The gut microbiome of cancer patients

The use of antibiotics can influence the efficacy of various chemotherapy regimens depending on their spectrum of activity and the timing of their use. Rational use of antibiotics and strengthening of the intestinal flora can reduce the loss of efficacy of oncological therapy.

The microbiome is essential for the development and maintenance of a large number of homeostatic processes in the human body and contributes significantly to the defense against pathogens. Chemotherapies affect the commensal gut microbiota and potentially generate new antimicrobial resistance by activating the bacterial SOS response. Bacteria then attempt to repair damaged DNA, with errors occurring. This can result in numerous mutations, such as antibiotic resistance. The use of antibiotics further disturbs the physiological balance of the gut microbiome. Antibiotics in combination with chemotherapies thus promote the overgrowth of pathogens and their migration from the intestinal lumen across the intestinal wall into the blood and lymph channels (Fig. 1). A healthy immune system can counteract this bacterial translocation and effectively prevent the development of sepsis. However, in immunocompromised patients, this process is impaired. In addition, the likelihood of translocation of pathogens increases if gastrointestinal mucositis is concomitant. The use of antibiotics at the time of chemotherapy has been associated with a poorer prognosis in a variety of different tumors. For example, in locally advanced head or neck tumors and ovarian cancer, a shortened overall survival was observed after antibiotic administration.

Antibiotic spectrum of activity and timing of antibiotic administration. Reduced antitumor effects of cyclophosphamide and platinum salts due to treatment with antibiotics directed against Gram-positive germs have already been observed in animal models. These effects are related to translocation of Gram-positive bacteria during mucositis (Fig. 1) with resulting formation of cytotoxic reactive oxygen species (ROS) and tumor invasion by pathogenic Th17 cells. In a clinical trial of 800 patients with chronic lymphocytic leukemia receiving cyclophosphamide and 122 patients with relapsed lymphoma receiving cisplatin, the impact of antibiotics on antitumor therapy was investigated. Patients who received antibiotics directed against Gram-positive pathogens – such as vancomycin, teicoplanin, linezolid, or daptomycin – showed a significantly lower response to therapy than patients who received no antibiotics or antibiotics with a different spectrum of activity. Progression-free and overall survival were significantly shorter in the group of patients receiving the relevant antibiotics.

Shortened progression-free and overall survival was observed in liver cancer patients who received broad-spectrum antibiotics from the carbapenems group before or during chemotherapy. Further evaluation revealed that the use of antianaerobic agents such as carbapenems, cefmetazole, flomoxef, cefpirome, cefepime, clindamycin, and pazufloxacin worsens the prognosis of patients with liver cancer, especially when used before chemotherapy. Shortening of progression-free and overall survival was evident even when drugs targeting anaerobes (e.g., carbapenems such as imipenem, meropenem, ertapenem ) were administered for less than eight days (Fig. 2).

Whether antibiosis has different influence before or during chemotherapy was investigated in a currently published study of 1,446 patients with advanced colorectal carcinoma. Antibiotic use before initiation of 5-FU-based chemotherapy was found to shorten progression-free and overall survival. However, this association was not observed provided that antibiotics were administered after the initiation of chemotherapy. Consequently, impairment of intestinal flora by antibiotics seems to have a greater impact on prognosis than tumor effects or interactions of antibiotics with cytostatics during chemotherapy. Caution should therefore be exercised, especially in the prophylactic use of broad-spectrum antibiotics. It is advantageous to carefully select the antibiotically active drug tailored to the oncological therapy. In addition, the timing of antibiotic administration is also decisive: antibiotics administered before the start of chemotherapy tend to have a more negative effect on the success of the therapy than antibiotics administered concomitantly with chemotherapy.

Adequate use of antibiotics
When used excessively, antibiotics lose their effectiveness. Infection with antibiotic-resistant bacteria complicates therapy, especially in tumor patients. To prevent the development of resistance, prophylactic antibiotic therapy is recommended only for patients at high risk of infection. In addition, antibiotics alter the microbiome composition. The extent of this change depends on the antibiotic class, its antibiotic spectrum of activity (targeting Gram-negative, Gram-positive, or anaerobic bacteria), dose, and duration of use. One approach is antibiotic stewardship, i.e., the rational and responsible use of antibiotics by detecting bacterial infection, choosing the adequate antibiotic, in adequate duration of therapy, dosage, and application. Antibiotics should be used in a very targeted manner, especially in cancer patients, because infections can lead to delays in chemotherapy cycles and to dose reductions – which significantly impairs the success of therapy – or even to the discontinuation of therapy.

Probiotics
The targeted supply of intestinal microorganisms appears to be useful prophylactically. In a placebo-controlled study involving 42 pediatric cancer patients receiving chemotherapy, the effect of enteral administration of the probiotic Bifidobacterium breve strain Yakult was investigated. In the probiotic group, the incidence of fever and the use of intravenous antibiotics were less frequent compared to the placebo group. This study provides preliminary evidence that administration of selected probiotics provides clinical benefits to immunocompromised patients by improving their intestinal environment. Translocation of bacteria across the intestinal mucosa is an important mechanism in the development of febrile neutropenia. A possible prophylactic approach to prevent intestinal colonization with pathogenic microorganisms and thus febrile neutropenia is the administration of lactic acid bacteria. The safety of administration of Enterococcus faecium M-74, various lactobacilli, such as Lactobacillus plantarum, has been demonstrated in small studies. In these studies, the microbial therapies were safe even in high-risk patients receiving hematopoietic stem cell transplantation. In addition, probiotics may be beneficial in the prophylaxis and therapy of chemotherapy-induced intestinal mucositis, a cause of febrile neutropenia. In addition, meta-analyses indicate the benefit of using probiotics for prophylaxis of antibiotic-associated diarrhea and Clostridioides difficile infection (CDI).

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Consequences of antibiotic-induced dysbiosis
Antibiotic-induced dysbiosis can cause diarrhea. The risk for such diarrhea increases especially after the prescription of broad-spectrum antibiotics. Tumor patients are at particularly high risk for Clostridioides difficile infection. Clostridioides (until August 2016 Clostridium) difficile (C. difficile), which causes approximately 15-20% of antibiotic-associated diarrhea and more than 95% of cases of pseudomembranous colitis, is a Gram-positive, obligate anaerobic rod bacterium with environmentally resistant spores. C. difficile is an intestinal bacterium that is harmless to healthy individuals. However, toxins can be formed during overgrowth of C. difficile. Toxin A and B are the most important disease-causing factors. Whether and to what degree a disease symptomatology develops depends on the patient’s condition. An important risk factor is a disturbed intestinal flora, e.g. due to previous antibiotic treatments. Comparable to the measures to prevent the development of resistance, the rational use of antibiotics is recommended to prevent CDI. In the therapy of CDI, if possible, therapy with antibiotics causing CDI should be stopped as soon as possible. An episode of illness with this pathogen can be treated with the antibiotics vancomycin, fidaxomicin, or metronidazole. In severe episodes, vancomycin or fidaxomicin may be used. Surgical therapy is necessary for intestinal perforation and severe refractory courses with toxic megacolon or ileus. Approximately one quarter of CDI patients relapse within a short period of time. Multiple relapses are treated with fidaxomicin or vancomycin.

Fecal transplantation for secondary prophylaxis
Fecal microbiota transfer (FMT) is available for secondary prophylaxis, which can prevent the occurrence of recurrence in about 80% after a single application and in about 90% after multiple applications. Its beneficial effect is probably based on the restoration of diversity and homeostasis of the gut microbiome. In addition, a single infusion of the human monoclonal antibody bezlotoxumab can be used to prevent recurrent CDI. The antibody binds to and neutralizes C. difficile toxin-B. Accompanying antibacterial therapy against CDI, bezlotoxumab can significantly reduce the recurrence rate.

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