Modulation of Gut Microbiota Metabolism in Obesity-Related Type 2 Diabetes Reduces Osteomyelitis Severity.
Modulation of Gut Microbiota Metabolism in Obesity-Related Type 2 Diabetes Reduces Osteomyelitis Severity.
复制标题
与肥胖相关2型糖尿病中肠道微生物群代谢的调节调节可降低骨髓炎的严重程度。
DOI：
10.1128/spectrum.00170-22
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发表时间：
2022-04-27
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
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作者：
金黄色葡萄球菌是一种机会性病原体，通过血液播散或污染植入物和骨科手术后开放性伤口引起骨髓炎。在肥胖相关的2型糖尿病（肥胖/T2D）中，由于慢性炎症损害适应性和先天免疫，金黄色葡萄球菌介导的骨髓炎的严重程度增强。肥胖引起的炎症与肠道生态失调有关，高纤维饮食对肠道微生物群的改变导致肥胖/T2D症状和并发症的减少。然而，我们对肠道菌群改变宿主感染反应的机制的理解是有限的。为了解决这一差距，我们监测了用胰岛素样果聚糖纤维低聚果糖治疗的肥胖/T2D小鼠的胫骨金黄色葡萄球菌感染。通过降低循环炎症因子（肿瘤坏死因子-α [TNF-α]）和趋化因子（干扰素-γ诱导的蛋白10 kDa [IP-10]、角化细胞来源的趋化因子[KC]、干扰素-γ诱导的单因子[MIG]、单核细胞趋化蛋白-1 [MCP-1]），以及激活后的调节，低聚果糖治疗显著降低了肥胖/T2D小鼠的金黄色葡萄球菌定植，降低了感染后的促炎信号。正常T细胞表达和推测分泌[RANTES])，表明炎症部分减少。低聚果糖显著改变了肥胖/T2D小鼠肠道微生物群的多样性，抗炎细菌假结肠双歧杆菌显著增加。盲肠和血浆代谢组分析表明，多胺的产生增加，特别是精胺和亚精胺。对肥胖/T2D小鼠口服这些多胺可降低感染严重程度，与补充低聚果糖相似，表明多胺可以介导纤维对骨髓炎严重程度的有益作用。这些结果表明，肠道微生物代谢物对控制远端肠道细菌感染和多胺作为肥胖/T2D骨髓炎的辅助治疗的贡献。肥胖相关的2型糖尿病（肥胖/T2D）患者在骨科手术后发生侵袭性金黄色葡萄球菌骨髓炎（骨感染）的风险增加了5倍。随着抗生素耐药性的增加和新抗生素的发现有限，我们必须探索其他治疗途径。在这项研究中，我们证明了膳食纤维低聚果糖显著降低了肥胖/T2D小鼠急性假体关节感染后的骨髓炎严重程度和高炎症。感染严重程度的降低与肠道微生物群组成和代谢的变化有关，肠道和循环血浆中天然多胺的产生增加表明了这一点。这项工作确定了肠道微生物群在调节细菌感染控制中的新作用，多胺作为有益代谢产物参与改善肥胖/T2D宿主对骨髓炎的反应。了解多胺对宿主免疫的影响以及降低严重种植体相关性骨髓炎易感性的机制对于改善这类患者的治疗策略至关重要。
Staphylococcus aureus is an opportunistic pathogen causing osteomyelitis through hematogenous seeding or contamination of implants and open wounds following orthopedic surgeries. The severity of S. aureus-mediated osteomyelitis is enhanced in obesity-related type 2 diabetes (obesity/T2D) due to chronic inflammation impairing both adaptive and innate immunity. Obesity-induced inflammation is linked to gut dysbiosis, with modification of the gut microbiota by high-fiber diets leading to a reduction in the symptoms and complications of obesity/T2D. However, our understanding of the mechanisms by which modifications of the gut microbiota alter host infection responses is limited. To address this gap, we monitored tibial S. aureus infections in obese/T2D mice treated with the inulin-like fructan fiber oligofructose. Treatment with oligofructose significantly decreased S. aureus colonization and lowered proinflammatory signaling postinfection in obese/T2D mice, as observed by decreased circulating inflammatory cytokines (tumor necrosis factor-α [TNF-α]) and chemokines (interferon-γ-induced protein 10 kDa [IP-10], keratinocyte-derived chemokine [KC], monokine induced by interferon-γ [MIG], monocyte chemoattractant protein-1 [MCP-1], and regulated upon activation, normal T cell expressed and presumably secreted [RANTES]), indicating partial reduction in inflammation. Oligofructose markedly shifted diversity in the gut microbiota of obese/T2D mice, with notable increases in the anti-inflammatory bacterium Bifidobacterium pseudolongum. Analysis of the cecum and plasma metabolome suggested that polyamine production was increased, specifically spermine and spermidine. Oral administration of these polyamines to obese/T2D mice resulted in reduced infection severity similar to oligofructose supplementation, suggesting that polyamines can mediate the beneficial effects of fiber on osteomyelitis severity. These results demonstrate the contribution of gut microbiota metabolites to the control of bacterial infections distal to the gut and polyamines as an adjunct therapeutic for osteomyelitis in obesity/T2D. IMPORTANCE Individuals with obesity-related type 2 diabetes (obesity/T2D) are at a five times increased risk for invasive Staphylococcus aureus osteomyelitis (bone infection) following orthopedic surgeries. With increasing antibiotic resistance and limited discoveries of novel antibiotics, it is imperative that we explore other avenues for therapeutics. In this study, we demonstrated that the dietary fiber oligofructose markedly reduced osteomyelitis severity and hyperinflammation following acute prosthetic joint infections in obese/T2D mice. Reduced infection severity was associated with changes in gut microbiota composition and metabolism, as indicated by increased production of natural polyamines in the gut and circulating plasma. This work identifies a novel role for the gut microbiome in mediating control of bacterial infections and polyamines as beneficial metabolites involved in improving the obesity/T2D host response to osteomyelitis. Understanding the impact of polyamines on host immunity and mechanisms behind decreasing susceptibility to severe implant-associated osteomyelitis is crucial to improving treatment strategies for this patient population.
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影响因子：
7.7
作者：
Cani, Patrice D.;Amar, Jacques;Burcelin, Remy
通讯作者：
Burcelin, Remy
DOI：
10.1038/s41366-021-00804-7
发表时间：
2021-06
期刊：
International journal of obesity (2005)
影响因子：
--
作者：
Batabyal R;Freishtat N;Hill E;Rehman M;Freishtat R;Koutroulis I
通讯作者：
Koutroulis I
DOI：
10.1038/ismej.2014.45
发表时间：
2014-10
期刊：
The ISME journal
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.3
作者：
Adams, Annette L.;Paxton, Elizabeth W.;Namba, Robert S.
通讯作者：
Namba, Robert S.
影响因子：
4.2
作者：
Dowsey, Michelle M.;Choong, Peter F. M.
通讯作者：
Choong, Peter F. M.