Correlation of gut microbiota metabolite trimethylamine N-oxide with inflammatory levels and osteoporosis in patients with diabetic nephropathy

BACKGROUND Diabetic nephropathy (DN) is one of the most serious microvascular complications of type 2 diabetes mellitus (T2DM), and its incidence increases with the global rise in diabetes prevalence. It is the leading cause of chronic kidney disease and end-stage kidney disease. Patients with DN often experience complex metabolic disorders and chronic inflammatory states, which not only accelerate the decline of renal function but are also closely related to complications such as cardiovascular events and osteoporosis (OP), seriously compromising quality of life. With the in-depth research on the gut microbiota and the emergence of concepts such as the "gut-kidney axis" and the "enteric-bone axis", the key roles of the gut microbiota and its metabolites in metabolic disorders, inflammatory responses, and target organ damage have been increasingly recognized. However, the specific role of gut microbiota in the pathogenesis of DN remains to be further explored. The results obtained may provide evidence to better understand the pathogenesis of DN and to identify high-risk populations at an early stage. This research direction is of strategic significance. AIM To assess the correlation of the gut microbiota metabolite trimethylamine N-oxide (TMAO) with inflammatory marker levels and OP in patients with DN. METHODS A total of 115 patients diagnosed with type 2 DN and treated at the Department of Endocrinology, Second Affiliated Hospital of Shandong First Medical University from August 2022 to December 2024 were enrolled in the DN group, and 115 patients with T2DM without nephropathy were included in the T2DM group. The two groups were compared in terms of gastrointestinal microbiota abundance and relative abundance at the genus level; levels of TMAO, inflammatory markers [including C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α)], and bone metabolism markers [including procollagen type I N-terminal propeptide (PINP), β-CrossLaps (β-CTX), and alkaline phosphatase (ALP)]; and lumbar spine and hip bone mineral density (BMD). The correlation of TMAO level with inflammatory factor and bone metabolism indicator levels was further analyzed. RESULTS The DN group had higher Chao1 and Simpson indices of gastrointestinal microbiota diversity than the T2DM group, whereas the ACE and Shannon indices were lower (P < 0.05). The relative abundance of Firmicutes was higher, and the relative abundances of Bacteroidetes, Proteobacteria, and Actinobacteria were lower in the DN group than in the T2DM group (P < 0.05). CRP, IL-6, IL-8, TNF-α, and TMAO levels were considerably elevated in the DN group compared to the T2DM group (P < 0.05). Moreover, the DN group had higher levels of bone turnover markers-including PINP, β-CTX, and ALP-but lower lumbar spine and hip BMDs than the T2DM group (P < 0.05). TMAO level positively correlated with the Chao1 and Simpson indices and negatively correlated with the ACE and Shannon indices of gut microbiota diversity. TMAO level also negatively correlated with the relative abundances of Bacteroidetes, Proteobacteria, and Actinobacteria and positively correlated with the abundance of Firmicutes. Additionally, TMAO level positively correlated with the inflammatory markers CRP, IL-6, IL-8, and TNF-α, as well as with the bone turnover markers PINP, β-CTX, and ALP. It negatively correlated with lumbar spine and hip BMDs (P < 0.05). CONCLUSION Inflammatory and bone metabolic levels in patients with DN were found to be associated with the gut microbiota–derived metabolite TMAO. Elevated TMAO levels may mediate inflammatory responses and bone metabolism disorders in patients with DN, thereby contributing to the progression of systemic inflammation and OP.