Dancing with the Stars: How Choreographed Bacterial Interactions Dictate Nososymbiocity and Give Rise to Keystone Pathogens, Accessory Pathogens, and Pathobionts

Abstract

Many diseases that originate on mucosal membranes ensue from the action of polymicrobial communities of indigenous organisms working in concert to disrupt homeostatic mechanisms. Multilevel physical and chemical communication systems among constituent organisms underlie polymicrobial synergy and dictate the community's pathogenic potential or nososymbiocity, that is, disease arising from living together with a susceptible host. Functional specialization of community participants, often originating from metabolic codependence, has given rise to several newly appreciated designations within the commensal-to-pathogen spectrum. Accessory pathogens, while inherently commensal in a particular microenvironment, nonetheless enhance the colonization or metabolic activity of pathogens. Keystone pathogens (bacterial drivers or alpha-bugs) exert their influence at low abundance by modulating both the composition and levels of community participants and by manipulating host responses. Pathobionts (or bacterial passengers) exploit disrupted host homeostasis to flourish and promote inflammatory disease. In this review we discuss how commensal or pathogenic properties of organisms are not intrinsic features, and have to be considered within the context of both the microbial community in which they reside and the host immune status.

Keywords: accessory pathogen; keystone pathogen; nososymbiocity; pathobiont; polymicrobial synergy.

Figure 1. Factors That Promote Dysbiosis

Mucosal inflammatory disease is induced under certain conditions by a polymicrobial community, in which different members have distinct and synergistic roles that promote destructive inflammation. Keystone pathogens — which are aided by accessory pathogens in terms of nutritional and/or colonization support — initially subvert host immunity leading to the emergence of a dysbiotic microbiota, in which commensal-turned pathobionts overactivate the inflammatory response and cause tissue destruction. Inflammation can exacerbate dysbiosis through several mechanisms ([–60]; see text for details), hence inflammation and dysbiosis positively reinforce each other. Additional risk factors that shift the balance towards dysbiosis and the emergence of inflammophilic pathobionts include (but are not limited to) frequent use of antibiotics, high-fat diet, tissue injury, and immune deficiencies. These factors could promote dysbiosis by acting individually or in combination.

Figure 2. Alpha-bugs and Colon Cancer

Enterotoxigenic B. fragilis (ETBF) drives persistent Th17- and IL-17-dependent inflammation by activating signal transducer and activator of transcription 3 (STAT3) signaling in the colon, which leads to colonic hyperplasia and tumor formation in the multiple intestinal neoplasia (Min) mouse model. Min mice are susceptible to development of intestinal adenomas, hence ETBF-induced carcinogenesis requires a host with predisposing genetic traits or, in general, particular disease modifiers. ETBF also secretes a pro-oncogenic toxin (B. fragilis toxin; BFT). In contrast, non-enterotoxigenic B. fragilis (NTBF) produces polysaccharide A (PSA) which inhibits intestinal Th17 responses. According to the ‘alpha-bug’ hypothesis, alpha-bugs are not simply pro-oncogenic but can remodel the colonic bacterial community to a state that enhances mucosal inflammation and pro-oncogenic activity, resulting in colon cancer. Consistent with this, an alpha bug could be the ‘driver’ in the bacterial driver–passenger model for colorectal cancer, where the consequences of its actions (inflammatory tumorigenic environment) could lead to the emergence of opportunistic pathogens (’passengers’) that can exacerbate pathology leading to colon cancer.