# Novel Insights on Plant Extracts to Prevent and Treat Recurrent Urinary Tract Infections
## 2 Pathogenesis of rUTI  
The most common risk factors for UTI are female anatomy, age, sexual, birth control activity, and menopause (Figure 1). However, other risk factors, such as abnormalities and blockages in the urinary tract, catheter, or recent urinary procedures should be considered [11]. The studies on hereditary UTI started when it was noticed that the infection tends to be clustered in specific individuals and is relevant among females with relatives that suffer from recurring UTI. The candidate genes determining human/animal UTI susceptibility have been identified starting from the early 1980s using various genetic and immunological tools [12]. These studies concluded that increased susceptibility to UTI is a complex heritable trait with numerous genes that seem to contribute to the UTI-prone phenotype. These genes are involved in antimicrobial defense [13]. The host resistance to recurrent UTI relies strongly on the pathways that signal the innate immune system and the genes that control those pathways. In contrast, different immune variants can exacerbate acute and chronic infection or be protective [12; 14].  
Based on the current knowledge about the pathogenesis of rUTI, there are three main components involved: pathogen virulence, the host's defense mechanism, and the environment [15]. The etiology of UTI includes Gram-positive and Gram-negative bacteria and fungi, but UPEC accounts for a significant proportion of rUTI [6]. Uropathogenic _E. coli_ strains from reservoirs (intestinal, perineal, vagina, and preputial microflora) invade the urinary tract. Bacterial virulence factors (e.g., flagella/pili, extracellular polysaccharides, toxins, and enzymes) may contribute to UTI recurrence [2; 14]. The bacterial urogenital  
Figure 1: The pathogenesis of rUTI and their effects on human urinary system homeostasis. The major sources of infection are intestinal, perineal, vaginal, and preputial microflora, then _E. coli_ (UPEC) migrate and invade the bladder tissue where they form biofilm and internalize. The migration of _E. coli_ (UPEC) affects the kidney’s normal functions as an effect of inflammation proliferation. The persistence of the inflammatory process at this level could determine bacterial translocation. The picture was created with the Biorender app.  
mucosa attachment activates a cascade of signaling molecules in the host from innate immune responses that stimulate cytokine release resulting in an inflammatory response and symptoms. In response, bacteria produce molecules that specifically inhibit the signaling pathways and use toxins to kill the mucosal barrier cells and enter the bloodstream in the acute phase of infection. Thus, the severity of a UTI depends on the innate defensive response of the host and the virulence of the infecting agents. In the case of rUTI, bacteria form biofilm. Moreover, they can persist in quiescent communities, surviving the immune response and resisting antibiotic attacks. Recurrent urinary tract infections are based on the same pathogenic microorganism that underwent the initial condition, _E. coli_ strains that use the reservoirs associated with the host in the gastrointestinal tract and bladder tissue to repopulate/reinforce the host [9]. In human anatomy, _E. coli_ is primarily found in the gastrointestinal tract. The proximity of the urethra to the anus, particularly in female patients, makes _E. coli_ a significant contributor or activator in most catheter-associated urinary tract infections (CAUTI) for intermittent catheter users [7]. Another cause of rUTI is bladder dysbiosis, an alteration of the urinary microbiota by strains from reservoirs that compete with the natural microbial community, and uropathogens can become dominant. Antibiotic prophylactic treatment is another critical factor affecting rUTI because it favors the development of multidrug-resistant (MDR) uropathogenic bacteria, which are more virulent and persistent [2; 14].