D'Mello Charlotte, Ronaghan Natalie, Zaheer Raza, Dicay Michael, Le Tai, MacNaughton Wallace K, Surrette Michael G, Swain Mark G
Immunology Research Group and.
Gastrointestinal Research Group and Inflammation Research Network, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada, and.
J Neurosci. 2015 Jul 29;35(30):10821-30. doi: 10.1523/JNEUROSCI.0575-15.2015.
Patients with systemic inflammatory diseases (e.g., rheumatoid arthritis, inflammatory bowel disease, chronic liver disease) commonly develop debilitating symptoms (i.e., sickness behaviors) that arise from changes in brain function. The microbiota-gut-brain axis alters brain function and probiotic ingestion can influence behavior. However, how probiotics do this remains unclear. We have previously described a novel periphery-to-brain communication pathway in the setting of peripheral organ inflammation whereby monocytes are recruited to the brain in response to systemic TNF-α signaling, leading to microglial activation and subsequently driving sickness behavior development. Therefore, we investigated whether probiotic ingestion (i.e., probiotic mixture VSL#3) alters this periphery-to-brain communication pathway, thereby reducing subsequent sickness behavior development. Using a well characterized mouse model of liver inflammation, we now show that probiotic (VSL#3) treatment attenuates sickness behavior development in mice with liver inflammation without affecting disease severity, gut microbiota composition, or gut permeability. Attenuation of sickness behavior development was associated with reductions in microglial activation and cerebral monocyte infiltration. These events were paralleled by changes in markers of systemic immune activation, including decreased circulating TNF-α levels. Our observations highlight a novel pathway through which probiotics mediate cerebral changes and alter behavior. These findings allow for the potential development of novel therapeutic interventions targeted at the gut microbiome to treat inflammation-associated sickness behaviors in patients with systemic inflammatory diseases.
This research shows that probiotics, when eaten, can improve the abnormal behaviors (including social withdrawal and immobility) that are commonly associated with inflammation. Probiotics are able to cause this effect within the body by changing how the immune system signals the brain to alter brain function. These findings broaden our understanding of how probiotics may beneficially affect brain function in the context of inflammation occurring within the body and may open potential new therapeutic alternatives for the treatment of these alterations in behavior that can greatly affect patient quality of life.
患有全身性炎症性疾病（如类风湿性关节炎、炎症性肠病、慢性肝病）的患者通常会出现因脑功能变化而导致的使人衰弱的症状（即疾病行为）。微生物群-肠道-脑轴会改变脑功能，摄入益生菌会影响行为。然而，益生菌如何做到这一点仍不清楚。我们之前曾描述过一种在外周器官炎症情况下从外周到脑的新型通讯通路，即单核细胞响应全身肿瘤坏死因子-α信号被招募到脑内，导致小胶质细胞活化，随后促使疾病行为的发展。因此，我们研究了摄入益生菌（即益生菌混合物VSL#3）是否会改变这种从外周到脑的通讯通路，从而减少随后疾病行为的发展。使用一个特征明确的肝脏炎症小鼠模型，我们现在表明益生菌（VSL#3）治疗可减轻肝脏炎症小鼠的疾病行为发展，而不影响疾病严重程度、肠道微生物群组成或肠道通透性。疾病行为发展的减轻与小胶质细胞活化和脑单核细胞浸润的减少有关。这些事件与全身免疫激活标志物的变化同时出现，包括循环肿瘤坏死因子-α水平降低。我们的观察结果突出了一条益生菌介导脑变化并改变行为的新途径。这些发现为针对肠道微生物群开发新型治疗干预措施以治疗全身性炎症性疾病患者的炎症相关疾病行为提供了可能性。
这项研究表明，摄入益生菌可以改善通常与炎症相关的异常行为（包括社交退缩和不动）。益生菌能够通过改变免疫系统向大脑发出信号以改变脑功能的方式在体内产生这种效果。这些发现拓宽了我们对益生菌在体内发生炎症情况下如何有益地影响脑功能的理解，并可能为治疗这些可极大影响患者生活质量的行为改变开辟潜在的新治疗选择。
