**2. Bacterial infections and the disruption of gut homeostasis**

Bacterial pathogens are microorganisms that have the ability to cause disease due to their specialized virulence factors or that can arise from a dysbiosis such as from antibiotic treatment that can eliminate the normal healthy flora of the gut leading to opportunistic infections from commensals or normally non-pathogenic organisms.

#### **2.1 Bacterial pathogens, virulence factors, and mechanisms of pathogenesis**

Some of the best-known bacterial pathogens are *Salmonella enterica*, *Listeria monocytogenes*, *Vibrio cholera*, *Shigella flexneri*, Shiga toxin producing *E. coli*

(STEC) (i.e. *E. coli* 0157:H7), *Clostridium difficile*, *Clostridium perfringens*, and *Clostridium botulinum*. Both Gram-positive and Gram-negative pathogens must develop mechanisms to outcompete the normal gut microbiota, bind/invade cells, avoid detection and killing from the host immune system. Some important pathogen virulence mechanisms consist of specialized secretion systems that encode factors important for all the above steps in pathogenesis. The type III secretion systems (TTSS/T3SS) encoded by some Gram-negative pathogens such as *Salmonella*, *Vibrio*, *Shigella*, *Escherichia coli*, and *Yersinia* are well-known examples. Other specialized secretion systems are the T4SS and T6SS. T6SSs are prevalent in both pathogens and commensals suggesting their importance in the intestinal environment [48]. For non-intracellular pathogens, bacterial toxins [i.e., Listeriolysin O (LLO), botulinum neurotoxins (BoNTs), alpha toxin-*C. perfringens*, TcdA/TcdB-*C. difficile*] are important virulence factors that can bind to and enter the intestinal epithelium and/or their target cells to effect their functions (i.e. cytotoxicity).

One important growth restriction system on the part of hosts/intestinal flora is the sequestration of iron, which is absolutely required for growth. For example, *Salmonella enterica* can evade lipocalin-2-mediated growth restriction by producing modified siderophores that cannot be bound by lipocalin-2 [49]. The T4SS and T6SS systems can be utilized for intra-and-inter bacterial species warfare. *Bacteroides* strains encoding the T6SS have been shown to target sensitive *Bacteroides* spp. suggesting they limit their competition [50–52]. *Salmonella*, *Vibrio*, and *E. coli* have also been shown to use T6SS against their competition, the intestinal microbiota [53–55].
