**4. Role of gut microbiota in cancer causation**

There has been an ongoing debate among researchers on the role of gut microbiota in the causation of cancer as cancer is neither a contagious nor an infectious disease [16]. The first proposition of the possible role of gut microbiota in cancer causation was given by Russel in 1890, which was supported by positive results over the subsequent years [52–54]. However, in 1963, a group of scientists from NCI, USA claimed that the bacteria found in the cancer tissues were probably contaminants [16]. This subject remained controversial until Marshall, in his study, proved the association between *H. pylori* and gastric adenocarcinoma [55]. This was a breakthrough study in this aspect and since then, a number of bacteria have been linked to a variety of cancers [56–58]. However, the mechanism by which the microbiota cause cancer is still unclear. While there is no concrete evidence supporting the causation of cancer, there may be a role of the bacteria in its progression [59].

Microbiota may act as a carcinogen in two ways, either by inducing a chronic inflammatory state or direct injury by material toxins and metabolites [16, 60–62]. Release of pro-inflammatory mediators like TNF-α and IL-1 and generation of reactive oxygen species (ROS) stimulates lymphoepithelial proliferation and cell division. This leads to immune dysregulation, thereby leading to tumorigenesis [27]. It causes alteration in the cell cycle leading to immunosuppression [63]. It also results in genetic and cellular damage and genomic instability which preclude carcinogenesis [64]. The bacterial toxins are genotoxins that cause DNA damage and may lead to the development of cancer [65, 66]. Thus, chronic bacterial infections demonstrate a dual role in carcinogenesis by both stimulating and inhibiting the immune system.
