Objective：To explore the effect of oral sodium butyrate on skeletal muscle atrophy in CT26 tumor mice through the gut microbiota - skeletal muscle axis and its potential mechanism.Methods：Sixty SPF BALB/c male mice aged 8 weeks were randomly divided into a normal control group （NC，n=12）and a ABX-depleted group (ABX，n=42).The ABX mice were pretreated with a quadruple antibiotic cocktail via oral gavage(0.2 ml per administration, once daily, 6 days per week, for 2 weeks) , whereas NC received an equal volume of sterile water. Six mice from each group were randomly selected for gut microbiota sequencing analysis.Following a 2-week antibiotic pretreatment, six mice were randomly selected from the ABX group to confirm successful microbiota depletion via gut microbiota sequencing. And the quadruple antibiotic cocktail consisted of metronidazole (1 g/L), vancomycin (0.5 g/L), ampicillin (1 g/L), and gentamicin (1 g/L).Following successful pretreatment, the remaining mice in ABX were subcutaneously inoculated in the dorsum with 0.2 mL of CT26 cell suspension (at a concentration of 1×10?cells/mL). Then these mice were then randomly allocated into three subgroups: a control tumor-bearing model group (0_NaB n=12), a tumor-bearing model group receiving low-dose oral sodium butyrate (L_NaB, n=12), a tumor-bearing model group receiving high-dose oral sodium butyrate (H_NaB, n=12). And Mice in NC were inoculated at the same site with 0.2 mL of normal saline.The administration dose for L_NaB was 0.3 g/ (kg·d), that for H_NaB was 0.5 g/ (kg·d), then NC and 0_NaB were given the same volume of normal saline (0.2ml per time, once daily, 6 days per week, for 4 weeks).General mouse condition was monitored, and forelimb grip strength gastrocnemius muscle mass and its muscle fiber cross-sectional area were measured for each group. The structural changes in gut microbiota were assessed by 16S rRNA sequencing of cecal contents. Pathological alterations in the intestinal wall were examined via HE staining. Serum and gastrocnemius muscle levels of TNF-α, IL-6, IL-1β, and LPS were quantified using ELISA. The protein expression of ZO-1 and Occludin in the small intestine, as well as proteins associated with the TLR4/MyD88/NF-κB signaling pathway in the gastrocnemius muscle, were detected by Western blot analysis. Results：(1) The α diversity in Abx was significantly lower than that in NC0 (P<0.05), with the majority of gut microbiota being effectively depleted. (2) Compared with NC, the subcutaneous tumors of mice in 0_NaB were prominent, a significant increase of the mass and muscle fiber cross-sectional area of the gastrocnemius，accompanied by a significant decrease in body weight at the end of the 3th and 4th (P < 0.05), and a significant weakening of the forelimb grasping strength at the 5th and 6th (P < 0.01). Compared with 0_NaB, the tumor mass of mice in L_NaB and H_NaB showed a significant decreasing trend, and the grip strength of the forelimbs significantly increased at the 5th and 6th (P<0.05, P<0.01). (3) Compared with 0_NaB, the Shannon and Observed species indices in α diversity of L_NaB and H_NaB were significantly increased (P<0.05). At the genus level, compared with 0_NaB, the relative abundance value of Escherichia-Shigella in H_NaB was significantly decreased (P<0.01).(4) Compared with 0_NaB , the small intestinal tissue structure in L_NaB and H_NaB was more intact, the infiltration of inflammatory cells was significantly reduced, and the capillaries were slightly dilated. And the expression levels of ZO-1 and Occludin proteins in L_NaB were significantly increased (P<0.01). (5) The LPS concentration in the gastrocnemius muscle and the protein expression levels of TLR4, MyD88, p-IκBα, and p-NF-κB p65 in L_NaB and H_NaB were significantly lower than those in 0_NaB (P < 0.05). The serum TNF-α concentration in H_NaB and TNF-αconcentration in the gastrocnemius muscle of the L_NaB and H_NaB were significantly lower than those in 0_NaB (P < 0.05，P < 0.01，P < 0.01).Conclusion: Oral administration of NaB can improve gut microbiota α diversity, adjusting its composition, improv?ing intestinal mucosal barrier function,reducing the LPS-induced pro-inflammatory response, and delaying skeletal muscle atrophy. The underlying mechanism may involve down regulation of TLR4/MyD88/NF-κB signaling in skeletal muscle.