An Aeromonas variant that produces aerolysin promotes susceptibility to ulcerative colitis.

Ulcerative colitis (UC) is a severe inflammatory bowel disease affecting millions of people worldwide, but the factors driving the condition are poorly understood. In tissue samples from individuals with UC, we found that macrophages were depleted from areas of the colon that did not yet exhibit overt epithelial inflammation. We hypothesized that toxins produced by bacteria could impair macrophages and that this could promote wider inflammation. We isolated a variant of Aeromonas genus from stool samples from UC patients, which we termed macrophage-toxic bacteria (MTB), because aerolysin secreted by MTB caused macrophage death. MTB colonized mice under pathogenic conditions and triggered colitis. Antibodies against aerolysin alleviated colitis induced by Aeromonas in mice. In a cohort, UC patients more frequently tested positive for Aeromonas than healthy controls did. Editor's summary: Ulcerative colitis (UC) is a debilitating inflammatory bowel disease linked to dysfunction of cells within the large intestine. Jiang et al. hypothesized that toxins produced by microbiota might impair macrophages in the gut and contribute to the pathology of UC (see the Perspective by Modilevsky and Bel). Stool samples from UC patients contained a species of bacteria, a variant of the Aeromonas genus, that released a toxin called aerolysin. Under pathological conditions, this Aeromonas variant could colonize mouse intestines, deplete macrophages, and increase the sensitivity of mice to gut inflammation. These effects were linked to the ability of aerolysin to kill macrophages directly. Administration of anti-aerolysin antibodies provided protection against colitis in mice that were exposed to the Aeromonas variant. —Sarah H. Ross INTRODUCTION: Ulcerative colitis (UC) is a multifactorial disease involving immune dysregulation, genetic susceptibility, aberrant inflammatory responses to intestinal microbiota, and environmental factors. UC is characterized by an unpredictable clinical course, often alternating between periods of exacerbation and remission. Because the inflammation and ulceration associated with UC are typically confined to the mucosal layer, UC has been often considered a disease of the epithelial barrier. The initiating factors responsible for epithelial barrier impairment remain unclear, and elucidating them could reveal how UC develops and inform new treatment strategies. RATIONALE: The gut epithelium contains one of the largest populations of tissue-resident macrophages, which serve as the first line of defense against pathogens invading from the intestinal lumen. We hypothesized that gut-resident macrophages are compromised in UC, leading to impaired epithelial integrity, and we therefore examined macrophages in UC colon tissues. RESULTS: In colon tissues isolated from UC patients, we found that tissue-resident macrophages were depleted in areas that did not show indications of inflammation. We hypothesized that macrophage loss preceded overt inflammation. In mouse models, chemical or genetic ablation of macrophages increased susceptibility to intestinal injury. To identify potential factors that might impair the function of macrophages, we examined bacteria present in fecal samples from UC patients. We identified a toxin-producing bacterium belonging to the Aeromonas genus, designated Aeromonas sp. MTB (macrophage-toxic bacteria), which expressed the virulence factor aerolysin. Macrophages exhibited higher sensitivity to aerolysin-induced cell death than epithelial cells, a result that we hypothesized could lead to barrier impairment without direct epithelial damage. MTB persistently colonized mice under pathological conditions, depleting macrophages and enhancing sensitivity to enteric stimuli. MTB promoted colitis in mice exposed to dextran sulfate sodium or lacking interleukin-10 expression, with phenotypes resembling UC, but not in germ-free mice. An aerolysin-deficient MTB mutant failed to cause colitis, supporting the role of this toxin. In mice, pretreatment with polyclonal anti-aerolysin antibodies prevented MTB-induced colitis, and a monoclonal anti-aerolysin ameliorated established disease. To determine the prevalence of this bacterium in UC patients versus healthy individuals, we developed a real-time polymerase chain reaction assay to detect Aeromonas species. Aeromonas species were detected more frequently in stools from UC patients compared with healthy controls. We also detected aerolysin in colon tissues isolated from UC patients. CONCLUSION: We identified a variant of Aeromonas in UC patients and demonstrated its ability to promote colon inflammation in mice through aerolysin-mediated impairment of tissue-resident macrophages. Treatment with an anti-aerolysin antibody alleviated disease severity in mice exposed to MTB. Our findings highlight how microbes may contribute to UC pathogenesis and suggest that targeting bacterial virulence factors could be a therapeutic strategy for UC. An Aeromonas variant, MTB, promotes susceptibility to ulcerative colitis (UC) by disrupting colonic macrophages.: Under physiological conditions, the macrophage (M ϕ) barrier beneath the colonic epithelium plays a vital role in protecting against gut microbes. However, upon colonization by Aeromonas sp. MTB (macrophage-toxic bacteria)—facilitated by conditions such as antibiotic use or intestinal insults—the toxin aerolysin produced by MTB preferentially disrupts tissue-resident macrophages. Loss of this macrophage barrier increases susceptibility to enteric inflammation, leading to the development of UC. Anti-aerolysin antibody treatment may prevent this process. [ABSTRACT FROM AUTHOR]