Antibiotic-induced disruption of the microbiome exacerbates chemotherapy-induced diarrhoea and can be mitigated with autologous faecal microbiota transplantation

Wardill, Hannah R.; Aa, Stijn A R van der; Ferreira, Ana Rita da Silva; Havinga, Rick; Tissing, Wim J. E.; Harmsen, Hermie J. M.

doi:10.1016/j.ejca.2021.05.015

Cited by 22 publications

(12 citation statements)

References 48 publications

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“… 40 The previous studies have identified dysbiosis in mucositis, such as a decrease in protective bacteria, Lactobacillus, and an increase in pathogens. 30 , 33 In agreement with this evidence, we showed that 5-FU treatment down-regulated an abundance of bacteria that have shown beneficial effects on inhibition of mucositis, such as Lactobacillus species 41 and Muribaculum species 42 in mice, and up-regulated an abundance of bacteria that are associated with gastrointestinal inflammation, such as Helicobacter species, which has a strong association with intestinal inflammatory disease diseases in patients. 43 The roles of B sartorii and M schaedleri that were regulated by 5-FU in mucositis remain unclear.…”

Section: Discussionsupporting

confidence: 86%

2’-Fucosyllactose Ameliorates Chemotherapy-Induced Intestinal Mucositis by Protecting Intestinal Epithelial Cells Against Apoptosis

Zhao¹,

Williams²,

Washington³

et al. 2022

Cellular and Molecular Gastroenterology and Hepatology

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This study shows a novel direct effect of 2'-fucosyllactose, an abundant oligosaccharide in human milk, in mitigating apoptosis stimulated by the chemotherapeutic agent 5-fluorouracil in intestinal epithelial cells. The results indicated that 2'-fucosyllactose ameliorates 5-fluorouracil-induced intestinal mucositis by supporting intestinal integrity for protection against injury.BACKGROUND & AIMS: Intestinal mucositis, a severe complication of antineoplastic therapeutics, is characterized by mucosal injury and inflammation in the small intestine. Therapies for the prevention and treatment of this disease are needed. We investigated whether 2'-fucosyllactose (2'-FL), an abundant oligosaccharide in human milk, protects intestinal integrity and ameliorates intestinal mucositis. METHODS:A mouse small intestinal epithelial (MSIE) cell line, mouse enteroid cultures, and human gastrointestinal tumor cell lines (AGS and HT29) were co-treated with the chemotherapy agent 5-fluorouracil (5-FU) and 2'-FL. Mice were injected intraperitoneally with 5-FU to induce intestinal mucositis. 2'-FL was administered in the drinking water to mice before (pretreatment) or concurrently with 5-FU injection. Body weight and pathologic changes were analyzed.RESULTS: 2'-FL alleviated 5-FU inhibition of cell growth in MSIE cells, but not in AGS and HT29 cells. The 5-FU-induced apoptosis in MSIE cells and enteroids was suppressed by 2'-FL. Compared with 5-FU treatment alone, 2'-FL pretreatment protected against body weight loss, and ameliorated inflammation scores, proinflammatory cytokine production, shortening of villi, epithelial cell apoptosis, goblet cell loss, and tight junctional complex disruption in the small intestine. 2'-FL concurrent treatment had less of an effect on intestinal mucositis than 2'-FL pretreatment. Interestingly, no effect of 2'-FL was observed on 5-FU-induced S-phase arrest in MSIE, AGS, and HT29 cells. Neither pretreatment nor concurrent treatment with 2'-FL affected 5-FU-induced inhibition of proliferation in MSIE cells. CONCLUSIONS:This study shows a novel direct effect of 2'-FL in protecting small intestinal epithelial cells against apoptosis stimulated by 5-FU, which may contribute to prevention of 5-FU-induced intestinal mucositis.

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Section: Discussionsupporting

confidence: 86%

2’-Fucosyllactose Ameliorates Chemotherapy-Induced Intestinal Mucositis by Protecting Intestinal Epithelial Cells Against Apoptosis

Zhao¹,

Williams²,

Washington³

et al. 2022

Cellular and Molecular Gastroenterology and Hepatology

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“…While it is unclear if melphalan has a direct cytotoxic effect on the microbiota, it is likely that MBI drives dysbiosis with antibiotics serving to exacerbate these changes, with previous data demonstrating no direct impact of specific chemotherapeutic agents on microbial viability 44 . As such, assuming dysbiosis is secondary to mucosal injury as recently demonstrated 45 , we anticipate that anakinra will still have an appreciable impact on the severity of dysbiosis and may even prompt more protocolised/limited antibiotic use. Similarly, while we used body temperature as an indicator of BSI, we did not culture peripheral blood or mesenteric lymph nodes as was performed in our animal model development.…”

Section: Discussionmentioning

confidence: 78%

Supporting the gastrointestinal microenvironment during high-dose chemotherapy and stem cell transplantation by inhibiting IL-1 signaling with anakinra

Wardill

Mooij

Ferreira

et al. 2022

Sci Rep

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High-dose chemotherapy causes intestinal inflammation and subsequent breakdown of the mucosal barrier, permitting translocation of enteric pathogens, clinically manifesting as fever. Antibiotics are mainstay for controlling these complications, however, they are increasingly recognized for their detrimental effects, including antimicrobial resistance and dysbiosis. Here, we show that mucosal barrier injury induced by the mucotoxic chemotherapeutic agent, high-dose melphalan (HDM), is characterized by hyper-active IL-1b/CXCL1/neutrophil signaling. Inhibition of this pathway with IL-1RA, anakinra, minimized the duration and intensity of mucosal barrier injury and accompanying clinical symptoms, including diarrhea, weight loss and fever in rats. 16S analysis of fecal microbiome demonstrated a more stable composition in rats receiving anakinra, with reduced pathogen expansion. In parallel, we report through Phase IIA investigation that anakinra is safe in stem cell transplant patients with multiple myeloma after HDM. Ramping-up anakinra (100–300 mg administered intravenously for 15 days) did not cause any adverse events or dose limiting toxicities, nor did it change time to neutrophil recovery. Our results reinforce that strengthening the mucosal barrier may be an effective supportive care strategy to mitigate local and systemic clinical consequences of HDM. We are now conducting a Phase IIB multicenter, placebo-controlled, double-blinded trial to assess clinical efficacy of anakinra (AFFECT-2).Trial registration: ClinicalTrials.gov identifier: NCT03233776.

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“…This led to higher mortality after gut disruption with methotrexate. Interestingly, fecal transplantation improved the animals´ prognoses [ 111 ]. This again clarifies the role of the microbiome as an actor or contributor in the disease process.…”

Section: Dose Of β-Lactams In Critical Illnessmentioning

confidence: 99%

β-Lactam Dosing in Critical Patients: A Narrative Review of Optimal Efficacy and the Prevention of Resistance and Toxicity

et al. 2022

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Antimicrobial prescription in critically ill patients represents a complex challenge due to the difficult balance between infection treatment and toxicity prevention. Underexposure to antibiotics and therapeutic failure or, conversely, drug overexposure and toxicity may both contribute to a worse prognosis. Moreover, changes in organ perfusion and dysfunction often lead to unpredictable pharmacokinetics. In critically ill patients, interindividual and intraindividual real-time β-lactam antibiotic dose adjustments according to the patient’s condition are critical. The continuous infusion of β-lactams and the therapeutic monitoring of their concentration have both been proposed to improve their efficacy, but strong data to support their use are still lacking. The knowledge of the pharmacokinetic/pharmacodynamic targets is poor and is mostly based on observational data. In patients with renal or hepatic failure, selecting the right dose is even more tricky due to changes in drug clearance, distribution, and the use of extracorporeal circuits. Intermittent usage may further increase the dosing conundrum. Recent data have emerged linking overexposure to β-lactams to central nervous system toxicity, mitochondrial recovery delay, and microbiome changes. In addition, it is well recognized that β-lactam exposure facilitates resistance selection and that correct dosing can help to overcome it. In this review, we discuss recent data regarding real-time β-lactam antibiotic dose adjustment, options in special populations, and the impacts on mitochondria and the microbiome.

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Antibiotic-induced disruption of the microbiome exacerbates chemotherapy-induced diarrhoea and can be mitigated with autologous faecal microbiota transplantation

Cited by 22 publications

References 48 publications

2’-Fucosyllactose Ameliorates Chemotherapy-Induced Intestinal Mucositis by Protecting Intestinal Epithelial Cells Against Apoptosis

2’-Fucosyllactose Ameliorates Chemotherapy-Induced Intestinal Mucositis by Protecting Intestinal Epithelial Cells Against Apoptosis

Supporting the gastrointestinal microenvironment during high-dose chemotherapy and stem cell transplantation by inhibiting IL-1 signaling with anakinra

β-Lactam Dosing in Critical Patients: A Narrative Review of Optimal Efficacy and the Prevention of Resistance and Toxicity

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