Objective To construct an animal model of type 2 diabetic nephropathy (DN) combined with the disease and syndrome of “ dampness syndrome” in traditional Chinese medicine, and to conduct a macroscopic characterization and microscopic index evaluation of the model. Methods Spontaneous db / db mice were fed a 60% high-fat diet to create internal dampness syndrome and construct an animal model of DN combined with damp syndrome ( TSSZ ). The general condition, body mass, and biochemical indicators ( urinary microalbumin-tocreatinine ratio, blood glucose, renal function, glucose and lipid metabolism) were monitored in each group of mice.Pathological changes in the kidney were observed by hematoxylin-eosin (HE), periodic acid-schiff (PAS), Masson,and Oil red O staining. Renal microinflammation and fibrosis were detected by polymerase chain reaction (PCR) and the degree of macrophage polarization in renal tissue was detected by immunofluorescence assay. The mucosal barrier of intestinal tissue was examined by HE staining and PCR. Mouse feces were collected and the fecal metabolome was determined using liquid chromatography / mass spectrometry. Results The unrinary microalbumin-to-creatinine ratio was increased in the model group compared with the control group( P<0. 05). HE and PAS staining indicated significant homogeneous thickening of the glomerular basement membrane and proliferation of the mesangial matrix in the model group, and PAS staining showed a significant increase in glycogen deposition (P<0. 05), which met the criteria for successful construction of a DN model. Macroscopically, compared with the model group, mice in the TSSZ group presented obvious symptoms such as greasy and oily skin and hair, loose stools, listlessness, fatigue, huddling and curling up, polyuria, and significantly increased body mass ( P<0. 05). In terms of lipid toxicity indicators, total cholesterol levels were significantly elevated in the TSSZ group ( P<0. 05). Oil red O staining showed significant lipid droplet deposition, and Masson staining indicated obvious blue staining of collagen and aggravated fibrosis in the glomerular interstitium in the TSSZ group (P<0. 001). mRNA levels of the pro-fibrotic factors α-smooth muscle actin, connective tissue growth factor, fibronectin, and transforming growth factor-β were significantly increased (P<0. 001), and in terms of microinflammation, levels of the inflammatory factors tumor necrosis factor-α, monocyte chemoattractant protein-1, and interleukin-6 were significantly elevated in the TSSZ group (P<0. 001), and polarization of M1-type macrophages was significantly enhanced ( P<0. 05). In terms of intestinal microecology, HE staining indicated aggravated intestinal injury in the TSSZ group. mRNA levels of intestinal ZO-1 and occludin were significantly decreased in the TSSZ group ( P<0. 001). Fecal metabolomics analysis showed that dampness syndrome modeling affected related metabolic pathways, including α-linolenic acid and tryptophan metabolism. Conclusions Feeding spontaneous db / db model mice with a 60% high-fat diet can successfully create a type 2 DN combined with dampness syndrome disease model. This provides an ideal animal model for further in-depth studies into the construction of a type 2 TSSZ animal model, as well as the pharmacodynamics of Chinese herbal compounds in DN.