Akkermansia | Genus: Acidaminococcus, Gemella | |||||||
| Age: Sarcopenic (83.1 ± 5.7) | |||||||||
| Not Sarcopenic (79.7 ± 6.2) | |||||||||
| Sex: Sarcopenic: women = 2 (11%) | |||||||||
| Not Sarcopenic: women = 17 (28%) | |||||||||
| Ni et al. (2021) | Hungry | Lung cancer | Cachexia according to aPG-SGA | Numbers: Cachexic lung cancer (n = 12) | Cross-sectional | 16S rRNA sequencing | Species: Klebsiella oxytoca | Species: Prevotella copri, Faecalibacterium prausnitzii, and Lactobacillus gasseri | 8 |
| Non-Cachexic lung cancer (n = 19) | |||||||||
| Age: Cachexic lung cancer (64.25 ± 4.16) | |||||||||
| Non-Cachexic lung cancer (64.11 ± 7.86) | |||||||||
| Sex: Cachexic lung cancer: women = 7 (58.3%) | |||||||||
| Non-Cachexic lung cancer: women = 5 (26.3%) | |||||||||
| Ticinesi et al. (2020) | Italy | Frailty according to SPPB | Sarcopenia according to SMI/height2 | Numbers: Sarcopenic Subjects (n = 5) | Cross-sectional | 16S rRNA sequencing | Species: Faecalibacterium prausnitzii, Roseburia inulinivorans, and Alistipes shahii | 8 | |
| Non-Sarcopenic Controls: (n = 12) | |||||||||
| Age: Sarcopenic Subjects (77 (75.5–86) ) | |||||||||
| Non-Sarcopenic Controls: (71.5 (70–75) ) | |||||||||
| Sex: Sarcopenic Subjects: women = 4 (80%) | |||||||||
| Non-Sarcopenic Controls: women = 10 (83.3%) | |||||||||
| Picca et al. (2019) | Italy | Frailty according to SPPB | Sarcopenia according to FNIH | Numbers: Frail and Sarcopenic (n = 18) | Cross-sectional | 16S rRNA sequencing | Family: Peptostreptococcaceae, Bifidobacteriaceae | Genus: Slackia, Eubacterium | 9 |
| Nonsarcopenic Nonfrail (n = 17) | Genus: Dialister, Pyramidobacter, and Eggerthella | ||||||||
| Age: Frail and Sarcopenic (75.5 ± 3.9) | |||||||||
| Nonsarcopenic Nonfrail (73.9 ± 3.2) | |||||||||
| Sex: Frail and Sarcopenic: women = 10 (56%) | |||||||||
| Nonsarcopenic Nonfrail: women = 5 (29%) |
L3 SMI: L3 skeletal muscle index; FNIH: Foundation for the National Institutes of Health; AWGS: Asian Working Group for Sarcopenia; CKD: Chronic Kidney Disease; EWGSOP: European Working Group on Sarcopenia in Older People, aPG-SGA: abridged Patient-Generated Subjective Global Assessment; SPPB: Short Physical Performance Battery; SMI: Skeletal Muscle Mass Index.
Characteristics of included human studies.
| Study | Country | Predisposing disease | Diagnosis method of muscle wasting | Population characteristics | Study design | Microbiota assessment method | Bacterial detected significantly higher abundance | Bacterial detected significantly lower abundance | Quality assessment score |
|---|---|---|---|---|---|---|---|---|---|
| Ren et al. (2021) | China | liver cirrhosis | Muscle-wasting according to L3 SMI index | Numbers: Case: Patients with liver cirrhosis and muscle wasting (n = 30) | Case-control | 16S rRNA sequencing | Genus: Weissella unclassified | Family: Lachnospiraceae bacterium, Erysipelotrichaceae bacterium | 9 |
| Control: Liver cirrhosis without muscle wasting (n = 30) | Species: Peptostreptococcus stomatis, Escherichia coli, Bacteroides coprocola, Bacteroides caccae, Eubacterium infirmum, and Bacteroides faecis | Genus: Granulicella unclassified, Eggerthella unclassified | |||||||
| Healthy controls (n = 30) | Species: Bacteroides uniformis, Clostridium clostridioforme, Clostridium asparagiforme, Ruminococcus flavefaciens, Anaerostipes hadrus, and Bifidobacterium catenulatum | ||||||||
| Age: Case (Patients with liver cirrhosis and muscle wasting) : 45.50 ± 12.74 | |||||||||
| Control (Liver cirrhosis without muscle wasting) : 42.21 ± 12.40 | |||||||||
| Sex: Case: Women = 10 (33.3%) | |||||||||
| Control: Women = 14 (46.7%) | |||||||||
| Ponziani et al. (2021) | Italy | liver cirrhosis | Sarcopenia according to FNIH | Numbers: Case: Cirrhosis Sarcopenia (n = 19) | Case-control | 16S rRNA sequencing | Genus: Eggerthella | Phylum: Proteobacteria, Euryarchaeota | 9 |
| Control: Cirrhosis no Sarcopenia (n = 31) | Family: Methanobrevibaceae, prevotellaceae | ||||||||
| Controls: Sarcopenia (n = 14) | Genus: Akkermansia, Methanobrevibacter, Prevotella, and Verrcumicrobiaceae | ||||||||
| Controls no Sarcopenia (n = 36) | |||||||||
| Age: Case: Cirrhosis Sarcopenia: 70 (63–74) | |||||||||
| Control: Cirrhosis no Sarcopenia: 66 (58.5–76.5) | |||||||||
| Controls: Sarcopenia: 75.5 (72–77.25) | |||||||||
| Controls no Sarcopenia: 72.5 (58.25–75.25) | |||||||||
| Sex: Case: Cirrhosis Sarcopenia: women = 7 (36.84%) | |||||||||
| Control: Cirrhosis no Sarcopenia: women = 8 (25.81%) | |||||||||
| Controls: Sarcopenia: women = 6 (42.86%) | |||||||||
| Controls no Sarcopenia: women = 15 (41.67%) | |||||||||
| Kang et al. (2021) | China | Advanced age | Sarcopenia or possible sarcopenia according to AWGS | Numbers: Case: Sarcopenic: (n = 11) | Case-control | 16S rRNA sequencing | Family: Porphyromonadaceae, Lactobacillaceae | Phylum: Firmicutes | 8 |
| preCase: possibly sarcopenic: (n = 16) | Genus: Lactobacillus | Genus: Lachnospira, Fusicatenibacter, Roseburia, Eubacterium, and Lachnoclostridium | |||||||
| Control: Healthy: (n = 60) | |||||||||
| Age: Case: Sarcopenic: (76.45 ± 8.58) | |||||||||
| preCase: possibly sarcopenic: (74.00 ± 6.94) | |||||||||
| Control: Healthy: (68.38 ± 5.79) | |||||||||
| Sex: Case: Sarcopenic: women = 7 (63.64%) | |||||||||
| preCase: possibly sarcopenic: women = 11 (68.75%) | |||||||||
| Control: Healthy: women = 33 (55.00%) | |||||||||
| Margiotta et al. (2021) | Italy | Stage IIIb-IV CKD + Advanced age | Sarcopenia according to EWGSOP2 | Numbers: Sarcopenic (n = 18) | Cross-sectional | 16S rRNA sequencing | Family: Micrococcaceae, Verrucomicrobiaceae | Family: Veillonellaceae, gemellaceae | 10 |
| Not Sarcopenic (n = 45) | Genus: Megasphaera, Veillonella, Rothia, Coprobacillu, and Akkermansia | Genus: Acidaminococcus, Gemella | |||||||
| Age: Sarcopenic (83.1 ± 5.7) | |||||||||
| Not Sarcopenic (79.7 ± 6.2) | |||||||||
| Sex: Sarcopenic: women = 2 (11%) | |||||||||
| Not Sarcopenic: women = 17 (28%) | |||||||||
| Ni et al. (2021) | Hungry | Lung cancer | Cachexia according to aPG-SGA | Numbers: Cachexic lung cancer (n = 12) | Cross-sectional | 16S rRNA sequencing | Species: Klebsiella oxytoca | Species: Prevotella copri, Faecalibacterium prausnitzii, and Lactobacillus gasseri | 8 |
| Non-Cachexic lung cancer (n = 19) | |||||||||
| Age: Cachexic lung cancer (64.25 ± 4.16) | |||||||||
| Non-Cachexic lung cancer (64.11 ± 7.86) | |||||||||
| Sex: Cachexic lung cancer: women = 7 (58.3%) | |||||||||
| Non-Cachexic lung cancer: women = 5 (26.3%) | |||||||||
| Ticinesi et al. (2020) | Italy | Frailty according to SPPB | Sarcopenia according to SMI/height2 | Numbers: Sarcopenic Subjects (n = 5) | Cross-sectional | 16S rRNA sequencing | Species: Faecalibacterium prausnitzii, Roseburia inulinivorans, and Alistipes shahii | 8 | |
| Non-Sarcopenic Controls: (n = 12) | |||||||||
| Age: Sarcopenic Subjects (77 (75.5–86) ) | |||||||||
| Non-Sarcopenic Controls: (71.5 (70–75) ) | |||||||||
| Sex: Sarcopenic Subjects: women = 4 (80%) | |||||||||
| Non-Sarcopenic Controls: women = 10 (83.3%) | |||||||||
| Picca et al. (2019) | Italy | Frailty according to SPPB | Sarcopenia according to FNIH | Numbers: Frail and Sarcopenic (n = 18) | Cross-sectional | 16S rRNA sequencing | Family: Peptostreptococcaceae, Bifidobacteriaceae | Genus: Slackia, Eubacterium | 9 |
| Nonsarcopenic Nonfrail (n = 17) | Genus: Dialister, Pyramidobacter, and Eggerthella | ||||||||
| Age: Frail and Sarcopenic (75.5 ± 3.9) | |||||||||
| Nonsarcopenic Nonfrail (73.9 ± 3.2) | |||||||||
| Sex: Frail and Sarcopenic: women = 10 (56%) | |||||||||
| Nonsarcopenic Nonfrail: women = 5 (29%) |
| Study | Country | Predisposing disease | Diagnosis method of muscle wasting | Population characteristics | Study design | Microbiota assessment method | Bacterial detected significantly higher abundance | Bacterial detected significantly lower abundance | Quality assessment score |
|---|---|---|---|---|---|---|---|---|---|
| Ren et al. (2021) | China | liver cirrhosis | Muscle-wasting according to L3 SMI index | Numbers: Case: Patients with liver cirrhosis and muscle wasting (n = 30) | Case-control | 16S rRNA sequencing | Genus: Weissella unclassified | Family: Lachnospiraceae bacterium, Erysipelotrichaceae bacterium | 9 |
| Control: Liver cirrhosis without muscle wasting (n = 30) | Species: Peptostreptococcus stomatis, Escherichia coli, Bacteroides coprocola, Bacteroides caccae, Eubacterium infirmum, and Bacteroides faecis | Genus: Granulicella unclassified, Eggerthella unclassified | |||||||
| Healthy controls (n = 30) | Species: Bacteroides uniformis, Clostridium clostridioforme, Clostridium asparagiforme, Ruminococcus flavefaciens, Anaerostipes hadrus, and Bifidobacterium catenulatum | ||||||||
| Age: Case (Patients with liver cirrhosis and muscle wasting) : 45.50 ± 12.74 | |||||||||
| Control (Liver cirrhosis without muscle wasting) : 42.21 ± 12.40 | |||||||||
| Sex: Case: Women = 10 (33.3%) | |||||||||
| Control: Women = 14 (46.7%) | |||||||||
| Ponziani et al. (2021) | Italy | liver cirrhosis | Sarcopenia according to FNIH | Numbers: Case: Cirrhosis Sarcopenia (n = 19) | Case-control | 16S rRNA sequencing | Genus: Eggerthella | Phylum: Proteobacteria, Euryarchaeota | 9 |
| Control: Cirrhosis no Sarcopenia (n = 31) | Family: Methanobrevibaceae, prevotellaceae | ||||||||
| Controls: Sarcopenia (n = 14) | Genus: Akkermansia, Methanobrevibacter, Prevotella, and Verrcumicrobiaceae | ||||||||
| Controls no Sarcopenia (n = 36) | |||||||||
| Age: Case: Cirrhosis Sarcopenia: 70 (63–74) | |||||||||
| Control: Cirrhosis no Sarcopenia: 66 (58.5–76.5) | |||||||||
| Controls: Sarcopenia: 75.5 (72–77.25) | |||||||||
| Controls no Sarcopenia: 72.5 (58.25–75.25) | |||||||||
| Sex: Case: Cirrhosis Sarcopenia: women = 7 (36.84%) | |||||||||
| Control: Cirrhosis no Sarcopenia: women = 8 (25.81%) | |||||||||
| Controls: Sarcopenia: women = 6 (42.86%) | |||||||||
| Controls no Sarcopenia: women = 15 (41.67%) | |||||||||
| Kang et al. (2021) | China | Advanced age | Sarcopenia or possible sarcopenia according to AWGS | Numbers: Case: Sarcopenic: (n = 11) | Case-control | 16S rRNA sequencing | Family: Porphyromonadaceae, Lactobacillaceae | Phylum: Firmicutes | 8 |
| preCase: possibly sarcopenic: (n = 16) | Genus: Lactobacillus | Genus: Lachnospira, Fusicatenibacter, Roseburia, Eubacterium, and Lachnoclostridium | |||||||
| Control: Healthy: (n = 60) | |||||||||
| Age: Case: Sarcopenic: (76.45 ± 8.58) | |||||||||
| preCase: possibly sarcopenic: (74.00 ± 6.94) | |||||||||
| Control: Healthy: (68.38 ± 5.79) | |||||||||
| Sex: Case: Sarcopenic: women = 7 (63.64%) | |||||||||
| preCase: possibly sarcopenic: women = 11 (68.75%) | |||||||||
| Control: Healthy: women = 33 (55.00%) | |||||||||
| Margiotta et al. (2021) | Italy | Stage IIIb-IV CKD + Advanced age | Sarcopenia according to EWGSOP2 | Numbers: Sarcopenic (n = 18) | Cross-sectional | 16S rRNA sequencing | Family: Micrococcaceae, Verrucomicrobiaceae | Family: Veillonellaceae, gemellaceae | 10 |
| Not Sarcopenic (n = 45) | Genus: Megasphaera, Veillonella, Rothia, Coprobacillu, and Akkermansia | Genus: Acidaminococcus, Gemella | |||||||
| Age: Sarcopenic (83.1 ± 5.7) | |||||||||
| Not Sarcopenic (79.7 ± 6.2) | |||||||||
| Sex: Sarcopenic: women = 2 (11%) | |||||||||
| Not Sarcopenic: women = 17 (28%) | |||||||||
| Ni et al. (2021) | Hungry | Lung cancer | Cachexia according to aPG-SGA | Numbers: Cachexic lung cancer (n = 12) | Cross-sectional | 16S rRNA sequencing | Species: Klebsiella oxytoca | Species: Prevotella copri, Faecalibacterium prausnitzii, and Lactobacillus gasseri | 8 |
| Non-Cachexic lung cancer (n = 19) | |||||||||
| Age: Cachexic lung cancer (64.25 ± 4.16) | |||||||||
| Non-Cachexic lung cancer (64.11 ± 7.86) | |||||||||
| Sex: Cachexic lung cancer: women = 7 (58.3%) | |||||||||
| Non-Cachexic lung cancer: women = 5 (26.3%) | |||||||||
| Ticinesi et al. (2020) | Italy | Frailty according to SPPB | Sarcopenia according to SMI/height2 | Numbers: Sarcopenic Subjects (n = 5) | Cross-sectional | 16S rRNA sequencing | Species: Faecalibacterium prausnitzii, Roseburia inulinivorans, and Alistipes shahii | 8 | |
| Non-Sarcopenic Controls: (n = 12) | |||||||||
| Age: Sarcopenic Subjects (77 (75.5–86) ) | |||||||||
| Non-Sarcopenic Controls: (71.5 (70–75) ) | |||||||||
| Sex: Sarcopenic Subjects: women = 4 (80%) | |||||||||
| Non-Sarcopenic Controls: women = 10 (83.3%) | |||||||||
| Picca et al. (2019) | Italy | Frailty according to SPPB | Sarcopenia according to FNIH | Numbers: Frail and Sarcopenic (n = 18) | Cross-sectional | 16S rRNA sequencing | Family: Peptostreptococcaceae, Bifidobacteriaceae | Genus: Slackia, Eubacterium | 9 |
| Nonsarcopenic Nonfrail (n = 17) | Genus: Dialister, Pyramidobacter, and Eggerthella | ||||||||
| Age: Frail and Sarcopenic (75.5 ± 3.9) | |||||||||
| Nonsarcopenic Nonfrail (73.9 ± 3.2) | |||||||||
| Sex: Frail and Sarcopenic: women = 10 (56%) | |||||||||
| Nonsarcopenic Nonfrail: women = 5 (29%) |
L3 SMI: L3 skeletal muscle index; FNIH: Foundation for the National Institutes of Health; AWGS: Asian Working Group for Sarcopenia; CKD: Chronic Kidney Disease; EWGSOP: European Working Group on Sarcopenia in Older People, aPG-SGA: abridged Patient-Generated Subjective Global Assessment; SPPB: Short Physical Performance Battery; SMI: Skeletal Muscle Mass Index.
Characteristics of included animal studies.
| Study | Species | Number of species | Induction condition | Type of decreased muscular mass | Microbiota assessment method | Bacterial detected significantly higher abundance | Bacterial detected significantly lower abundance | Quality assessment score (unclear: 1, low risk: 2, highrisk: 0) |
|---|---|---|---|---|---|---|---|---|
| Pötgens et al., 2021 | Male, 7-week-old CD2F1 mice | Control (n = 8) cachectic mice (n = 8) | Colon carcinoma 26 (C26) | Cachexia | 16S rRNA sequencing | Phylum: Proteobacteria, Deferribacteres, and Verrucomicrobia | Phylum: Firmicutes | 7 |
| Family: Enterobacteriaceae, Deferribacteraceae, Enterococcaceae, Verrucomicrobiaceae, and Staphylococcaceae | Family: Lactobacillaceae, Ruminococcaceae | |||||||
| Chen et al. (2020) | Male, 5-week-old Sprague-Dawley rats | Control (n = 8) 5-Fu group (n = 8) | Chemotherapy-induced malnutrition | Muscle wasting according to grip strength tester (YLS-13A) | 16S rRNA sequencing | Phylum: Verrucomicrobia, Proteobacteria | Phylum: Firmicutes, Cyanobacteria | 10 |
| Family: Enterobacteriaceae, Verrucomicrobiaceae, Enterococcaceae, and Eubacteriaceae | Order: Clostridiales, Bacteroidales | |||||||
| Family: Lactobacillaceae, Prevotellaceae, Lachnospiraceae, and Porphyromonadaceae | ||||||||
| Pötgens et al. (2018) | Male, 7-week-old CD2F1 mice | Control group (n = 8) C26 group (n = 8) PFtoCT group (n = 8) PFtoC26 group (n = 8) | Colon carcinoma 26 (C26) | Cachexia | 16S rRNA sequencing | Phylum: Verrucomicrobia, Proteobacteria | Phylum: Bacteroidetes, Firmicutes, Family: Ruminococcaceae, Lachnospiraceae, Porphyromonadaceae, and Unclassified Clostridiales | 9 |
| Family: Enterobacteriaceae | ||||||||
| Species: Klebsiella oxytoca | ||||||||
| Bindels et al. (2018) | Male, 7-week-old CD2F1 mice | Control (n = 8) cachectic mice (n = 8) | Colon carcinoma 26 (C26) | Cachexia | 16S rRNA sequencing | Phylum: Verrucomicrobia | Order: unclassified_Bacteroidales | 10 |
| Class: unclassified Clostridia | Family: Ruminococcaceae | |||||||
| Order: Enterobacteriales | Genus: Dorea, ClostridiumlV, and Oscillibacter | |||||||
| Family: Enterococcaceae, Verrucomicrobiaceae, and Enterobacteriaceae | Species: Erysipelotrichaceae_incertae_sedis | |||||||
| Genus: Enterococcus, Flavonifractor, Akkermansia, Serratia, Raoultella, and ClostridiumXlVa | ||||||||
| Siddharth et al. (2017) | Male Wistar rats | 8 months rats (n = 9), 18 months rats, (n = 10) 24 months rats (n = 8) | Advanced age | Sarcopenia | 16S rRNA sequencing | Genus: Sutterella | Genus: Barnesiella | 6 |
| Study | Species | Number of species | Induction condition | Type of decreased muscular mass | Microbiota assessment method | Bacterial detected significantly higher abundance | Bacterial detected significantly lower abundance | Quality assessment score (unclear: 1, low risk: 2, highrisk: 0) |
|---|---|---|---|---|---|---|---|---|
| Pötgens et al., 2021 | Male, 7-week-old CD2F1 mice | Control (n = 8) cachectic mice (n = 8) | Colon carcinoma 26 (C26) | Cachexia | 16S rRNA sequencing | Phylum: Proteobacteria, Deferribacteres, and Verrucomicrobia | Phylum: Firmicutes | 7 |
| Family: Enterobacteriaceae, Deferribacteraceae, Enterococcaceae, Verrucomicrobiaceae, and Staphylococcaceae | Family: Lactobacillaceae, Ruminococcaceae | |||||||
| Chen et al. (2020) | Male, 5-week-old Sprague-Dawley rats | Control (n = 8) 5-Fu group (n = 8) | Chemotherapy-induced malnutrition | Muscle wasting according to grip strength tester (YLS-13A) | 16S rRNA sequencing | Phylum: Verrucomicrobia, Proteobacteria | Phylum: Firmicutes, Cyanobacteria | 10 |
| Family: Enterobacteriaceae, Verrucomicrobiaceae, Enterococcaceae, and Eubacteriaceae | Order: Clostridiales, Bacteroidales | |||||||
| Family: Lactobacillaceae, Prevotellaceae, Lachnospiraceae, and Porphyromonadaceae | ||||||||
| Pötgens et al. (2018) | Male, 7-week-old CD2F1 mice | Control group (n = 8) C26 group (n = 8) PFtoCT group (n = 8) PFtoC26 group (n = 8) | Colon carcinoma 26 (C26) | Cachexia | 16S rRNA sequencing | Phylum: Verrucomicrobia, Proteobacteria | Phylum: Bacteroidetes, Firmicutes, Family: Ruminococcaceae, Lachnospiraceae, Porphyromonadaceae, and Unclassified Clostridiales | 9 |
| Family: Enterobacteriaceae | ||||||||
| Species: Klebsiella oxytoca | ||||||||
| Bindels et al. (2018) | Male, 7-week-old CD2F1 mice | Control (n = 8) cachectic mice (n = 8) | Colon carcinoma 26 (C26) | Cachexia | 16S rRNA sequencing | Phylum: Verrucomicrobia | Order: unclassified_Bacteroidales | 10 |
| Class: unclassified Clostridia | Family: Ruminococcaceae | |||||||
| Order: Enterobacteriales | Genus: Dorea, ClostridiumlV, and Oscillibacter | |||||||
| Family: Enterococcaceae, Verrucomicrobiaceae, and Enterobacteriaceae | Species: Erysipelotrichaceae_incertae_sedis | |||||||
| Genus: Enterococcus, Flavonifractor, Akkermansia, Serratia, Raoultella, and ClostridiumXlVa | ||||||||
| Siddharth et al. (2017) | Male Wistar rats | 8 months rats (n = 9), 18 months rats, (n = 10) 24 months rats (n = 8) | Advanced age | Sarcopenia | 16S rRNA sequencing | Genus: Sutterella | Genus: Barnesiella | 6 |
Characteristics of included animal studies.
| Study | Species | Number of species | Induction condition | Type of decreased muscular mass | Microbiota assessment method | Bacterial detected significantly higher abundance | Bacterial detected significantly lower abundance | Quality assessment score (unclear: 1, low risk: 2, highrisk: 0) |
|---|---|---|---|---|---|---|---|---|
| Pötgens et al., 2021 | Male, 7-week-old CD2F1 mice | Control (n = 8) cachectic mice (n = 8) | Colon carcinoma 26 (C26) | Cachexia | 16S rRNA sequencing | Phylum: Proteobacteria, Deferribacteres, and Verrucomicrobia | Phylum: Firmicutes | 7 |
| Family: Enterobacteriaceae, Deferribacteraceae, Enterococcaceae, Verrucomicrobiaceae, and Staphylococcaceae | Family: Lactobacillaceae, Ruminococcaceae | |||||||
| Chen et al. (2020) | Male, 5-week-old Sprague-Dawley rats | Control (n = 8) 5-Fu group (n = 8) | Chemotherapy-induced malnutrition | Muscle wasting according to grip strength tester (YLS-13A) | 16S rRNA sequencing | Phylum: Verrucomicrobia, Proteobacteria | Phylum: Firmicutes, Cyanobacteria | 10 |
| Family: Enterobacteriaceae, Verrucomicrobiaceae, Enterococcaceae, and Eubacteriaceae | Order: Clostridiales, Bacteroidales | |||||||
| Family: Lactobacillaceae, Prevotellaceae, Lachnospiraceae, and Porphyromonadaceae | ||||||||
| Pötgens et al. (2018) | Male, 7-week-old CD2F1 mice | Control group (n = 8) C26 group (n = 8) PFtoCT group (n = 8) PFtoC26 group (n = 8) | Colon carcinoma 26 (C26) | Cachexia | 16S rRNA sequencing | Phylum: Verrucomicrobia, Proteobacteria | Phylum: Bacteroidetes, Firmicutes, Family: Ruminococcaceae, Lachnospiraceae, Porphyromonadaceae, and Unclassified Clostridiales | 9 |
| Family: Enterobacteriaceae | ||||||||
| Species: Klebsiella oxytoca | ||||||||
| Bindels et al. (2018) | Male, 7-week-old CD2F1 mice | Control (n = 8) cachectic mice (n = 8) | Colon carcinoma 26 (C26) | Cachexia | 16S rRNA sequencing | Phylum: Verrucomicrobia | Order: unclassified_Bacteroidales | 10 |
| Class: unclassified Clostridia | Family: Ruminococcaceae | |||||||
| Order: Enterobacteriales | Genus: Dorea, ClostridiumlV, and Oscillibacter | |||||||
| Family: Enterococcaceae, Verrucomicrobiaceae, and Enterobacteriaceae | Species: Erysipelotrichaceae_incertae_sedis | |||||||
| Genus: Enterococcus, Flavonifractor, Akkermansia, Serratia, Raoultella, and ClostridiumXlVa | ||||||||
| Siddharth et al. (2017) | Male Wistar rats | 8 months rats (n = 9), 18 months rats, (n = 10) 24 months rats (n = 8) | Advanced age | Sarcopenia | 16S rRNA sequencing | Genus: Sutterella | Genus: Barnesiella | 6 |
| Study | Species | Number of species | Induction condition | Type of decreased muscular mass | Microbiota assessment method | Bacterial detected significantly higher abundance | Bacterial detected significantly lower abundance | Quality assessment score (unclear: 1, low risk: 2, highrisk: 0) |
|---|---|---|---|---|---|---|---|---|
| Pötgens et al., 2021 | Male, 7-week-old CD2F1 mice | Control (n = 8) cachectic mice (n = 8) | Colon carcinoma 26 (C26) | Cachexia | 16S rRNA sequencing | Phylum: Proteobacteria, Deferribacteres, and Verrucomicrobia | Phylum: Firmicutes | 7 |
| Family: Enterobacteriaceae, Deferribacteraceae, Enterococcaceae, Verrucomicrobiaceae, and Staphylococcaceae | Family: Lactobacillaceae, Ruminococcaceae | |||||||
| Chen et al. (2020) | Male, 5-week-old Sprague-Dawley rats | Control (n = 8) 5-Fu group (n = 8) | Chemotherapy-induced malnutrition | Muscle wasting according to grip strength tester (YLS-13A) | 16S rRNA sequencing | Phylum: Verrucomicrobia, Proteobacteria | Phylum: Firmicutes, Cyanobacteria | 10 |
| Family: Enterobacteriaceae, Verrucomicrobiaceae, Enterococcaceae, and Eubacteriaceae | Order: Clostridiales, Bacteroidales | |||||||
| Family: Lactobacillaceae, Prevotellaceae, Lachnospiraceae, and Porphyromonadaceae | ||||||||
| Pötgens et al. (2018) | Male, 7-week-old CD2F1 mice | Control group (n = 8) C26 group (n = 8) PFtoCT group (n = 8) PFtoC26 group (n = 8) | Colon carcinoma 26 (C26) | Cachexia | 16S rRNA sequencing | Phylum: Verrucomicrobia, Proteobacteria | Phylum: Bacteroidetes, Firmicutes, Family: Ruminococcaceae, Lachnospiraceae, Porphyromonadaceae, and Unclassified Clostridiales | 9 |
| Family: Enterobacteriaceae | ||||||||
| Species: Klebsiella oxytoca | ||||||||
| Bindels et al. (2018) | Male, 7-week-old CD2F1 mice | Control (n = 8) cachectic mice (n = 8) | Colon carcinoma 26 (C26) | Cachexia | 16S rRNA sequencing | Phylum: Verrucomicrobia | Order: unclassified_Bacteroidales | 10 |
| Class: unclassified Clostridia | Family: Ruminococcaceae | |||||||
| Order: Enterobacteriales | Genus: Dorea, ClostridiumlV, and Oscillibacter | |||||||
| Family: Enterococcaceae, Verrucomicrobiaceae, and Enterobacteriaceae | Species: Erysipelotrichaceae_incertae_sedis | |||||||
| Genus: Enterococcus, Flavonifractor, Akkermansia, Serratia, Raoultella, and ClostridiumXlVa | ||||||||
| Siddharth et al. (2017) | Male Wistar rats | 8 months rats (n = 9), 18 months rats, (n = 10) 24 months rats (n = 8) | Advanced age | Sarcopenia | 16S rRNA sequencing | Genus: Sutterella | Genus: Barnesiella | 6 |
Primary outcomes
Age-related sarcopenia in human studies
Multiple alterations in gut microbiota composition were detected between age-related sarcopenia cases and healthy controls when comparing the abundance of different bacteria. Porphyromonadaceae, Lactobacillaceae, Peptostreptococcaceae, and Bifidobacteriaceae families were more detected in individuals with age-related sarcopenia. At the genus level, these patients had a higher amount of Lactobacillus, Dialister, Pyramidobacter, and Eggerthella. On the other hand, firmicutes were found to be lower in these patients compared to the control group. The genera that decreased in individuals with age-related sarcopenia were Lachnospira, Fusicatenibacter, Roseburia, Eubacterium, Lachnoclostridium, and Slackia. Also, the lower amount of some species, including F. prausnitzii, R. inulinivorans, and A. shahii were detected in these patients (Picca et al. 2019, Ticinesi et al. 2020, Kang et al. 2021). Fig. 2 illustrates a schematic chart of bacterial taxonomy of altered gut microbiota composition in age-related sarcopenia among human studies.
Schematic chart of bacterial taxonomy of altered gut microbiota composition in age-related sarcopenia among human studies.
Muscle wasting in patients with liver cirrhosis
The human studies investigating the microbial composition of muscle wasting in patients with liver cirrhosis showed a significant increase in W. unclassified and Eggerthella. Moreover, species that were more abundant in the individual with muscle wasting due to liver cirrhosis were P. stomatis, E. coli, B. coprocola, B. caccae, E. infirmum, and B. faecis. At the same time, the proteobacteria and euryarchaeota phyla were less present in these patients. Lachnospiraceae bacterium, E. bacterium, and Methanobrevibaceae, families were significantly detected lower than controls. At the genus level, G. unclassified, E. unclassified, Akkermansia, Methanobrevibacter, Prevotella, and Verrcumicrobiaceae were less abundant than healthy individuals. Among the species, B. uniformis, C. clostridioforme, C. asparagiforme, R. flavefaciens, A. hadrus, and B. catenulatum were detected to be significantly decreased in these patients (Ponziani et al. 2021, Ren et al. 2021).
Muscle wasting in elderlies with renal failure sarcopenia and lung cancer
There are two other human studies that fulfilled our criteria in this review. Margiotta et al. (Margiotta et al. 2021) investigated the gut microbiota composition in Stage IIIb-IV CKD with advanced age with and without sarcopenia. This study revealed the abundance of Micrococcaceae, and Verrucomicrobiaceae at the family level and Megasphaera, Veillonella, Rothia, Coprobacillu, and Akkermansia at the genus level were significantly increased. In contrast, the abundance of Veillonellaceae and gemellaceae at the family level and Acidaminococcus, and Gemella at the genus level were significantly decreased. Ni et al. (2021) studied the relationship between lung cancer-induced cachexia and gut microbiota. This study indicated that three species, including P. copri, F. prausnitzii, and L. gasseri were significantly decreased. Moreover, they suggested that there is a positive correlation between K. oxytoca and lung cancer-induced cachexia.
Colon carcinoma-induced cachexia in animal studies
Among animal studies, four articles investigated the effect of colon carcinoma induction on the gut microbiota composition. At the phylum level, three phyla, including Proteobacteria (Pötgens et al. 2018, Chen et al. 2020, Pötgens et al. 2021), and Deferribacteres (Pötgens et al. 2021), and Verrucomicrobia (Bindels et al. 2018, Pötgens et al. 2018, Chen et al. 2020, Pötgens et al. 2021), were reported to be significantly higher in abundance than control groups, whereas Firmicutes (Pötgens et al. 2018, Chen et al. 2020, Pötgens et al. 2021), Cyanobacteria (Chen et al. 2020), and Bacteroidetes (Pötgens et al. 2018) were lower in the gut microbiota of cachectic animals.
Enterobacteriaceae (Bindels et al. 2018, Pötgens et al. 2018, Chen et al. 2020, Pötgens et al. 2021), Deferribacteraceae (Pötgens et al. 2021), Enterococcaceae (Bindels et al. 2018, Chen et al. 2020, Pötgens et al. 2021), Verrucomicrobiaceae (Bindels et al. 2018, Chen et al. 2020, Pötgens et al. 2021), Staphylococcaceae (Pötgens et al. 2021), and Eubacteriaceae (Chen et al. 2020) families were higher in animals with cachexia than control groups, and the abundance of Lactobacillaceae (Chen et al. 2020, Pötgens et al. 2021), Ruminococcaceae (Bindels et al. 2018, Pötgens et al. 2018, Pötgens et al. 2021), Prevotellaceae (Chen et al. 2020), Lachnospiraceae (Pötgens et al. 2018, Chen et al. 2020), Porphyromonadaceae (Chen et al. 2020), Porphyromonadaceae (Pötgens et al. 2018), and Unclassified Clostridiales (Pötgens et al. 2018) were decreased in cachectic animals.
Enterobacteriales as the order was found to be more dominant in the microbiota of cachectic animals (37). Also, Enterococcus, Flavonifractor, Akkermansia, Serratia, Raoultella, and ClostridiumXlVa were genera reported to have higher abundance than the control group, while Dorea, ClostridiumlV, and Oscillibacter were less in cases with muscle wasting compared to healthy animals (Bindels et al. 2018). The species more present in animals with muscle wasting was K. oxytoca (Pötgens et al. 2018), where E._incertae_sedis was significantly decreased in the microbial profile of cachectic animals (Bindels et al. 2018).
Discussion
This systematic review demonstrated some alterations in the gut microbiota composition of muscle-wasted humans and animals due to the different conditions and diseases.
In age-related sarcopenia, there was a decrease in the abundance of Lachnospira, Fusicatenibacter, Roseburia, and Lachnoclostridium that are from the Lachnospiraceae family (Ticinesi et al. 2020, Kang et al. 2021). Lachnospiraceae comprises 58 genera and multiple unclassified strains, which all of them are obligate anaerobic and share a common capacity to synthesize short-chain fatty acids (SCFAs) , especially butyrate, a crucial molecule that impact host physiology (Vacca et al. 2020). SCFAs are derived from the gut microbiota fermentation of indigestible carbohydrates and absorbed from the intestinal lumen. These products have crucial physiological activities by modulating metabolic response in various organ sites, including skeletal muscle. SCFAs have been illustrated to diminish inflammation and play a critical role in preserving skeletal muscle mass (González Hernández et al. 2019, Hsu et al. 2021). Butyrate enhances the intestinal barrier function by supporting tight junction assembly, which would consequently result in attenuation of endotoxin translocation and a reduction of systematic inflammation (Bach Knudsen et al. 2018, Bridgeman et al. 2020). Moreover, a reduction in SCFA production could cause insulin resistance and fatty acid accumulation within muscle cells (Gao et al. 2009). SCFAs improve insulin sensitivity and glucose uptake in hepatic and peripheral tissues via several mechanisms, including suppressing inflammatory pathways via activating regulatory T cells, decreasing the production of adipose tissue-derived cytokines and chemokines, and decreasing lipid overflow, which may result in reducing fat storage and increasing fat oxidation in muscle tissue (Canfora et al. 2015). These data indicate a correlation between a decrease in the abundance of butyrate-producing families and the evolution of muscle loss. Interestingly, F. prausnitzii from the Oscillospiraceae family, as a main SCFA-producing bacterial group, has been reported to decrease in frail patients. This observation fortifies one of the possible hypotheses describing the role of these bacteria in the human gut and their direct relationship in causing muscle loss in the elderly (Ticinesi et al. 2020). Moreover, these studies have been shown that Porphyromonadacea, which is associated with metabolic syndrome, increases in abundance in sarcopenic elderlies (Li et al. 2019, Zhang et al. 2021). Accumulation of intramuscular fat in muscle wasting may be associated with metabolic syndrome via the interplay of diverse factors, such as insulin resistance, oxidative stress, body adiposity, and increased proinflammatory cytokines (Li et al. 2019, Zhang et al. 2021).
In this systematic review, we have also demonstrated gut dysbiosis in some chronic diseases such as liver cirrhosis with sarcopenia (Ponziani et al. 2021, Ren et al. 2021). The results showed decreased alpha diversity and variations in gut microbiota composition in sarcopenic cirrhotic patients compared with their nonsarcopenic counterparts as well as with sarcopenic controls. This result indicated that the gut microbiota alteration in sarcopenia due to chronic diseases is different from sarcopenia due to normal aging. For instance, in muscle wasting due to liver cirrhosis Akkermansia, Methanobrevibacter, Prevotella, and Verrcumicrobiaceae showed a significant decrease compared to healthy individuals (Ponziani et al. 2021, Ren et al. 2021). The critical role of Methanobrevibacter in increasing lean body mass by enhancing the digestion of polysaccharide through the synthesis of SCFAs has been shown in vitro and in vivo studies (Samuel and Gordon 2006, Samuel et al. 2007, Kamil et al. 2021). Prevotella species are small anaerobic gram-negative rods of the Bacteroidetes phylum, which have an essential role in promoting immune responses by activating Toll-like receptor 2, resulting in secretion of interleukin-23 (IL-23) and IL-1. Moreover, Prevotella induces gut epithelial cells to produce IL-8, IL-6, and CCL20, enhancing mucosal Th17 immune responses and neutrophil recruitment (Larsen 2017). The increase in Prevotella has been shown in young professional athletes, and the decrease in Prevotella in frailty compared to less frail elderly is the evidence that reinforces the hypothesis that this bacterium may participate in mechanisms associated with the maintenance of muscle strength by altering gut permeability as reported in muscle-wasting diseases (Fielding et al. 2019). Another crucial factor that could describe the effect of Prevotella reduction in gut microbiota composition in these patients is the drop in absorption of SCFAs, especially propionate and butyrate, which have muscular mass-improving properties (Louis and Flint 2017). Furthermore, the abundance of some other bacteria increases significantly in liver cirrhotic patients with muscle wasting compared with patients with normal muscle mass. Peptostreptococcus stomatis and E. coli are among the bacteria that increase significantly in cirrhotic patients with sarcopenia (Ren et al. 2021). These bacteria cause inflammation and endotoxemia in the patients, which would deteriorate the progression of liver cirrhosis. The overexpression of cytokines or chemokines expressed in sarcopenic cirrhotic patients may be justified by the dysbiosis associated with this disease, including the increase in microbes that cause inflammation mentioned above and the decrease of bacteria with anti-inflammatory effects such as Akkermansia (Ponziani et al. 2021, Ren et al. 2021).
In the animal studies, there was consensus on some special bacteria in most studies. Four studies have indicated that Verrucomicrobia and Enterobacteriaceae increased in muscle-wasted animals compared to control groups (Bindels et al. 2018, Pötgens et al. 2018, Chen et al. 2020, Pötgens et al. 2021). Enterobacteriaceae are facultative anaerobes, rod-shaped Gram-negative bacteria that trigger pro-inflammatory processes via lipopolysaccharides (LPS) binding on Toll-like receptor 4 (TLR4) (Lüthje and Brauner 2014). LPS is recognized by TLR4 in muscle cells, which initiate the NF-kB pathway (Wang and Pessin 2013). Recent studies have been indicated the role of NF-kB in cachexia in animal models via inducing inflammation and inhibiting the regeneration of myofibers after muscle atrophy (Fry et al. 2016, Thoma and Lightfoot 2018, Dasgupta et al. 2020). Moreover, NF-kB boosts the ubiquitin-proteasome system that participates in the degradation of muscle proteins during atrophy in response to TNF-a (Li et al. 2008). Also, Proteobacteria is shown to be significantly abundant in muscle-wasted animals in three studies and can influence muscle mass by the same pathway as its family subtype (Enterobacteriaceae) (Pötgens et al. 2018, Chen et al. 2020, Pötgens et al. 2021).
There are some strengths and limitations in this systematic review. This review included both human and animal studies that investigate the alterations of gut microbiota composition in muscle loss conditions. This review captured data with a comprehensive systematic search using all relevant keywords and summarized the results to explain the probable role of gut microbiota dysbiosis in skeletal muscle wasting. There are also some limitations in this study. Various types of the investigated muscle loss diseases and differences in the design and the participants' basic characteristics of the included studies caused discrepancies in the available evidence, making it complicated to achieve a single integrated microbial profile describing the underlying pathophysiology.
Conclusion
In conclusion, this systematic review presents a novel perspective on the gut microbiota alterations associated with skeletal muscle wasting as a complication of various pathologies, including aging sarcopenia, renal failure, and cancer cachexia in both human and animal studies. The possible mechanism that could justify this pathology is an increase in the bacteria that trigger inflammation in the body and a decrease in the bacteria that produce beneficiary substances in the intestine, such as SCFAs, which have been demonstrated to have protective effects against muscle wasting.
Acknowledgements
Not applicable
Conflict of interest
No conflict of interest declared.
Funding
Not applicable.
Ethics declarations and consent to participate
Not applicable.
Consent for publication
Not applicable.
Authors contributions
The concept of this study was proposed by H.-S.E., This study was designed by H.-S.E., B.L., Data collection or processing was done by A.N., M.T., F.E., A.P., F.H., Interpretation was performed by H.-S.E., A.N. Literature search was done by H.-S.E., A.N. This study was written by A.N., H.-S.E., All authors have read and approved the manuscript.
Availability of data and materials
All information has been collected from open-access publications, available in public domain and have been appropriately cited at respective sections.
