Good news!
"Researchers narrowed in on one of the most common IBD [inflammatory bowel disease] types, ulcerative colitis (UC). When they biopsied the colon tissue of UC patients, they noticed that macrophages, a crucial type of immune cell in the gut, were nearly missing. Studying the patients’ poop revealed a likely cause: a toxic substance called aerolysin that gets secreted by a specific genus of bacteria and damages the macrophages so that the gut is susceptible to inflammation.
Lab experiments infecting mice with the bacteria caused worsening UC symptoms, while administering antibodies targeting aerolysin alleviated them.
The final confirmation of aerolysin’s destructive role came from fecal samples and colon biopsies of hundreds of UC patients and healthy individuals; more than 70% of patients had aerolysin-producing bacteria, while only 12% of healthy people did. ..."
"Recently, the research team led by Professor Zhu Minsheng from the Medical School of Nanjing University has made a groundbreaking discovery in understanding the etiology of ulcerative colitis (UC), providing the first evidence that the disease is caused by infection with a novel subspecies of Aeromonas (Aeromonas sp. MTB). ..."
From the abstract of the Perspective:
"Koch’s postulates, formulated in 1884 by Robert Koch and Friedrich Loeffler, state that a microorganism causes a disease if it is found in all disease cases, can be isolated and grown in culture, causes the disease when introduced into a healthy host, and can be reisolated from that host.
These criteria have been revised to account for “unculturable” microbes, such as viruses, and to recognize microbial genes as disease agents rather than the microbes themselves.
No microorganism that fits Koch’s revised postulates has been identified as the cause of ulcerative colitis. On page 805 of this issue, Jiang et al. (4) report that a bacterial strain isolated from patients with ulcerative colitis drives gut inflammation in mice by producing aerolysin, which is toxic to protective immune cells. The findings suggest a previously unidentified mechanism by which a microbe might contribute to the progression of ulcerative colitis."
From the editor's summary and abstract:
"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 ... 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.
Abstract
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."
A bacterial toxin disarms gut defenses against inflammation (Perspective, no public access)
Zhu Minsheng's Team has identified the causative bacterium for Ulcerative Colitis (original news release)
An Aeromonas variant that produces aerolysin promotes susceptibility to ulcerative colitis (no public access)
An Aeromonas variant, MTB, promotes susceptibility to ulcerative colitis (UC) by disrupting colonic macrophages.
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