Doxycycline-induced gastrointestinal injury

Affolter, Kajsa; Samowitz, Wade S.; Boynton, Kathleen K.; Kelly, Erinn Downs

doi:10.1016/j.humpath.2017.02.011

Cited by 58 publications

(26 citation statements)

References 8 publications

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“…Doxycycline can potentially have multiple activities in vivo, including anti-inflammatory activities (51) and effects on the intestinal microbiota (52). Doxycycline can induce esophageal ulceration mimicking a benign form of esophageal cancer (53)(54)(55), can cause gastrointestinal injury (56,57), and can stimulate colonic tumor growth (58). On the other hand, doxycycline can also have antitumorigenic effects (59)(60)(61)(62).…”

Section: Discussionmentioning

confidence: 99%

Temporal Control of the Helicobacter pylori Cag Type IV Secretion System in a Mongolian Gerbil Model of Gastric Carcinogenesis

Lin

McClain

Beckett

et al. 2020

mBio

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The Helicobacter pylori Cag type IV secretion system (T4SS) translocates the effector protein CagA and nonprotein bacterial constituents into host cells. In this study, we infected Mongolian gerbils with an H. pylori strain in which expression of the cagUT operon (required for Cag T4SS activity) is controlled by a TetR/tetO system. Transcript levels of cagU were significantly higher in gastric tissue from H. pylori-infected animals receiving doxycycline-containing chow (to derepress Cag T4SS activity) than in tissue from infected control animals receiving drug-free chow. At 3 months postinfection, infected animals receiving doxycycline had significantly increased gastric inflammation compared to infected control animals. Dysplasia (a premalignant histologic lesion) and/or invasive gastric adenocarcinoma were detected only in infected gerbils receiving doxycycline, not in infected control animals. We then conducted experiments in which Cag T4SS activity was derepressed during defined stages of infection. Continuous Cag T4SS activity throughout a 3-month time period resulted in higher rates of dysplasia and/or gastric cancer than observed when Cag T4SS activity was limited to early or late stages of infection. Cag T4SS activity for the initial 6 weeks of infection was sufficient for the development of gastric inflammation at the 3-month time point, with gastric cancer detected in a small proportion of animals. These experimental results, together with previous studies of cag mutant strains, provide strong evidence that Cag T4SS activity contributes to gastric carcinogenesis and help to define the stages of H. pylori infection during which Cag T4SS activity causes gastric alterations relevant for cancer pathogenesis. IMPORTANCE The “hit-and-run model” of carcinogenesis proposes that an infectious agent triggers carcinogenesis during initial stages of infection and that the ongoing presence of the infectious agent is not required for development of cancer. H. pylori infection and actions of CagA (an effector protein designated a bacterial oncoprotein, secreted by the Cag T4SS) are proposed to constitute a paradigm for hit-and-run carcinogenesis. In this study, we report the development of methods for controlling H. pylori Cag T4SS activity in vivo and demonstrate that Cag T4SS activity contributes to gastric carcinogenesis. We also show that Cag T4SS activity during an early stage of infection is sufficient to initiate a cascade of cellular alterations leading to gastric inflammation and gastric cancer at later time points.

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Section: Discussionmentioning

confidence: 99%

Temporal Control of the Helicobacter pylori Cag Type IV Secretion System in a Mongolian Gerbil Model of Gastric Carcinogenesis

Lin

McClain

Beckett

et al. 2020

mBio

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“…Gastric mucosal toxicity has been reported after oral use of DXC. Gastric mucosal erosions covered with adherent exudate have been repeatedly observed by esophagogastroduodenoscopy in patients assuming DXC orally [18, 19]. Microscopic analysis of biopsies from the gastric lesions revealed superficial mucosal necrosis and capillary vascular degeneration, usually resolving upon discontinuation of the drug.…”

Section: Discussionmentioning

confidence: 99%

Radiosensitization of orthotopic GIC-driven glioblastoma by doxycycline causes skin damage

et al. 2019

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Doxycycline (DXC) is a tetracycline antibiotic which has been proposed as a breast cancer radiosensitizer by specifically reducing the expression of the DNA repair enzyme DNA PK in breast cancer initiating cells. Since DXC presents favorable pharmacokinetics properties including the capacity to cross the blood-brain barrier, it has been hypothesized that it could radiosensitize brain tumors as well. We have investigated the radiosensitizing capacity of DXC towards human glioma initiating cells (GIC)-driven orthotopic glioblastomas (GB) in NOD/SCID mice that faithfully mimic the growth properties of the clinical tumors of origin. DXC at 10 mg/Kg body weight was subcutaneously delivered daily, 5 days/week for 4 weeks. At the same time, radiotherapeutic fractions of 0.25 Gy to the head were delivered every 3–4 days (twice/week) for 15 weeks. No survival advantage was observed in DXC-treated mice as compared to vehicle-treated mice by this radiosensitizing protocol. On the contrary, skin damage with hair loss and deep ulcers were observed after 4 weeks in DXC-treated mice leading to discontinuation of drug treatment. These results do not support the use of DXC as a radiosensitizer for brain tumors and indicate skin damage as an important side effect of DXC.

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“…Doxycycline is already associated with a range of side effects, including pain, increased pressure inside the skull 35 , and gastrointestinal injury 36 . The nuances of these associations are not well understood.…”

Section: Discussionmentioning

confidence: 99%

Lyme Disease Patient Trajectories Learned from Electronic Medical Data for Stratification of Disease Risk and Therapeutic Response

Ichikawa

Glicksberg

Genes

et al. 2019

Sci Rep

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Lyme disease (LD) is the most common tick-borne illness in the United States. Although appropriate antibiotic treatment is effective for most cases, up to 20% of patients develop post-treatment Lyme disease syndrome (PTLDS). There is an urgent need to improve clinical management of LD using precise understanding of disease and patient stratification. We applied machine-learning to electronic medical records to better characterize the heterogeneity of LD and developed predictive models for identifying medications that are associated with risks of subsequent comorbidities. For broad disease categories, we identified 3, 16, and 17 comorbidities within 2, 5, and 10 years of diagnosis, respectively. At a higher resolution of ICD-9 codes, we identified known associations with LD including chronic pain and cognitive disorders, as well as particular comorbidities on a timescale that matched PTLDS symptomology. We identified 7, 30, and 35 medications associated with risks of these comorbidities within 2, 5, and 10 years, respectively. For instance, the first-line antibiotic doxycycline exhibited a consistently protective association for typical symptoms of LD, including backache. Our approach and findings may suggest new hypotheses for more personalized treatments regimens for LD patients.

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Doxycycline-induced gastrointestinal injury

Cited by 58 publications

References 8 publications

Temporal Control of the Helicobacter pylori Cag Type IV Secretion System in a Mongolian Gerbil Model of Gastric Carcinogenesis

Temporal Control of the Helicobacter pylori Cag Type IV Secretion System in a Mongolian Gerbil Model of Gastric Carcinogenesis

Radiosensitization of orthotopic GIC-driven glioblastoma by doxycycline causes skin damage

Lyme Disease Patient Trajectories Learned from Electronic Medical Data for Stratification of Disease Risk and Therapeutic Response

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