## 4 Diet and the Gut Microbiota
### The Mediterranean Diet and Nutritional Supplements  
The relationship between the Mediterranean diet and health has been known since the mid-twentieth century. A Mediterranean diet features a high concentration of antioxidants (fruits and vegetables), foods low in cholesterol, and unsaturated fatty acids (present in fish and olive oil) [32]. Several studies have shown that high consumption of products belonging to the Mediterranean diet is inversely correlated with the risks of breast, colorectal, gastric, prostate, liver, head and neck, pancreatic, and lung cancer [33]. This protective effect is due to, amongst other causes, the anti-inflammatory effect of this diet, the positive regulation of the microbiome, and the greater presence of the species _Filobacillus frimicutes_.  
In addition to the above, nutritional supplements that contain arginine, omega-3 fatty acids, or nucleotides increase the action of the immune system and the consequent destruction of tumour cells in oncological pathologies [34]. The activation of the immune system is dependent on innate immunity, which is carried out by activating key enzymatic processes in the antitumor function of these cells [35]. It has been observed that administering these supplements to cancer patients reduces their infections after surgery and reduces their  
The inhibition of T cells by tumour cells is performed through the two main inhibitory pathways best described for T cells: the cytotoxic T-lymphocyte antigen 4 (CTLA-4) protein receptor and programmed cell death protein 1 (PD-1) [45; 46]. These two are the pathways through which immune checkpoint inhibitors (ICIs) act by negatively regulating these receptors and consequently stimulating the T lymphocytes.  
Various factors are known as predictors or modifiers of the response to immunotherapy or, more accurately, to ICIs in solid tumours. Amongst the best known are the PD-L1 marker, the performance status, the mutational load or the tumour mutation burden, and tumour-infiltrating lymphocytes (TILs). However, these biomarkers are far from perfect, and biomarkers with greater sensitivity and specificity in response prediction are currently under investigation. Because of this, the microbiome is currently one of the main points under study that influences the response to ICIs [47].  
The use of antibiotics during or before treatment by ICIs could compromise its outcome. The administration of antibiotics leads to a decrease in _Bacteroid_ and _Burkholderian_ species, which shows that antibiotics weaken the effect of anti-CTLA4 drugs in animal models [48]. The reestablishment of the microbiome in these cases may increase the response to ICIs (especially to anti-CTLA4). In the same way, it has been observed in mice that the restoration of the intestinal flora by faecal transplantation or by the administration of probiotics of the species _Bifidobacterium_ produces a stronger response to anti-PD1 treatments [49].  
The effect of gut microbiota in the response to immunotherapy is currently under investigation. It is vital to take this role into account not only as a predictor of the response but also as a modifiable factor during or prior to treatment with ICIs that could increase the survival rate of patients who do not respond to treatment or who initially have characteristics that predict a poor response to treatment. The main immunotherapy drugs currently in the treatment of solid tumours are summarized in Table 2.