Guidelines for reporting on animal fecal transplantation (GRAFT) studies: recommendations from a systematic review of murine transplantation protocols.

Fecal microbiota transplant (FMT) is a powerful tool used to connect changes in gut microbial composition with a variety of disease states and pathologies. While FMT enables potential causal relationships to be identified, the experimental details reported in preclinical FMT protocols are highly inconsistent and/or incomplete. This limitation reflects a current lack of authoritative guidance on reporting standards that would facilitate replication efforts and ultimately reproducible science.

Diarrhea Induced by Small Molecule Tyrosine Kinase Inhibitors Compared With Chemotherapy: Potential Role of the Microbiome.

Small molecule receptor tyrosine kinase inhibitors (SM-TKIs) are among a group of targeted cancer therapies, intended to be more specific to cancer cells compared with treatments, such as chemotherapy, hence reducing adverse events. Unfortunately, many patients report high levels of diarrhea, the pathogenesis of which remains under investigation. In this article, we compare the current state of knowledge of the pathogenesis of chemotherapy-induced diarrhea (CID) in comparison to SM-TKI-induced diarrhea, and investigate how a similar research approach in both areas may be beneficial.

Selective MMP Inhibition, Using AZD3342, to Reduce Gastrointestinal Toxicity and Enhance Chemoefficacy in a Rat Model.

Background: The common cytotoxic mechanisms that underpin chemoefficacy and toxicity have hampered efforts to deliver effective supportive care interventions, particularly for gastrointestinal (GI) toxicity. Matrix metalloproteinases (MMPs) have been implicated in both tumor growth and GI toxicity, and as such MMP inhibitors present as a novel therapeutic avenue to simultaneously enhance treatment efficacy and reduce toxicity.

Objectives: The aim of this study was to determine the efficacy of an MMP-9/12 inhibitor, AZD3342, on tumor growth and GI toxicity in a rat model.

Prophylactic probiotics for cancer therapy-induced diarrhoea: a meta-analysis.

Purpose Of Review: Strong preclinical data support prophylactic probiotics as an effective preventive strategy for diarrhoea secondary to anticancer therapies. To determine the composite evidence that this approach translates to the clinic, we performed a meta-analysis of randomized controlled trials (RCTs) of prophylactic probiotics for the prevention of cancer therapy-induced diarrhoea.

Recent Findings: A three-step search strategy was used to identify relevant studies (1 June 2000-1 June 2017) investigating probiotic intervention for diarrhoea secondary to any cancer therapy (cytotoxic, targeted and immunotherapies).

Dacomitinib-induced diarrhea: Targeting chloride secretion with crofelemer.

Dacomitinib, an irreversible small-molecule pan-ErbB TKI, has a high incidence of diarrhea, which has been suggested to be due to chloride secretory mechanisms. Based on this hypothesis, crofelemer, an antisecretory agent may be an effective intervention. T84 monolayers were treated with 1 µM dacomitinib and 10 µM crofelemer, and mounted into Ussing chambers for electrogenic ion analysis.

Dacomitinib-induced diarrhoea is associated with altered gastrointestinal permeability and disruption in ileal histology in rats.

Dacomitinib-an irreversible pan-ErbB tyrosine kinase inhibitor (TKI)-causes diarrhoea in 75% of patients. Dacomitinib-induced diarrhoea has not previously been investigated and the mechanisms remain poorly understood. The present study aimed to develop an in-vitro and in-vivo model of dacomitinib-induced diarrhoea to investigate underlying mechanisms.

TLR4-Dependent Claudin-1 Internalization and Secretagogue-Mediated Chloride Secretion Regulate Irinotecan-Induced Diarrhea.

We have previously shown increased intestinal permeability, to 4-kDa FITC-dextran, in BALB/c mice treated with irinotecan. Importantly, genetic deletion of Toll-like receptor 4 (TLR4; Tlr4) protected against loss of barrier function, indicating that TLR4 is critical in tight junction regulation. The current study aimed (i) to determine the molecular characteristics of intestinal tight junctions in wild-type and Tlr4 BALB/c mice and (ii) to characterize the secretory profile of the distal colon.

Cytokine-mediated blood brain barrier disruption as a conduit for cancer/chemotherapy-associated neurotoxicity and cognitive dysfunction.

Neurotoxicity is a common side effect of chemotherapy treatment, with unclear molecular mechanisms. Clinical studies suggest that the most frequent neurotoxic adverse events affect memory and learning, attention, concentration, processing speeds and executive function. Emerging preclinical research points toward direct cellular toxicity and induction of neuroinflammation as key drivers of neurotoxicity and subsequent cognitive impairment.

Irinotecan-Induced Gastrointestinal Dysfunction and Pain Are Mediated by Common TLR4-Dependent Mechanisms.

Strong epidemiological data indicate that chemotherapy-induced gut toxicity and pain occur in parallel, indicating common underlying mechanisms. We have recently outlined evidence suggesting that TLR4 signaling may contribute to both side effects. We therefore aimed to determine if genetic deletion of TLR4 improves chemotherapy-induced gut toxicity and pain.

Tight junction defects are seen in the buccal mucosa of patients receiving standard dose chemotherapy for cancer.

Purpose: Oral mucositis is one of the most common and debilitating side effects of chemotherapy treatment. Patients are often unable to eat and drink, which can lead to poor clinical outcomes and extensive resource utilisation. The primary aim of this study was to determine the molecular integrity of oral epithelial tight junctions in patients undergoing chemotherapy.

Management of Mucositis During Chemotherapy: From Pathophysiology to Pragmatic Therapeutics.

Chemotherapy-induced mucositis is a common condition caused by the breakdown of the mucosal barrier. Symptoms can include pain, vomiting and diarrhoea, which can often necessitate chemotherapy treatment breaks or dose reductions, thus compromising survival outcomes. Despite the significant impact of mucositis, there are currently limited clinically effective pharmacological therapies for the pathology.

ErbB small molecule tyrosine kinase inhibitor (TKI) induced diarrhoea: Chloride secretion as a mechanistic hypothesis.

Diarrhoea is a common, debilitating and potentially life threatening toxicity of many cancer therapies. While the mechanisms of diarrhoea induced by traditional chemotherapy have been the focus of much research, the mechanism(s) of diarrhoea induced by small molecule ErbB TKI, have received relatively little attention. Given the increasing use of small molecule ErbB TKIs, identifying this mechanism is key to optimal cancer care.

Toll-like receptor 4 signaling: a common biological mechanism of regimen-related toxicities: an emerging hypothesis for neuropathy and gastrointestinal toxicity.

Regimen-related toxicities remain a priority concern within the field of supportive care in cancer. Despite this, many forms of toxicity are under reported and consequently poorly characterised. Although there have been significant improvements in our understanding of regimen-related toxicities, symptom management continues to occur independently raising concerns such as drug interactions and the tendency to emphasise management of a single symptom at the expense of others.