Intervertebral disc degeneration (IDD) is the main cause of back pain, and its treatment is a serious socio‐economic burden. The safety and treatment of fecal microbiota transplantation (FMT) has been established. However, the relationship between FMT and IDD still unclear. We aimed to explore whether FMT plays a role in IDD to provide a reference for the treatment of IDD.An experimental model of IDD was established using 2‐month‐old male Sprague–Dawley rats. FMT was performed by intragastric gavage of IDD rats with a fecal bacterial solution. Rat serum, feces, and vertebral disc tissue were collected after surgery for 2 months. The levels of TNF‐α, IL‐1β, IL‐6, matrix metalloproteinase (MMP)‐3, MMP‐13, Collagen II, and aggrecan in the serum or vertebral disc tissue were measured by an enzyme‐linked immunosorbent assay, immunohistochemistry, quantitative real‐time polymerase chain reaction, or western blotting. We also examined the pathology of the vertebral disc tissue using hematoxylin and eosin (HE) and safranin O‐fast green staining. Finally, we examined the gut microbiota in rat feces using 16 S rRNA gene sequencing.We found that the expression of TNF‐α, IL‐1β, IL‐6, MMP‐3, MMP‐13, NLRP3 and Caspase‐1 increased in the IDD group rats. In contrast, Collagen II and aggrecan levels were downregulated. Additionally, vertebral disc tissue was severely damaged in the IDD group, with disordered cell arrangement and uneven safranin coloration. FMT reversed the effects of IDD modeling on these factors and alleviated cartilage tissue damage. In addition, FMT increased the gut microbiota diversity and microbial abundance in rats treated with IDD.Our findings suggest that FMT has a positive effect in maintaining cellular stability in the vertebral disc and alleviating histopathological damage. It affects the diversity and abundance of gut microbiota in rats with IDD. Therefore, FMT may serve as a promising target for amelioration of IDD. Fecal microbiota transplantation (FMT) inhibited TNF‐α, IL‐1β, IL‐6, MMP‐3, MMP‐13, NLRP3, and Caspase‐1 levels, up‐regulated collagen II and aggrecan expression, restored gut microbiota homeostasis, thereby improving intervertebral disc degeneration in mice. FMT is a therapeutic approach for colonizing the patient's gut with fecal suspension from a healthy individual.Fecal microbiota transplantation (FMT) is associated with inflammation regulation and bacterial flora homeostasis The experimental animals were Sprague–Dawley (SD) rats . The rats were purchased from Hunan SJA Laboratory Animal Co., Ltd. . Rats were randomly divided into three groups: control, IDD, and IDD + FMT. Rats were anesthetized with 2% pentobarbital (40 mg/kg). Grades 7–8 (Co7‐8) and 8–9 (Co8‐9) of the rat coccyx were punctured from the back with a 20‐gauge needle.We collected 10 g of fresh feces from 2‐month‐old male rats. Fifty milliliters of sterile physiological saline was added and stirred at 37°C. The fecal solution was filtered through a double layer of sterile gauze. The filtered fecal residue was suspended in 100 mL of sterile physiological saline to obtain a fecal bacterial solution. Rats in the IDD + FMT group were intragastrically administered (5 mL/kg) by gavage once a day for 14 days (from the second day after the IDD operation).We determined the levels of TNF‐α, IL‐1β, IL‐6, matrix metalloproteinase (MMP)‐3, MMP‐13, Collagen II, and aggrecan in the serum and vertebral disc tissue. We used TNF‐α , IL‐1β , IL‐6 , MMP‐3 , MMP‐13 , Collagen II , and aggrecan  Enzyme‐Linked Immunosorbent Assay (ELISA) kits to measure relative factors.Danvers, MA, USA), Caspase‐1 primary antibody , MMP‐3 primary antibody , and Collagen II primary antibody  were incubated. The secondary antibodies were then added for incubation. Subsequently, the sections were cultured with 3,3′‐diaminobenzidine (DAB), hematoxylin, and alcohol dehydration. Finally, the sections were blocked with a neutral resin and examined under a microscope .Immunohistochemical (IHC) was used to measure the distribution of NLRP3, Caspase‐1, MMP‐3, and Collagen II in vertebral disc tissue. After dehydration, the sections were placed in 0.01 M citrate buffer (pH 6.0) and kept at a high temperature for 20 min. After the sections were cooled and washed, 1% periodic acid was used for 10 min to eliminate endogenous enzymes. Next, NLRP3 primary antibody . Tissue sections were baked at 60°C, soaked in xylene, and dehydrated in alcohol. The sections were stained with hematoxylin for 5 min and stained with eosin for 5 min. After washing with distilled water, the sections were dehydrated in an alcohol gradient. Finally, the sections were blocked with neutral resin and examined under a microscope .We also examined the pathology of the vertebral disc tissue with S‐O. Tissue sections were baked at 60°C, soaked in xylene, and dehydrated in alcohol. Sections were stained with fast green stain for 5 min and then stained with safranin O solution again for 30 s. Sections were dehydrated after washing with distilled water. Finally, the sections were blocked with neutral resin and examined under a microscope .First, we extracted fecal DNA using a genomic DNA extraction kit . Next, bacterial primers for the V3‐V4 region (341F:5’‐CCTACGGGNGGCWGCAG‐3′ and 805R:5’‐GACTACHVGGGTATCTAATCC‐3′) and the fusion enzyme  were used for PCR amplification. Raw data were obtained using an Illumina Novaseq6000 PE250. The Qiime 2 (2020.2) analysis process was used to call DADA2 for quality control in order to obtain useful clean data. Each amplicon sequence variant/OTU sequence was annotated using the silvA‐132‐99 database to obtain information on the corresponding species. The alpha diversity index of each sample was calculated using Qiime 2 software. The distance matrix was obtained based on the Bray–Curtis algorithm, which was used for beta diversity analysis and visualization.−△△CT was used to assess relative mRNA levels.We examined the expression of TNF‐α, IL‐1β, IL‐6, MMP‐3, MMP‐13, Collagen II, aggrecan, NLRP3, and Caspase‐1 in vertebral disc tissue. First, total RNA was extracted using TRIzol Reagent . Next, mRNA was reverse‐transcribed to cDNA using an mRNA reverse transcription kit . Primers for TNF‐α, IL‐1β, IL‐6, MMP‐3, MMP‐13, Collagen II, aggrecan, NLRP3, Caspase‐1, and β‐actin were provided by Sangon Biotech  . Subsequently, the grinding fluid was centrifuged, and the supernatant was collected. The protein content was measured using a BCA protein kit .Based on the protein quantification results, the markers and denatured proteins were dotted into the wells. Electrophoresis was performed at a constant voltage of 75 V for 130 min. Electrophoresis was terminated when bromophenol blue was electrophoresed at the bottom of the gel. After the transfer, the membrane was removed and washed once with 1 × PBST. Subsequently, we disposed the membrane for 1.5 h under PBST (5% skimmed milk) powder. Next, we added primary and secondary antibodies. A chemiluminescence imaging system  was used to calculate the protein samples on the membrane. β‐actin was used as an internal reference. Antibody information is presented in Table P‐Value <0.05 was considered statistically significant.Graphpad Priam  was used for statistical analysis. Kolmogorov–Smirnov test was used to analyze whether the data conformed to a normal distribution. The normally distributed continuous variables were represented as the mean ± standard deviation (X̅ ± SD). One‐way analysis of variance (ANOVA) was used to compare the data differences between multiple groups. First, we analyzed the histopathological findings of the vertebral discs. The cells in the vertebral disc tissue of the control group were normal and regular, and no lesions were observed. In the IDD group, the number of cells decreased, and the arrangement was disordered. The IDD + FMT group showed a therapeutic effect, and tissue damage was effectively alleviated Figure . The S‐OTo investigate whether FMT affects inflammatory factors, we first assessed the expression of TNF‐α, IL‐1β, and IL‐6 in the rat serum and vertebral disc tissue. ELISA, quantitative real‐time polymerase chain reaction (qRT‐PCR), and western blotting showed that TNF‐α, IL‐1β, and IL‐6 were upregulated in the IDD group compared to the control group Figure . FMT revImbalance of the extracellular matrix in the vertebral disc tissue leads to problems such as abnormal stress in the vertebral disc and eventually causes IDD. Therefore, we investigated the effects of FMT on vertebral disc ECM homeostasis. We found that the levels of MMP‐3 and MMP‐13 in the IDD group were significantly upregulated by qRT‐PCR Figure . After FNext, the influence of FMT on vertebral disc tissue pyroptosis factor was examined. We assessed changes in pyroptotic factors (NLRP3 and Caspase‐1) in vertebral disc tissues using qRT‐PCR, western blotting, and IHC. The changes in the levels of pyroptosis factors in the three assays were consistent Figure . IDD modMuribaculaceae, Lactobacillus, Clostridia_UCG‐014, Prevotellaceae Ga6A1 group, Lachnospiraceae, Ruminococcus, Lachnospiraceae NK4A136 group, UCG‐005, Clostridium sensu stricto 1, Bacilli, Treponema, Monoglobus, Romboutsia, RF39, Prevotella, Oscillospiraceae, Turicibacter, [Eubacterium] coprostanoligenes group, Ruminococcaceae, and Roseburia  in both groups Figure . We founa Figure .Muribaculaceae. FMT down‐regulated this relative abundance. Next, we explored differences in community structure among the groups. The obtained value (R) = 0.263, and P = 0.001 indicated that there was a significant difference between the groups  1/3 induces pyroptosis and NLRP3 inflammasome activation by upregulating ROS/NF‐κB signaling.via TXNIP.In the IDD group, the expression of inflammatory factors  and pyroptosis factors (NLRP3 and Caspase‐1) increased, and FMT reversed these changes. Previous studies have shown that the expression of TNF‐α, IL‐1β, and IL‐6 decreases when inflammation is decreased.Muribaculaceae and Lactobacillus, and decreased the abundance of Clostridia_UCG‐014. FMT further increased the abundance of Lactobacillus and decreased that of Clostridia_UCG‐014. These studies demonstrate that IDD may have a potential therapeutic effect through the auxiliary metabolism of gut microbes.Although fecal microbiota supernatants contain pro‐inflammatory metabolites, they can be removed by repeated washing.The advantage of this study were: (i) FMT maintained cellular stability, alleviated histopathological damage; and (ii) FMT influenced the gut microbiota in IDD rats. FMT may serve as a promising target for ameliorating IDD and for palliative therapy.However, several limitations of this study must be considered. Owing to the limitations of experimental funds and conditions, we did not conduct experiments to explore the influence of specific components of fecal bacteria on IDD. In addition, the maintenance time of FMT treatment effect on IDD needs to be further explored.These findings suggest that FMT has a positive effect on maintaining cellular stability and alleviating histopathological damage. FMT decreased level of inflammatory factors, catabolic enzyme, and pyroptotic factors, and increased extracellular matrix levels. Besides, FMT alleviated the injury of intervertebral disc tissue in IDD rats. In addition, we found that FMT affected the gut microbiota diversity and microbial abundance in IDD rats. Therefore, FMT may serve as a promising target for ameliorating IDD and palliative therapy.All animal experiments were approved by the Animal Ethics Committee of Xiangya Third Hospital of Central South University (No.2020‐S292).This study was supported by the Hunan Health Commission's 2019 Medical Service and Support Capability Improvement Subsidy Fund (No. 2019‐57) and General Items of the Hunan Provincial Health Commission (No. 202204074627).Ziwei Han and Li Wan conceived the design; Bo Yao, Youquan Cai, and Weiguo Wang carried out the experiment; Jia Deng, Lei Zhao, Ziwei Han, and Li Wan carried out the data visualization. Bo Yao wrote the first draft, and Ziwei Han and Li Wan directed the revisions. All authors have checked the final manuscript.