Gut microbiota and metabolomics in degenerative rotator cuff tendinopathy: a case-control study
Patients with symptomatic degenerative rotator cuff tendinopathy show gut dysbiosis with enrichment of pro-inflammatory bacteria and depletion of SCFA producers, associated with tryptophan metabolism and ferroptosis pathway alterations — an unfavorable direction in cases versus controls, with no causal inference possible.
| Population | 60 adults with symptomatic dRCT confirmed by clinical examination and MRI (after excluding 1), group-matched with 60 healthy controls by age, sex, and BMI |
|---|---|
| Exposure | Gut microbiota profiling (16S rRNA amplicon sequencing) and untargeted plasma metabolomics |
| Comparator | 60 healthy controls group-matched by age, sex, and BMI |
| Outcome | Gut microbiota β-diversity; Pro-inflammatory bacterial abundance (Segatella, Megamonas, Klebsiella, Desulfovibrio); SCFA-producing bacteria abundance (Gemmiger, Eubacterium_ruminantium); Differential tryptophan metabolites (including indole-3-acetaldehyde); Ferroptosis-related metabolomics; Segatella/Megamonas correlation with vitamin E and indole-3-acetaldehyde; Predicted microbial functional pathways (PICRUSt2): LPS biosynthesis, flagellar assembly |
Summary of findings
| Outcome | Effect | 95% CI | Certainty | Clinical relevance | Notes |
|---|---|---|---|---|---|
| Gut microbiota β-diversity | P = 0.014 (no effect size or 95% CI reported) | — | Low | — | 1 studies |
| Pro-inflammatory bacterial abundance (Segatella, Megamonas, Klebsiella, Desulfovibrio) | LEfSe enrichment in dRCT group (LDA score not reported in available text) | — | Low | — | 1 studies |
| SCFA-producing bacteria abundance (Gemmiger, Eubacterium_ruminantium) | LEfSe enrichment in controls vs dRCT (LDA score not reported in available text) | — | Low | — | 1 studies |
| Differential tryptophan metabolites (including indole-3-acetaldehyde) | KEGG enrichment significant; in the effect size or 95% CI reported | — | Low | — | 1 studies |
| Ferroptosis-related metabolomics | KEGG enrichment significant in positive ion mode; in the effect size or 95% CI reported | — | Low | — | 1 studies |
| Segatella/Megamonas correlation with vitamin E and indole-3-acetaldehyde | negative correlation reported; r value and 95% CI not reported in available text | — | Low | — | 1 studies |
| Predicted microbial functional pathways (PICRUSt2): LPS biosynthesis, flagellar assembly | inferred upregulation in dRCT via PICRUSt2; in the direct measurement, in the effect size reported | — | Very low | — | 1 studies |
Context
Degenerative rotator cuff tendinopathy affects over 15% of individuals above 60 years and carries a post-surgical retear rate of 20–60%, suggesting unaddressed systemic components. The gut-tendon axis hypothesis is biologically plausible but lacked direct human evidence. This is the first human multi-omics study to systematically address this relationship.
What the study showed
β-diversity differed significantly between groups (P = 0.014). The dRCT group was enriched in Bacteroidota, Pseudomonadota, and pro-inflammatory genera (Segatella, Megamonas, Klebsiella, Desulfovibrio); controls were enriched in Bacillota and SCFA producers (Gemmiger, Eubacterium_ruminantium). Metabolomics identified 309 differential metabolites in positive ion mode and 226 in negative ion mode, with alterations in tryptophan metabolism and ferroptosis pathways. Segatella and Megamonas correlated negatively with indole-3-acetaldehyde and vitamin E; Gemmiger correlated positively with quinic acid — none of these correlations establish causality.
How it was done
Case-control study with group-level matching (age, sex, BMI); n = 120 (60 dRCT, 60 controls) after excluding 1 participant for insufficient sample volume. Single time-point fecal and plasma collection; 16S rRNA sequencing for microbiota, untargeted metabolomics for plasma, functional prediction via PICRUSt2, and microbiota-metabolome correlation analysis.
Effect magnitude
No effect size with 95% CI was reported for primary outcomes of β-diversity or taxon abundance; β-diversity statistical significance was P = 0.014 without a quantified effect measure (no RR, OR, SMD, or MD reported in available text).
Risk of bias
Cross-sectional (case-control) design precludes causal inference. No adjustment for dietary confounders, antibiotic use, comorbidities, or medications — all with direct microbiota impact. PICRUSt2 generates inferred, not directly measured, microbial functional predictions. No formal bias assessment tool was applied (ROBINS-I would be appropriate for observational studies). Single sampling point prevents temporal variability analysis.
What this study does NOT prove
This study does NOT prove that dysbiosis causes tendinopathy — association is not causation in a case-control design. Findings are not generalizable to other ethnicities, asymptomatic dRCT populations, or other tendinopathy subtypes.
In clinical practice
This study provides no basis for clinical microbiota interventions in dRCT patients. There is no evidence that probiotics, prebiotics, or dietary modulation alter tendinopathy course. Clinicians should await longitudinal and interventional studies before any recommendation based on these findings.
Limitations
Cross-sectional (case-control) design precludes causal inference. No adjustment for dietary confounders, antibiotic use, comorbidities, or medications — all with direct microbiota impact. PICRUSt2 generates inferred, not directly measured, microbial functional predictions. No formal bias assessment tool was applied (ROBINS-I would be appropriate for observational studies). Single sampling point prevents temporal variability analysis.
What is still missing
Longitudinal studies with repeated measures and animal models of microbiota manipulation are needed to test causality. Randomized trials testing microbiota interventions with tendon functional outcomes represent the critical next question.
Technical appendix
Version history
- 1.0 · 2026-10-05 — Auto-generated under Evidence Standard v1.0