An Aeromonas variant that produces aerolysin promotes susceptibility to ulcerative colitis

Bacterial virulence factors as therapeutic targets in ulcerative colitis?

Ulcerative colitis (UC) is an inflammatory bowel disease characterized by a highly variable clinical course. Although treatment options have increased considerably in recent years, durable remission is often not achieved. Organ damage may occur, and up to one-quarter of patients eventually require colectomy. The pathogenesis of UC is still incompletely understood; multiple factors, including dysregulation of the intestinal immune system, dysbiosis, and defects of the mucosal barrier contribute to disease development. However, the mechanisms underlying disruption of the epithelial barrier have not yet been fully elucidated. Tissue-resident macrophages, as part of the innate immune system, constitute a central first line of defense against pathogens and play an important role in maintaining the epithelial barrier. 
In their study, Jiang et al. observed a reduction in subepithelial, tissue-resident macrophages not only in inflamed tissue but in areas that had not yet exhibited inflammation, leading them to conclude that macrophage loss precedes the onset of inflammation. Bacteria-free supernatants derived from stool cultures of patients with UC exerted cytotoxic effects on murine bone marrow–derived macrophages in vitro. The authors identified an Aeromonas variant that produces the macrophage-toxic protein aerolysin. In vitro experiments and additional mouse models demonstrated that macrophages are more susceptible to aerolysin-induced cell death than epithelial cells, suggesting that aerolysin-mediated barrier dysfunction occurs without direct epithelial damage. The identified Aeromonas strain, referred to as macrophage-toxic bacteria (MTB), was able to persistently colonize mice following pretreatment with antibiotics or dextran sulfate sodium (DSS), whereas colonization under physiological conditions was not sustained. MTB promoted inflammation in 2 different murine colitis models, and aerolysin production was required for this effect. Polyclonal anti-aerolysin antibodies prevented MTB-induced colitis, whereas monoclonal anti-aerolysin antibodies attenuated inflammation. 
Furthermore, the authors demonstrated that Aeromonas species were detected more frequently in stool samples from patients with UC than from healthy donors, and aerolysin was identified in intestinal biopsy specimens from patients with UC. The authors conclude that MTB and aerolysin may represent diagnostic biomarkers and potential therapeutic or preventive targets for antimicrobial or antibody-based treatments. However, UC is a complex, multifactorial, immune-mediated disease in which bacterial toxins do not represent the primary pathogenic factor. Antitoxin antibodies neutralize toxin-mediated effects but do not eliminate toxin-producing bacteria and lack immunomodulatory properties, making their efficacy during active inflammation uncertain.
Moreover, it remains unclear which additional bacterial toxins may be pathogenic and would require simultaneous targeting. The use of multiple antibody-based therapies would be costly and potentially associated with increased adverse effects. Antibiotic therapy in UC is currently indicated only in cases of confirmed infection or specific complications and is not recommended for modulation of the gut microbiota, as protective bacteria may also be depleted or eliminated. Fecal microbiota transplantation is presently under investigation as a treatment for UC in clinical trials. Overall, this study is convincingly conducted and sheds light on a mechanism that contributes to UC pathogenesis. Further investigations focusing on interactions between the intestinal immune system and the gut microbiome are essential to advance understanding of disease mechanisms.