Animal models of mucositis: critical tools for advancing pathobiological understanding and identifying therapeutic targets

Wardill, Hannah R.; Tissing, Wim J. E.; Kissow, Hannelouise; Stringer, Andrea M.

doi:10.1097/spc.0000000000000421

Cited by 17 publications

(19 citation statements)

References 165 publications

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“…Despite decades of experimental and clinical investigations of CIM, no effective therapeutic interventions are available today for treating it ( Ribeiro et al, 2016 ; Wardill et al, 2019 ). What treatments that do exist aim at reducing secondary complications to treatment, such as pain and diarrhoea.…”

Section: Possible Treatment Options For Cimmentioning

confidence: 99%

Chemotherapeutics-Induced Intestinal Mucositis: Pathophysiology and Potential Treatment Strategies

et al. 2021

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The gastrointestinal tract is particularly vulnerable to off-target effects of antineoplastic drugs because intestinal epithelial cells proliferate rapidly and have a complex immunological interaction with gut microbiota. As a result, up to 40–100% of all cancer patients dosed with chemotherapeutics experience gut toxicity, called chemotherapeutics-induced intestinal mucositis (CIM). The condition is associated with histological changes and inflammation in the mucosa arising from stem-cell apoptosis and disturbed cellular renewal and maturation processes. In turn, this results in various pathologies, including ulceration, pain, nausea, diarrhea, and bacterial translocation sepsis. In addition to reducing patient quality-of-life, CIM often leads to dose-reduction and subsequent decrease of anticancer effect. Despite decades of experimental and clinical investigations CIM remains an unsolved clinical issue, and there is a strong consensus that effective strategies are needed for preventing and treating CIM. Recent progress in the understanding of the molecular and functional pathology of CIM had provided many new potential targets and opportunities for treatment. This review presents an overview of the functions and physiology of the healthy intestinal barrier followed by a summary of the pathophysiological mechanisms involved in the development of CIM. Finally, we highlight some pharmacological and microbial interventions that have shown potential. Conclusively, one must accept that to date no single treatment has substantially transformed the clinical management of CIM. We therefore believe that the best chance for success is to use combination treatments. An optimal combination treatment will likely include prophylactics (e.g., antibiotics/probiotics) and drugs that impact the acute phase (e.g., anti-oxidants, apoptosis inhibitors, and anti-inflammatory agents) as well as the recovery phase (e.g., stimulation of proliferation and adaptation).

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Section: Possible Treatment Options For Cimmentioning

confidence: 99%

Chemotherapeutics-Induced Intestinal Mucositis: Pathophysiology and Potential Treatment Strategies

et al. 2021

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“…However, these models are mostly outdated, do not report key toxicity outcome measures and lack synergy with the clinical dynamics of HDM transplantation. As such, there is a clear disconnect between the clinical understanding of HDM-induced gut toxicity and our ability to identify targetable mechanisms in a preclinical setting, hindering efforts to develop interventions that successfully translate to the clinic [24]. The current study therefore aimed to develop and characterize a new preclinical model of HDM-induced gut toxicity and identify candidate pathways for therapeutic intervention.…”

Section: Introductionmentioning

confidence: 99%

Translational model of melphalan-induced gut toxicity reveals drug-host-microbe interactions that drive tissue injury and fever

Wardill

Mooij

Ferreira

et al. 2021

Cancer Chemother Pharmacol

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Purpose Conditioning therapy with high-dose melphalan (HDM) is associated with a high risk of gut toxicity, fever and infections in haematopoietic stem cell transplant (HSCT) recipients. However, validated preclinical models that adequately reflect clinical features of melphalan-induced toxicity are not available. We therefore aimed to develop a novel preclinical model of melphalan-induced toxicity that reflected well-defined clinical dynamics, as well as to identify targetable mechanisms that drive intestinal injury. Methods Male Wistar rats were treated with 4–8 mg/kg melphalan intravenously. The primary endpoint was plasma citrulline. Secondary endpoints included survival, weight loss, diarrhea, food/water intake, histopathology, body temperature, microbiota composition (16S sequencing) and bacterial translocation. Results Melphalan 5 mg/kg caused self-limiting intestinal injury, severe neutropenia and fever while impairing the microbial metabolome, prompting expansion of enteric pathogens. Intestinal inflammation was characterized by infiltration of polymorphic nuclear cells in the acute phases of mucosal injury, driving derangement of intestinal architecture. Ileal atrophy prevented bile acid reabsorption, exacerbating colonic injury via microbiota-dependent mechanisms. Conclusion We developed a novel translational model of melphalan-induced toxicity, which has excellent homology with the well-known clinical features of HDM transplantation. Application of this model will accelerate fundamental and translational study of melphalan-induced toxicity, with the clinical parallels of this model ensuring a greater likelihood of clinical success. Graphic abstract

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“…Its main cytotoxic effect is due to cross-linking of nucleic acid strands and inhibition of protein synthesis (Iqubal et al, 2018). In animals, cyclophosphamide (50-400 mg/kg) induces changes similar to those described for 5-FU, such as diarrhea and dyskinesia (Wardill et al, 2019). Some studies also observed this chemotherapy leads to increased intestinal permeability (Xiang et al, 2010) and epithelial destruction, in addition to dysfunction of the intestinal immunity (Owari et al, 2012).…”

Section: Animal Models Of Intestinal Mucositismentioning

confidence: 89%

“…The different treatment schemes, including dosing schedules, routes of administration, duration of treatments, and period of experimental follow-up, generally reflect the five-phase model of intestinal mucositis: initiation, messenger signaling, signal amplification, ulceration with inflammation, and healing (Sonis et al, 2004;Sougiannis et al, 2021). The main drugs used in rodent models of intestinal mucositis include 5fluorouracil (5-FU) and irinotecan; however, cyclophosphamide, cisplatin, and etoposide are also used (Ribeiro et al, 2016;Wardill et al, 2019).…”

Section: Animal Models Of Intestinal Mucositismentioning

confidence: 99%

“…The lamina propria is densely populated by cells of the immune system that provide protection against damaging substances. (Bowen et al, 2011) are less commonly used but are also valuable models (Wardill et al, 2019) which provide information regarding the underlying mechanisms of cancer therapyinduced mucosal damage.…”

Section: Animal Models Of Intestinal Mucositismentioning

confidence: 99%

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Beneficial Effects of Polysaccharides on the Epithelial Barrier Function in Intestinal Mucositis

Silva¹,

Silveira²,

Bueno³

et al. 2021

Front. Physiol.

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Intestinal mucositis is a clinically relevant side effect of anticancer therapies. It is experienced by 60–100% of patients undergoing treatment with high doses of chemotherapy, radiation therapy, and bone marrow transplantation. Intestinal mucositis can manifest as pain, weight loss, inflammation, diarrhea, rectal bleeding, and infection; affecting normal nutritional intake and intestinal function. It often impacts adherence to anticancer therapy as it frequently limits patient’s ability to tolerate treatment, causing schedule delays, interruptions, or premature discontinuation. In some cases, local and systemic secondary infections are observed, increasing the costs toward medical care and hospitalization. Several strategies for managing mucositis are available which do not always halt this condition. In this context, new therapeutic strategies are under investigation to prevent or treat intestinal mucositis. Polysaccharides from natural resources have recently become promising molecules against intestinal damage due to their ability to promote mucosal healing and their anti-inflammatory actions. These effects are associated with the protection of intestinal mucosa and regulation of microbiota and immune system. This review aims to discuss the recent advances of polysaccharides from natural resources as potential therapies for intestinal mucositis. The source, species, doses, treatment schedules, and mechanisms of action of polysaccharides will be discussed in detail.

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Animal models of mucositis: critical tools for advancing pathobiological understanding and identifying therapeutic targets

Cited by 17 publications

References 165 publications

Chemotherapeutics-Induced Intestinal Mucositis: Pathophysiology and Potential Treatment Strategies

Chemotherapeutics-Induced Intestinal Mucositis: Pathophysiology and Potential Treatment Strategies

Translational model of melphalan-induced gut toxicity reveals drug-host-microbe interactions that drive tissue injury and fever

Beneficial Effects of Polysaccharides on the Epithelial Barrier Function in Intestinal Mucositis

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