2020-02-22 Alexander 2017 Nat Rev Gastroenterol Hepatol

Cytotoxic drugs continue to be the mainstay of medical treatment for most patients with advanced disease, yet they have an unpredictable treatment response and considerable treatment-related morbidity and mortality.

Despite this progress, we are still lacking a complete map of microbiota–host–drug interactions in cancer, and biological complexity remains a considerable obstacle to the development of these ‘precision’ therapies. For example, the gut microbiota exert both direct and indirect effects on chemotherapy toxicity and efficacy through a large suite of chemical signaling cascades (FIG. 1); as a result, it seems to exert its influence on almost all classes of chemotherapeutic agents and it achieves this on a moving playing field.

The majority of cancers strike at extremes of age, in which the structural ecology of the gut might be immature or perturbed through exposure to a lifetime of environmental modifiers. 年龄和既往生活史影响肠道环境
Moreover, pathological disease states or surgical and medical therapies might also create a state of dysbiosis, further exaggerating the influence of deleterious bacteria, reducing efficacy and exacerbating the toxicity of chemotherapy. 病理状态、手术和药物治疗导致肠道生态失调，引起药效降低，加重化疗毒性
A paradox also exists, as chemotherapeutics might further exacerbate any dysbiotic state rather than correct it, with potentially serious implications for drug toxicity. 化疗可能会进一步恶化失调状态，对药物毒性有潜在的严重影响

‘TIMER’ mechanistic framework

Translocation
Immunomodulation
Metabolism
Enzymatic degradation
Reduced diversity>

The importance of gut microbial facilitation of immune responses in cancer treatment extends to novel targeted immunotherapies, such as synthetic monoclonal antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed cell death 1 ligand 1 (anti-PD-L1).

MCA205 sarcoma progression is controlled by CTLA-4-specific antibodies in specific pathogen-free mice, but not in germ-free mice or those treated with broad-spectrum antibiotics2