Chronic tinnitus is a central nervous system disorder. Currently, the effects of gut microbiota on tinnitus remain unexplored. To explore the connection between gut microbiota and tinnitus, we conducted 16S rRNA sequencing of fecal microbiota and serum metabolomic analysis in a cohort of 70 patients with tinnitus and 30 healthy volunteers. We used the weighted gene co-expression network method to analyze the relationship between the gut microbiota and the serum metabolites. The random forest technique was utilized to select metabolites and gut taxa to construct predictive models. A pronounced gut dysbiosis in the tinnitus group, characterized by reduced bacterial diversity, an increased Firmicutes/Bacteroidetes ratio, and some opportunistic bacteria including Aeromonas and Acinetobacter were enriched. In contrast, some beneficial gut probiotics decreased, including Lactobacillales and Lactobacillaceae. In serum metabolomic analysis, serum metabolic disturbances in tinnitus patients and these differential metabolites were enriched in pathways of neuroinflammation, neurotransmitter activity, and synaptic function. The predictive models exhibited great diagnostic performance, achieving 0.94 (95% CI: 0.85–0.98) and 0.96 (95% CI: 0.86–0.99) in the test set. Our study suggests that changes in gut microbiota could potentially influence the occurrence and chronicity of tinnitus, and exert regulatory effects through changes in serum metabolites. Overall, this research provides new perceptions into the potential role of gut microbiota and serum metabolite in the pathogenesis of tinnitus, and proposes the “gut-brain-ear” concept as a pathomechanism underlying tinnitus, with significant clinical diagnostic implications and therapeutic potential. IMPORTANCE: Tinnitus affects millions of people worldwide. Severe cases may lead to sleep disorders, anxiety, and depression, subsequently impacting patients’ lives and increasing societal healthcare expenditures. However, tinnitus mechanisms are poorly understood, and effective therapeutic interventions are currently lacking. We discovered the gut microbiota and serum metabolomics changes in patients with tinnitus, and provided the potential pathological mechanisms of dysregulated gut flora in chronic tinnitus. We proposed the innovative concept of the “gut-brain-ear axis,” which underscores the exploration of gut microbiota impact on susceptibility to chronic tinnitus through serum metabolic profile modulation. We also reveal novel biomarkers associated with chronic tinnitus, offering a new conceptual framework for further investigations into the susceptibility of patients, potential treatment targets for tinnitus, and assessing patient prognosis. Subsequently, gut microbiota and serum metabolites can be used as molecular markers to assess the susceptibility and prognosis of tinnitus.Furthermore, fecal transplantation may be used to treat tinnitus.

Prolonged or excessive exposure to noise can lead to hearing loss, tinnitus and hypersensitivity to sound. The effects of noise exposure on main excitatory and inhibitory neurotransmitter systems in auditory pathway have been extensively investigated. However, little is known about aberrant changes in neuromodulator systems caused by noise exposure. In the current study, we exposed 2-month-old mice to a narrow band noise at 116 dB SPL for 6 h or sham exposure, assessed auditory brainstem responses as well as examined the expression of serotonin reuptake transporter (SERT) in the cochlear nucleus (CN), inferior colliculus (IC), and primary auditory cortex (Au1) using immunohistochemistry. We found that noise exposure resulted in a significant increase in hearing thresholds at 4, 8, 16, 24, and 32 kHz, as well as led to a significant reduction of SERT in dorsal cochlear nucleus (DCN), dorsal IC (ICd), external IC (ICe), and Au1 layers I-IV. This reduction of SERT in these subregions of central auditory system was partially recovered 15 or 30 days after noise exposure. Furthermore, we examined efficacy of resveratrol (RSV) on hearing loss and loss of SERT induced by noise exposure. The results demonstrated that RSV treatment significantly attenuated threshold shifts of auditory brainstem responses and loss of SERT in DCN, ICd, ICe, and Au1 layers I-IV. These findings show that noise exposure can cause hearing loss and subregion-specific loss of SERT in the central auditory system, and RSV treatment could attenuate noise exposure-induced hearing loss and loss of SERT in central auditory system.

Type 2 diabetes mellitus (T2DM) and its associated complications represent a significant public health issue affecting hundreds of millions of people globally; thus, measures to prevent T2DM are urgently needed. Chuju has been proven to possess antihyperglycemic activity. However, the bioactive ingredients in chuju that contribute to its antihyperglycemic activity, as well as the relationship between its antihyperglycemic activity and the gut microbiota, remain unclear. To understand the potential effects that it has on T2DM, the glycolipid metabolism and gut microbiota regulation of flavonoid-rich extracts from chuju (CJE) were investigated. The results showed that the top ten flavonoid compounds in CJE are Apigenin 6, 8-digalactoside, Apigenin 6-C-glucoside 8-C-arabinoside, Luteolin-4′-O-glucoside, Isoshaftoside, Scutellarin, Quercetin 3-O-malonylglucoside, Chrysoeriol 7-O-glucoside, Quercetin-3,4′-O-di-beta-glucoside, Luteolin 6-C-glucoside 8-C-arabinoside, and Homoorientin. Furthermore, CJE mitigated hyperglycemia and glycolipid metabolism by reducing the abundance of Faecalibaculum, Coriobacteriaceae, and Romboutsia and increasing the abundance of Alistipes. In addition, the results of Western blot analysis showed that CJE could enhance glycogen synthesis and glucose transport by up-regulating the phosphorylation of IRS1-PI3K-Akt and AMPK-GLUT4. Simultaneously, CJE could decrease gluconeogenesis by down-regulating the phosphorylation of FoxO1/GSK 3β. In conclusion, the findings of this study provide new evidence supporting the hypothesis that CJE can be used as part of a therapeutic approach for treating disturbances in glycolipid metabolism via regulating the gut microbiota and mediating the IRS1-PI3K-Akt-FoxO1/GSK 3β and AMPK-GLUT4 pathways.

Mammals have a dorsal cochlear nucleus (DCN), which is thought to be a cerebellum-like structure with similar features in terms of structure and microcircuitry to the cerebellum. Both the DCN and cerebellum perform their functions depending on synaptic and neuronal networks mediated by various glutamate receptors. Kainate receptors (KARs) are one class of the glutamate receptor family and are strongly expressed in the hippocampus, the cerebellum, and cerebellum-like structures. The cellular distribution and the potential role of KARs in the hippocampus have been extensively investigated. However, the cellular distribution and the potential role of KARs in cerebellum-like structures, including the DCN and cerebellum, are poorly understood. In this review, we summarize the similarity between the DCN and cerebellum at the levels of structure, circuitry, and cell type as well as the investigations referring to the expression patterns of KARs in the DCN and cerebellum according to previous studies. Recent studies on the role of KARs have shown that KARs mediate a bidirectional modulatory effect at parallel fiber (PF)–Purkinje cell (PC) synapses in the cerebellum, implying insights into their roles in cerebellum-like structures, including the DCN, that remain to be explored in the coming years.

The prevention of type 2 diabetes mellitus (T2DM) and its associated complications is an urgent public health issue that affects hundreds of millions of people globally. Chuju has been proved to possess antihyperglycemic activity. However, the bioactive ingredients in chuju that contribute to antihyperglycemic activity as well as the relation between its antihyperglycemic activity and gut microbiota remain unclear. To understand the potential effect it has on T2DM, the glycolipid metabolism and gut microbiota regulation of flavonoids-rich extracts from chuju (CJE) were investigated. The results showed that CJE remarkably mitigated hyperglycemia and glycolipid metabolism by regulating the gut microbiota in T2DM mice. Furthermore, the macro-genome sequencing results showed that CJE intervention regulated the composition of gut microbiota in T2DM mice, characterized by downregulating the abundance of Faecalibaculum, Coriobacteriaceae, Romboutsia and up-regulating the abundance of Alistipes. In addition, CJE could promote glycogen synthesis, gluconeogenesis, glucose transport and inhibite glycolysis by regulating the expression of insulin-mediated IRS1-PI3K-Akt-FoxO1/GSK 3β pathway and non-insulin-mediated AMPK-GLUT4 pathway. Taken together, the results provided new evidence that CJE alleviate disturbance of glycolipid metabolism via regulating gut microbiota and mediating IRS1-PI3K-Akt-FoxO1/GSK 3β, AMPK-GLUT4 pathway.