Antibiotic Treatment Affects Intestinal Permeability and Gut Microbial Composition in Wistar Rats Dependent on Antibiotic Class

Antibiotics are frequently administered orally to treat bacterial infections not necessarily related to the gastrointestinal system. This has adverse effects on the commensal gut microbial community, as it disrupts the intricate balance between specific bacterial groups within this ecosystem, potentially leading to dysbiosis. We hypothesized that modulation of community composition and function induced by antibiotics affects intestinal integrity depending on the antibiotic administered. To address this a total of 60 Wistar rats (housed in pairs with 6 cages per group) were dosed by oral gavage with either amoxicillin (AMX), cefotaxime (CTX), vancomycin (VAN), metronidazole (MTZ), or water (CON) daily for 10–11 days. Bacterial composition, alpha diversity and caecum short chain fatty acid levels were significantly affected by AMX, CTX and VAN, and varied among antibiotic treatments. A general decrease in diversity and an increase in the relative abundance of Proteobacteria was observed for all three antibiotics. Additionally, the relative abundance of Bifidobacteriaceae was increased in the CTX group and both Lactobacillaceae and Verrucomicrobiaceae were increased in the VAN group compared to the CON group. No changes in microbiota composition or function were observed following MTZ treatment. Intestinal permeability to 4 kDa FITC-dextran decreased after CTX and VAN treatment and increased following MTZ treatment. Plasma haptoglobin levels were increased by both AMX and CTX but no changes in expression of host tight junction genes were found in any treatment group. A strong correlation between the level of caecal succinate, the relative abundance of Clostridiaceae 1 family in the caecum, and the level of acute phase protein haptoglobin in blood plasma was observed. In conclusion, antibiotic-induced changes in microbiota may be linked to alterations in intestinal permeability, although the specific interactions remain to be elucidated as changes in permeability did not always result from major changes in microbiota and vice versa.

抗生素常经口给药，用于治疗未必与胃肠道相关的细菌感染。此举会对肠道共生微生物群落产生不良影响，因其会破坏该生态系统内特定细菌类群间的复杂平衡，进而可能引发菌群失调（dysbiosis）。我们提出假说：抗生素诱导的群落组成与功能调控，会依所用抗生素种类不同而对肠道完整性产生影响。为验证该假说，本研究共选取60只Wistar大鼠（按每笼2只饲养，每组设6笼），每日分别经口灌胃给予阿莫西林（amoxicillin, AMX）、头孢噻肟（cefotaxime, CTX）、万古霉素（vancomycin, VAN）、甲硝唑（metronidazole, MTZ）或无菌水（对照组, CON），连续给药10~11天。阿莫西林、头孢噻肟与万古霉素可显著改变细菌组成、α多样性（alpha diversity）及盲肠短链脂肪酸水平，且不同抗生素处理组间存在差异。上述三种抗生素处理后，均观察到群落多样性普遍下降，且变形菌门（Proteobacteria）的相对丰度升高。此外，与对照组相比，头孢噻肟组的双歧杆菌科（Bifidobacteriaceae）相对丰度升高，万古霉素组的乳杆菌科（Lactobacillaceae）与疣微菌科（Verrucomicrobiaceae）相对丰度均有所上升。甲硝唑处理组未观察到微生物群组成或功能的改变。经4 kDa异硫氰酸荧光素葡聚糖（FITC-dextran）检测的肠道通透性，在头孢噻肟与万古霉素处理后有所下降，而在甲硝唑处理后则升高。阿莫西林与头孢噻肟均可升高血浆触珠蛋白（haptoglobin）水平，但所有处理组的宿主紧密连接（tight junction）基因表达均未出现明显变化。研究还发现，盲肠琥珀酸水平、盲肠梭菌科1群（Clostridiaceae 1）相对丰度与血浆急性期蛋白触珠蛋白水平三者间存在显著相关性。综上，抗生素诱导的微生物群改变可能与肠道通透性变化相关，但二者间的具体相互作用仍有待阐明——肠道通透性变化并非总由微生物群的显著改变引起，反之亦然。