Muscular dystrophies are primarily caused by genetic mutations and may show clinical heterogeneity among patients. Alterations in gut microbiota (GM) and its microbial metabolites may disturb skeletal muscle metabolism and affect muscle dystrophies.^{Reference Russo, Surdo, Valle and Malaguernera1} The authors have provided important clinical data on understanding how the gut–muscle axis works in fascioscapulohumeral dystrophy (FSHD), which is caused by the altered expression of the double homeobox protein 4 (DUX4) transcription factor in skeletal muscle.^{Reference Hangul, Ozyurt and Baldi2}

In this case-control study, 28 FSHD patients with different clinical severities are matched with healthy controls (HC). The authors hypothesized that dysbiosis of the GM and associated microbial metabolites may be contributing factors in FSHD pathogenesis. Therefore, the association between clinical severity of the disease and D4Z4 methylation with GM and free fatty acids was investigated.

The authors demonstrated significant differences in alpha and beta diversity indices between patients and HC, suggesting gut dysbiosis in FSHD. Severe patients had increased Pasteurellaceae species compared to mild ones. The authors provide a number of suggestions on how GM and microbial metabolites might play a role in FSHD pathogenesis. GM-derived short-chain fatty acids (SCFAs) broadly support muscle health.^{Reference Liu, Xu, Wang and Zhu3} The authors report a significant decrease in fecal SCFAs of FSHD patients but an increase in circulating levels, which seems contradictory. However, this finding is explained by the impaired intestinal barrier permeability, which allows SCFAs to enter the systemic circulation as mentioned in other reports.^{Reference Russo, Surdo, Valle and Malaguernera1,Reference Zhang, Tang and Guo4,Reference Chew, Lim and Lim5} A significant increase in butyric acid plasma levels is observed, which is a potent inhibitor of histone deacetylase (HDAC) activity. HDAC inhibition, in turn, may have increased DUX4 gene expression and DUX4 protein through hypomethylation in myocytes of FSHD patients, which has a pivotal role in disease pathogenesis.

The authors concluded that modulation of GM may represent a promising therapeutic avenue for the management of FSHD. This clinical study is noteworthy considering the scarcity of clinical trials on GM changes in dystrophies, a field that has thus far been predominantly informed by results from animal studies. As clinical studies increase, potential interventions to improve the disease course will become clearer. The authors have pointed out that some factors such as diet, which could affect microbiota changes, were beyond their control and were among the limitations of the study. Further clinical studies may bring a range of new approaches such as customized diets and pre/probiotics to design or protect GM for the sake of muscle health in dystrophies.