抗生素暴露与结肠癌风险增加有关 Antibiotics exposure linked to increased colon cancer risk

在英国医疗记录的广泛“数据挖掘”分析中,约翰霍普金斯基梅尔癌症中心的研究人员得出结论,即使服用一个疗程的抗生素也可能会增加 – 尽管是轻微 – 患结肠癌的风险 – 但不是直肠癌 – 十年后来。报告作者称,8月20日期刊“肠道”报道的调查结果强调了明智地使用这类药物的必要性,这些药物往往是不正确或过度使用的。

“这项研究的主要信息是抗生素管理的重要性:不用抗生素治疗常见的病毒感染,尽可能在最短的时间内使用它们,并使用靶向抗生素而不是广谱抗生素,”研究负责人Cynthia L. Sears说, MD,Bloomberg~Kimmel约翰霍普金斯Kimmel癌症中心癌症免疫疗法教授。 “这项研究增加了我们的理解,即这些药物可能具有显着的脱靶效应,包括诱发慢性疾病。”

西尔斯提醒说,像她这样的医疗记录研究并不是为了证明因果关系,而是为了确定风险因素和疾病之间可能存在的联系。但她指出,由于数据库在很长一段时间内掌握了如此多的具体信息,研究作者得出的结论是,结肠癌风险增加的最可能解释是抗生素对微生物群的影响 – 细菌的收集住在肠子里。

抗生素在世界范围内被广泛用于治疗细菌感染,并且有越来越多的证据,包括一些流行病学数据库研究,将这些药物的使用与结直肠癌的风险联系起来,Sears和贾嘉嘉解释说,医学博士,公共卫生硕士,彭博社〜吉梅尔癌症免疫治疗研究所研究员。然而,调查人员说,这些过去的研究有各种各样的缺点,包括未能控制其他结肠直肠癌风险因素(家族史,肥胖史,吸烟,饮酒和糖尿病)的回忆偏见患者对抗生素的回忆使用,未能分离关于结肠癌和直肠癌的数据,以及太少的研究参与者产生有意义的结论。

为了解更多有关抗生素与结直肠癌之间关系的信息,Sears,Zhang和他们的同事从临床实践研究数据链(CPRD)中挖掘了数据,这是世界上最大的“匿名”临床记录电子病历数据库之一。不识别个别患者。 CPRD拥有英国1100多万名患者的信息,包括药物处方和诊断数据,使这项研究成为第一项以人群为基础的研究,旨在研究抗生素暴露与结直肠癌风险之间的关系。

专注于从1989年1月1日至2012年12月31日的23年间,研究人员发现了28,890例结直肠癌。他们将这些患者记录中的每一个与最多五名从未患过这种疾病的健康“对照”相匹配,但他们具有相似的特征,包括年龄,性别和全科医生所在的位置,共计137,077个“对照”病例进行比较。

然后,他们使用医疗记录来识别和评估结肠直肠癌风险因素的每个病史,例如肥胖,吸烟,饮酒和糖尿病的历史,以及抗生素的使用。

正如预期的那样,研究人员发现那些患有结肠直肠癌的患者更有可能患有一种或多种已知的危险因素。然而,当他们在统计评估中考虑这些因素时,他们发现患有结肠癌的人更容易接触抗生素(71.3%与69.1%相比)。与健康受试者相比,那些患有直肠癌的人没有表现出这种相关性并且具有相同的抗生素暴露。

进一步的研究表明,抗生素暴露仅与近端结肠癌(结肠的第一部分和中部)的癌症风险增加约15%有关,而与远端结肠(结肠的最后部分)的风险增加无关,并且这种风险特别严重。在暴露于杀死厌氧菌的抗生素类之后,例如青霉素家族中的那些。

研究人员表示,令人信服的研究结果显示,结肠癌风险增加迅速,仅开始抗生素暴露15-30天(风险增加约8%,总抗生素暴露15-30天,增加约15%)暴露于抗生素总量30天或以上的风险)。然而,直肠癌的相关性被逆转:抗生素暴露总量越多,特别是60天或更长时间的总暴露量,他们在该位置患癌症的可能性就越小。结肠癌发生的癌症至少在10年前与抗生素暴露有关。

西尔斯解释说,尽管抗生素在消除细菌感染方面通常非常有效,但他们也可以通过杀死有益细菌并让病原体茁壮成长来改变肠道生物群系的平衡。 这些幸存的细菌中的一些可能致癌,促使息肉生长并发展成恶性肿瘤。

她指出,近年来,富含益生菌的食物和补品已经变得流行,部分原因是为了解决肠道生物群落的不平衡问题。 但她补充说,关于益生菌的数据是混合的,一些研究显示出积极效果,而其他研究表明使用这些补充剂没有任何影响或负面影响。 西尔斯说,不是试图将有益细菌添加回肠道,而是通过更加谨慎的抗生素处方来避免使用抗生素可能增加结肠癌风险的更好方法。

Antibiotics exposure linked to increased colon cancer risk

Study adds to research promoting careful antibiotic stewardship

JOHNS HOPKINS MEDICINE

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CREDIT: GUT

In an extensive “data mining” analysis of British medical records, researchers at the Johns Hopkins Kimmel Cancer Center conclude that taking even a single course of antibiotics might boost–albeit slightly–the risk of developing colon cancer–but not rectal cancer–a decade later. The findings, reported in the August 20 issue of the journal Gut , highlight the need for judicious use of this broad category of drugs, which are frequently improperly or overprescribed, the report authors say.

“The primary message of this study is the importance of antibiotic stewardship: not treating common viral infections with antibiotics, using them for the shortest time period possible, and using targeted antibiotics rather than broad spectrum ones,” says study leader Cynthia L. Sears, M.D., Bloomberg~Kimmel Professor of Cancer Immunotherapy at the Johns Hopkins Kimmel Cancer Center. “This research adds to our understanding that these drugs can have significant off-target effects, including the induction of chronic illnesses.”

Sears cautions that medical records studies like hers are not designed to demonstrate cause and effect, but to identify possible associations between risk factors and disease. But she notes that because the database held so much specific information over a long period of time that the study authors concluded that the most likely explanation for the bump in colon cancer risk is the radical change that antibiotics wreak on the microbiome–the collection of bacteria that live in the intestines.

Antibiotics are widely prescribed throughout the world to treat bacterial infections, and there is growing evidence, including several epidemiological database studies, that link use of these drugs to the risk of colorectal cancer, explains Sears and Jiajia Zhang, M.D., M.P.H., a Bloomberg~Kimmel Institute for Cancer Immunotherapy researcher. However, the investigators say, these past studies have had a variety of drawbacks, including failure to control for other colorectal cancer risk factors (family history, history of obesity, smoking, alcohol use, and diabetes) recall bias in patients’ recollections about antibiotic use, failure to separate data about colon and rectal cancers, and too few study participants to produce meaningful conclusions.

To learn more about the association between antibiotics and colorectal cancers, Sears, Zhang, and their colleagues mined data from the Clinical Practice Research Datalink (CPRD), one of the world’s largest electronic medical record databases of “anonymized” clinical records, information that does not identify individual patients. CPRD holds information on more than 11 million patients in the U.K., including data on drug prescribing and diagnoses, making this study the first population-based study to examine the association of antibiotic exposure and risk of colorectal cancer.

Focusing on a 23-year period from January 1, 1989, to December 31, 2012, the researchers found 28,890 cases of colorectal cancer. They matched each of these patient records with up to five healthy “controls” who never developed this disease, but who had similar characteristics, including age, gender, and where their general practitioner practiced, for a total of 137,077 “control” cases for comparison.

They then used the medical records to identify and evaluate each case history for colorectal cancer risk factors, such as a history of obesity, smoking, alcohol use, and diabetes, as well as antibiotic use.

As expected, the researchers found that those patients who developed colorectal cancer were more likely to have one or more of the known risk factors. However, when they accounted for these factors in their statistical evaluation, they found that those who developed colon cancer were slightly more likely to have been exposed to antibiotics (71.3% compared to 69.1%). Those with rectal cancers did not show that association and had about the same antibiotic exposure compared to healthy subjects.

Further investigation showed that antibiotic exposure was only associated with increased risk of approximately 15% for cancer in the proximal colon (the first and middle parts of the colon) but not the distal colon (last part of the colon), and this risk happened particularly after exposure to classes of antibiotics that kill anaerobic bacteria, such as those in the penicillin family.

Among the compelling findings, the researchers say, was the rapid onset of increased colon cancer risk, beginning with only 15-30 days of total antibiotic exposure (approximately 8% increased risk with 15-30 days of total antibiotic exposure and approximately 15% increased risk with 30 or more days of total antibiotic exposure). However, the association was reversed for rectal cancer: the more total antibiotic exposure, specifically total exposures of 60 days or more, the less likely they were to have cancer in this location. Cancers that developed in the colon were linked with antibiotic exposure at least 10 years earlier. There was no increased risk with exposures less than 10 years prior.

Although antibiotics are most often highly effective at eradicating bacterial infections, Sears explains, they also can change the balance of the gut biome by killing beneficial bacteria and allowing pathogenic ones to thrive. Some of these surviving bacteria could be carcinogenic, encouraging polyps to grow and develop into malignant tumors.

In recent years, she notes, probiotic-rich foods and supplements have become popular, in part to address gut biome imbalances. But the data on probiotics is mixed, she adds, with some studies showing positive effects and others showing no effects or negative effects of using these supplements. Rather than trying to add beneficial bacteria back to the intestines, Sears says, a better way to avoid potentially increased colon cancer risk from antibiotic use is through more cautious prescribing of antibiotics.

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Other researchers who participated in this study include Charles Haines, Alastair Watson, Andrew Hart, Mary Jane Platt, Drew M. Pardoll, Sara E. Cosgrove, and Kelly A. Gebo.

This study was supported by the Fisher Center for Environmental Infectious Diseases.

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