Irritable bowel syndrome (IBS) is a symptom-based disorder of gut-brain interactions generating abdominal pain. It is also associated with a vulnerability to develop extraintestinal symptoms, with fatigue often reported as one of the most disturbing. Fatigue is related to brain function and inflammation in several disorders, however, the mechanisms of such relations in IBS remain elusive. This study aimed to elucidate fatigue and its association with a resting state network of mesocorticolimbic regions of known importance in fatigue, and to explore the possible role of circulating TNF-α levels in IBS and healthy controls (HC). Resting state functional magnetic resonance imaging (fMRI) was conducted in 88 IBS patients and 47 HC of similar age and gender to investigate functional connectivity between mesocorticolimbic regions. Further, fatigue impact on daily life and plasma levels of the proinflammatory cytokine tumor necrosis factor-α (TNF- α), of known relevance to immune activation in IBS, were also measured. The selected mesocorticolimbic regions indeed formed a functionally connected network in all participants. The nucleus accumbens (NAc), in particular, exhibited functional connectivity to all other regions of interest. In IBS, fatigue impact on daily life was negatively correlated with the connectivity between NAc and dorsolateral prefrontal cortex bilaterally (left p = 0.019; right p = 0.038, corrected for multiple comparisons), while in HC, fatigue impact on daily life was positively correlated to the connectivity between the right NAc and anterior middle insula in both hemispheres (left p = 0.009; right p = 0.011). We found significantly higher levels of TNF- α in IBS patients compared to HC (p=0.001) as well as a positive correlation between TNF- α and fatigue impact on daily life in IBS patients (rho=0.25, p=0.02) but not in HC (rho=-0.13, p=0.37).There was no association between functional connectivity in the mesocorticolimbic network and plasma levels of TNF- α in either group In summary, this novel multimodal study provides the first evidence that the vulnerability to fatigue in IBS is associated with connectivity within a mesocorticolimbic network as well as immune activation. These findings warrant further investigation, both peripherally and potentially with measurements of central immune activation as well.

中文翻译：

---

肠易激综合征中的疲劳与血浆 TNF-α 水平和中脑边缘连接性有关

肠易激综合征 (IBS) 是一种基于症状的肠-脑相互作用疾病，会产生腹痛。它还与发展肠外症状的脆弱性有关，疲劳通常是最令人不安的一种。疲劳与几种疾病的脑功能和炎症有关，然而，IBS 中这种关系的机制仍然难以捉摸。本研究旨在阐明疲劳及其与已知在疲劳中重要的皮质边缘区域的静息状态网络的关联，并探索循环 TNF-α 水平在 IBS 和健康对照 (HC) 中的可能作用。在 88 名 IBS 患者和 47 名年龄和性别相似的 HC 中进行了静息状态功能磁共振成像 (fMRI)，以研究皮质边缘区域之间的功能连接。更远，疲劳对日常生活的影响和已知与 IBS 中的免疫激活相关的促炎细胞因子肿瘤坏死因子-α (TNF-α) 的血浆水平也进行了测量。选定的中脑边缘区域确实在所有参与者中形成了一个功能连接的网络。特别是伏隔核 (NAc) 表现出与所有其他感兴趣区域的功能连接。在 IBS 中，疲劳对日常生活的影响与双侧 NAc 和背外侧前额叶皮层之间的连接呈负相关（左 p = 0.019；右 p = 0.038，校正多重比较），而在 HC 中，疲劳对日常生活的影响呈正相关两个半球右侧 NAc 和前中岛岛之间的连通性（左侧 p = 0.009；右侧 p = 0.011）。我们发现 IBS 患者的 TNF-α 水平显着高于 HC（p=0.001），并且 TNF-α 与疲劳对 IBS 患者日常生活的影响呈正相关（rho=0.25，p=0.02），但不是在 HC 中 (rho=-0.13, p=0.37)。在任一组中，皮质边缘网络中的功能连接性与血浆 TNF-α 水平之间没有关联 总之，这项新颖的多模式研究提供了第一个证据表明易受疲劳影响在 IBS 中，与中脑边缘网络内的连通性以及免疫激活有关。这些发现值得进一步研究，包括外周和潜在的中枢免疫激活测量。p=0.02）但在 HC 中没有（rho=-0.13，p=0.37）。在任一组中，皮质边缘网络中的功能连接性与血浆 TNF-α 水平之间没有关联 总之，这项新颖的多模式研究提供了第一个有证据表明 IBS 易受疲劳影响与中脑边缘网络内的连通性以及免疫激活有关。这些发现值得进一步研究，包括外周和潜在的中枢免疫激活测量。p=0.02）但在 HC 中没有（rho=-0.13，p=0.37）。在任一组中，皮质边缘网络中的功能连接性与血浆 TNF-α 水平之间没有关联 总之，这项新颖的多模式研究提供了第一个有证据表明 IBS 易受疲劳影响与中脑边缘网络内的连通性以及免疫激活有关。这些发现值得进一步研究，包括外周和潜在的中枢免疫激活测量。这项新颖的多模式研究提供了第一个证据，表明 IBS 易受疲劳影响与中脑边缘网络内的连通性以及免疫激活有关。这些发现值得进一步研究，包括外周和潜在的中枢免疫激活测量。这项新颖的多模式研究提供了第一个证据，表明 IBS 易受疲劳影响与中脑边缘网络内的连通性以及免疫激活有关。这些发现值得进一步研究，包括外周和潜在的中枢免疫激活测量。