<p>Functional dyspepsia (FD) is a symptom-based disorder of gut-brain interactions, causing epigastric pain or discomfort, with immune activation presumed to play a key role. Peripheral cytokines contribute to hyperalgesia and are thought to be related to the severity of FD symptoms, while brain functional networks are also involved in these symptoms, although the mechanisms underlying these relationships remain unclear. This study aims to investigate the topological reorganization of brain functional networks in FD and their associations with peripheral cytokines, FD symptoms, anxiety, and depression. Resting-state functional magnetic resonance imaging was conducted on 40 FD patients and 40 healthy controls, assessing topological changes using small-world properties, network efficiency, nodal centrality, and whole-brain functional connectivity. FD patients had higher anxiety and depression scores than healthy controls, along with greater global efficiency, local efficiency, and clustering coefficient. They also had higher nodal centralities in the salience network (SN) and prefrontal cortex, but lower nodal centralities in the default mode network (DMN). Specifically, the nodal local efficiency of the right amygdala correlated with clinical symptom scores in FD. Whole-brain functional disconnection was found in the DMN, SN and sensorimotor network (SMN). FD patients also exhibited higher peripheral cytokines, particularly tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10), which were positively correlated with gastrointestinal symptoms. In conclusion, FD patients showed significant topological reorganization in the DMN, SN, and SMN. Furthermore, the right amygdala’s nodal local efficiency was correlated with clinical symptom severity, and elevated TNF-α and IL-10 levels were associated with gastrointestinal symptom severity in FD.</p>