Carpal tunnel at the wrist is an anatomical space that contains the carpal bones, transverse carpal ligament, median nerve, and finger flexor tendons. Pathologically, compression of the median nerve in the wrist as it passes through the space-constrained carpal tunnel can cause CTS[5]. In effect, anything that causes a reduction in the volume of this compartment or increases the pressure within the compartment (such as edema, tendon inflammation, endocrine changes and physical activity) may precipitate or cause the symptoms of carpal tunnel syndrome[22, 5]. To our knowledge, this is the first time to investigate the causal associations comprehensively and deeply between gut microbiome and CTS based on publicly available genetic databases. Findings of our research suggested that multiple gut microbial taxa play crucial roles in the development of CTS, including 4 causal microbial taxa and 11 protective taxa.
By comparing our results with previous studies, it was found that these significant CTS-related gut microbial taxa can affect CTS directly or indirectly through several ways, such as Lachnospira genus and Victivallis genus. Results from a study of a continuous cross-sectional cohort by Zhang Li et al. showed that the abundance of Lachnospira was significantly lower in patients with ankylosing spondylitis than in healthy controls[23]. A study of Immune-mediated inflammatory disease (IMID) showed that abundances of Lachnospira were significantly lower in all disease cohorts including rheumatoid arthritis (RA) relative to healthy control[24]. Some gut microbiome such as Lachnospira genus and Victivallis genus[25] that produce short-chain fatty acids (SCFAs) are thought to have anti-inflammatory properties[26]. It is now believed that systemic low-grade chronic inflammation can play a key role in CTS by promoting median nerve vascular atherosclerosis and sub-synovial connective tissue fibrosis[27]. In addition, new researches emerged in recent years showed the positive effects of SCFAs on bone health. The study of Yao et al.[28] showed that the levels of four SCFAs (acetate, propionate, butyrate, and valerate) were lower in RA patients. They then performed intervention experiments in collagen-induced arthritis (CIA) mice and found that acetate, propionate and butyrate alone can improve CIA, but a combination of all three is best. An animal study[29] that examined whether SCFAs affects bone metabolism showed a significant increase in bone mass and a decrease in bone resorption in mice treated with SCFAs for 8 weeks. Another animal study[30] showed that SCFAs have positive effects on skeletal muscle physiology and pathophysiology. Long-term administration of butyrate to regularly aged mice prevented hindlimb muscle atrophy, prevented intramuscular fat accumulation, increased markers of mitochondrial biogenesis, and reduced markers of oxidative stress and apoptosis[30]. In conclusion, SCFAs may influence bone metabolism through multiple mechanisms, including inhibition of inflammatory responses, improvement of intestinal calcium absorption, promotion of osteoblast differentiation via regulatory T cells (Tregs), and direct inhibition of osteoclast differentiation[31].
In our study, Actinobacteria is positively associated with CTS. However, several previous studies have reported that Actinobacteria exhibits a positive effect on bone. A study focusing on older populations by C Li et al. showed that Actinobacteria was positively related to BMD and T-scores[32]. In one study, a decrease of Actinobacteria enhanced intestinal permeability, leading to the entry of lipopolysaccharides (LPS) into the serum[33]. The physiological importance of alterations in intestinal permeability and inflammation has been highlighted in previous rodent studies, in those studies, gut microbiome that reduce intestinal permeability or reduce inflammation may reduce bone resorption and prevent bone loss[34]. In addition, some LPS-associated gut microbiome were identified in our study, such as Alphaproteobacteria, Butyrivibrio and Victivallis. LPS is an endotoxin associated with the outer membrane of various Gram-negative pathogens[35]. LPS has been shown to be a key factor in triggering episodes of low-grade inflammation and insulin resistance[36]. By causing systemic low-grade inflammation, LPS enters the body's circulation and affects many organs, including joints[37]. Studies have shown that LPS decreases intestinal barrier permeability both in vitro and in vivo[38], which in turn affects the absorption of calcium, phosphorus, etc. LPS has the potential to inhibit osteoclast production and suppress bone resorption[39]. A correlation study between LPS and OA showed that serum LPS was correlated with the severity of knee osteoarthrosis as well as a positive correlation between LPS and the severity of knee gap narrowing and the total Western Ontario and McMaster Osteoarthritis Index(WOMAC) score[37].
However, some of gut microbiome found in our study were contrary to previous research findings, such as Methanobacteriaceae and Rikenellaceae. A rat experiment showed that in diet-induced obesity rat, Methanobacteriaceae showed a positive correlation with pro-inflammatory factors in serum, synovial fluid and Mangin scores[40]. The functions of Rikenellaceae are not yet well understood. In our result, Rikenellaceae was negatively associated with the risk of CTS. A study[41] by Ozaki et al. showed that Rikenellaceae were higher in the low BMD group and in the high tartrate-resistant acid phosphatase 5b group, suggesting that this family may be negative for bone resorption and bone density. An animal study showed that Alistipes, which belongs to the Rikenellaceae family, has a negative effect on bone metabolism[42]. In metabolism, Rikenellaceae are abundant in people with diabetes[43]. In addition to the mentioned gut microbial taxa above, our study also identified several gut microbial taxa such as Intestinimonas, Lachnoclostridium, Oxalobacter are causally associated with CTS, and yet further studies are expected to support our observations.
According to the results of sensitivity analysis, there was no evidence of horizontal pleiotropy but there was heterogeneity in the included IVs of Actinobacteria class (P = 0.003) and Butyrivibrio genus. Reverse-direction MR analysis showed that there is not causal effect of CTS on 15 gut microbial taxa.
Combining the above studies, we hypothesize that gut microbiome-mediated alterations in bone mass show a U-shaped curve in the development of CTS. Excessive bone mass leads to narrowing of the carpal tunnel and compression of the median nerve and blood vessels, resulting in CTS; when bone mass decreases, the increased risk of osteoporosis and distal radius fracture also leads to CTS. However, more epidemiological studies on this issue are still required. In addition, gut microbiome can influence the development of CTS by affecting metabolic-related risk factors for CTS such as obesity, diabetes mellitus, and abnormal thyroid function. Previous studies showed that Actinobacteria[44] were positively associated with obesity and Porphyromonadaceae[45], Blautia[46], Turicibacter[47] were negatively associated with obesity; Actinobacteria[48] showed a high positive association with FBG and HbA1c and Blautia[49] was negatively associated with FBG and HbA1c levels. Rikenellaceae were enriched in participants without type 2 diabetes[50].
There were several strengths and limitations in our study. The approach was based on large-scale GWAS summary statistics that are publicly available, thus offers an efficient option to mine reliable genetic information without additional experiment costs. This study was based on a large number of study samples, reducing errors due to the small sample size. However, there are some limitations: first, although these gut microbiome taxa have been identified, further studies are needed to reveal the role in the pathogenesis of CTS. Second, the lack of individual data prevented further population stratification studies (e.g., sex) and exploration of possible differences in different populations. Most important, the GWASs data in this study were derived from European ancestry, so our findings may not be generalizable across ethnic groups.
In conclusion, this study systematically explored the relationships between gut microbiome and CTS. The causal relationship between multiple gut microbes and CTS was found. These findings could contribute to an in-depth understanding of the mechanisms of CTS and provide new therapeutic targets.