Despite evidence suggesting that altered GM has been implicated in the pathogenesis of several complicated diseases, little work has been done to explore the genetic association between GM and HGS. In this study, using PRS and GWEIS analysis, several genetic associations between GM and HGS were identified, as well as significant loci interacted with GM effecting HGS. Polygenic risk scores (PRSs) analyses incorporating G × E effects provided evidence of shared aetiologies between HGS and GM, which might improve efficiency for candidate gene discovery.
Bifidobacteria was found to be associated with both left and right HGS in this study. Bifidobacteria are a group of bacteria that normally live in the intestines, most of which can be considered as a probiotic and taken by mouth as medicine. The role of Bifidobacteria in muscle function has been well studied recently. An experimental study investigated the effects of Bifidobacterium breve B-3 (B-3) on muscle function on mice[35]. And it turned out that the administration of B-3 on the mouse model could increase muscle mass and affect muscle metabolism, and the grip strength of heat-killed B-3 group was significantly higher than that of the control group[35]. Similarity, another study suggested that dietary supplementation with Bifidobacterium breve BR03 attenuates performance decrements and muscle tension in the days following muscle-damaging exercise [36]. Furthermore, Ni et al. and colleagues found Lactobacillus and Bifidobacterium supplementation enhanced muscle strength and function in aged mice by the GM regulation [37]. Also, the protecting role of Bifidobacterium in against obesity has been proposed [38]. Taken altogether, findings from previous work we discussed above indicated the important role of Bifidobacterium in muscle mass and metabolism on mice. However, the number of evidences about this relationship in human studies remained scarce. In our analysis, we found Bifidobacteria was associated with both right and left HGS in human. Further supporting evidence is needed to prove our results.
G_Butyricicoccus is another common significant GM associated with both right and left HGS in our study. Interesting, the interaction between nutrients and the GM in the context of obesity and related metabolic diseases has been well studied [39].Among them, Butyricicoccus is one of the obesity related GM. For example, an experimental analysis found after transplantation of the GM from obese individuals to high-fat diet-fed mice, they responded differently to inulin supplementation, with Butyricimonas associated with the observed metabolic outcomes (decrease in adiposity and hepatic steatosis) in human-obesity mice[40]. Furthermore, Butyricicoccus drives the decrease of body mass index in response to inulin in obese individuals, suggesting the important role of characterizing the specific consortia of bacteria in the context of obesity and metabolic diseases when improving in metabolic disorders by inulin[40]. Studies showed the potential role of Butyricicoccus in exercise physiology. For example, Tung et al. found a greater abundance and diversity of GM in intrinsic high exercise capacity mice than in low exercise capacity mice, indicating the potential effect of GM and functional proteins on intrinsic exercise capacity[41]. The important role of nutrients in muscle strength and HGS has been revealed in previous study[42], which is consistent with our results.
O_Lactobacillales is found to be associated with left HGS in our analysis. Lactobacillales is a well-known probiotic among the ingested-microorganism probiotics. Various biological function of Lactobacillales has been explored, including treating obesity [43], enhancing muscle strength and function[37], improving insulin sensitivity[44]. A study conducted on mouse model found forelimb grip strengths were 1.31 and 1.40 fold higher in the Lactobacillus plantarum TWK10-1X and Lactobacillus plantarum TWK10-5X groups than in the vehicle treatment group, indicating long-term supplementation with Lactobacillus plantarum TWK10 might increase in muscle mass and strength [45]. Similar conclusion about the role of Lactobacillus plantarum TWK10 in physiological homeostasis and health promotion was also drawn in human study [46]. In addition, another study evaluated the effect of Lactobacillus rhamnosus on GM, changes in permeability, and insulin sensitivity and signaling in high-fat diet and control animals, and they suggested the important role of probiotics to prevent and treat patients with obesity and insulin resistance [47].
G_Veillonella, G_Ruminococcus and P_Firmicutes were also identified to be related with HGS in our study. An analysis found Ruminococcus and Veillonella were significantly related to muscle improvement outcomes after soy-whey blended protein (SWP) treatment in hematopoietic stem cell transplantation patients, suggesting that intestinal microbiota might affect the regulation of muscle metabolism [48]. Interesting, gender and body mass index may influence intestinal microbiota. It was found that Veillonella is significantly higher in fecal samples in men compared to women, and these differences may be influenced by the grade of obesity [49]. The Firmicutes is one of two groups of beneficial bacteria that dominant in the human gut. A meta-analysis concluded that changes in Firmicutes and Bacteroidetes phyla/species levels might be significant indicators for childhood obesity[50]. Likewise, same conclusion was also drawn by other literature [51]. A high value of evidence indicated that muscle mass is an important criterion in nutrition status diagnosis, and HGS is used as an efficient tool for evaluating muscle functioning. Given the fact that the important role of HGS as an outcome predictor and marker of nutritional status[52], the relationship among microbiota, HGS and obesity deserves to be deeply explored. Our results were consistent with previous studies.
For GWEIS analysis, several significant SNPs were identified to be interacted with G_Butyricicoccus for HGS. Among them, rs41310432 is the most significant one (NASP, P = 3.86 × 10− 8). Nuclear autoantigenic sperm protein (NASP) encodes a H1 histone binding protein and it is cell-cycle regulated [53]. It is expressed in all cells undergoing division. Functions of NASP mainly involve liver cancer [54], immune response [55], and cell proliferation [56]. For example, previous studies have shown that in lupus model mice, NASP gene mutation can change the proportion of immune cells in the spleen and aggravate the autoimmune response [55]. In addition, Yang and colleagues found somatic NASP negatively regulates TRAF6, and is a key regulator of innate immunity [57]. Interestingly, TRAF6 has been demonstrated to be a novel regulator of skeletal muscle atrophy [58]. Another study showed that overexpression of miR-125b-5p targeting TRAF6 may provide a promising therapeutic approach to treat muscle atrophy [59]. We found NASP is interacted with G_Butyricicoccus for HGS in our study. Given the potential role of inflammation [60] and muscle mass in HGS based on previous studies, the association between HGS and NASP needs to be studied further.
Another suggestive gene we identified in GWEIS analysis is CACNA1H. Calcium Voltage-Gated Channel Subunit Alpha1 H (CACNA1H), encodes a T-type member of the alpha-1 subunit family, a protein in the voltage-dependent calcium channel complex. Previous study indicated compound heterozygous CACNA1H mutations might lead to severe congenital amyotrophy [61]. Another experimental analysis suggested reduced expression of CACNA1H related to multiple vaginal delivery is associated with muscular atrophy, indicating the key regulator role of CACNA1H in skeletal muscle function[62]. In our study, we found CACNA1H is interacted with G_Butyricicoccus and might affect HGS in UK Biobank samples. Further analyses are warranted to validate our results.
In this study, we analyzed the association between HGS and GM using large sample from UK Biobank via utilizing PRS and GWEIS analysis. PRSs analyses incorporating G × E effects provided evidence of shared aetiologies between HGS and GM. As far as we known, this is the first systemic study exploring the effect of GM as environmental factor on HGS. Besides, insight on interactions between GM and muscle mass from previous studies are mostly based on mouse studies rather than human studies. In addition, the large sample sizes guaranteed the accuracy of our results. Our study holds great potential for clarifying the functional relevance of GM with HGS.
Several issues in our study should be noted. Although several significant GM were identified to share common genetic etiology with HGS, as well as significant genes interacted with GM for HGS, further biological research should determine if these genes are true susceptibility loci for HGS in relation to GM. In addition, participants from our study are all European ancestry and so the conclusions that can be drawn are limited. Further analysis should include other ethnic groups.