Battling IBD with H2S

TORONTO—Antibe Therapeutics Inc. announced yesterday that researchers at the University of Calgary have identified a key mechanism underlying the ability of certain intestinal bacteria to contribute to the ulceration and inflammation that is characteristic of Crohn’s disease and ulcerative colitis, the two forms of IBD. They have demonstrated that novel hydrogen sulfide-releasing drugs can reverse these effects, leading to resolution of the inflammation and healing of intestinal ulcers.

 

The research was directed by two of Antibe’s founders, Dr. Andre Buret and Dr. John Wallace, and was supported by grants to Buret and Wallace from the Canadian Institutes of Health Research, Crohn’s Colitis Canada and the National Science and Engineering Research Council of Canada. The research article, “Iron Sequestration in Microbiota Biofilms As A Novel Strategy for Treating Inflammatory Bowel Disease,” was published in the journal Inflammatory Bowel Diseases.

 

According to the article, “ATB-428 and ATB-429 are compounds consisting of mesalamine covalently linked to an H₂S-donor: 4-hydroxythiobenzamide (TBZ) in the case of ATB-428, and (5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione, ADT-OH) in the case of ATB-429.”

 

“Upon exposure to ATB-429, biofilm intake of purine nucleosides (guanosine) was reduced, whereas release of urate and hypoxanthine, 2 metabolites of purine catabolism, were increased. Biofilm secretion of uracil, a pyrimidine nucleobase, was significantly reduced with the addition of ATB-429. The ATB-429 alone (media + ATB-429) had no effect on relative concentrations of metabolites in bacterial media,” the article says. “Together, these data demonstrated that ATB-429 reduces iron intake by colitis-associated microbiota. ATB-429 had a profound effect on microbiota biofilm metabolism, without significantly changing the microbiota species composition.”

 

Dr. Buret explained that “intestinal bacteria that cause damage and bleeding in patients with IBD are described as ‘virulent’ (harmful, destructive), and this virulence is dependent upon the availability of iron to the bacteria within the intestine. Depriving bacteria of access to iron markedly reduces virulence, resulting in a dramatic reduction of the severity of colitis.”

 

“Importantly, we demonstrate that exposing bacteria (and not the host cells) to ATB-429 was sufficient to reduce the host inflammatory response toward virulent IBD microbiota. This direct property of ATB-429 could have significant therapeutic advantages in vivo during colitis. Indeed, a significant shift in the amount of Clostridiales such as Ruminococcaceae and Eubacteriaceae, and decreased Enterococcaceae have been reported in animal models given exogenous H₂S-donors,” noted the article. “Apart from its iron-scavenging mechanism of action, we further discovered that bacteria exposed to ATB-429 significantly altered their purine (reduced intake of nucleoside, increased release of xanthine and urate) and pyrimidine metabolism (reduced uracil release). An iron-deprived environment induced by ATB-429 could lead to impaired function of enzymes involved in the catabolism of purine nucleosides (xanthine oxidase and xanthine dehydrogenase) that is regulated by redox mechanisms and the formation of iron-sulfur clusters.”

 

The Calgary research team demonstrated that novel hydrogen sulfide-releasing drugs (ATB-428 and ATB-429) were capable of scavenging iron within the intestines, depriving bacteria of access to that iron, and thereby markedly reducing bacterial virulence. Wallace mentioned that “the hydrogen sulfide-releasing drugs did not cause dramatic changes to the types of bacteria that reside in the intestine; rather, the treatment rendered the intestinal bacteria much less toxic to the intestinal tissues.”

 

Studies were performed both in rats in which colitis had been induced, and using tissues obtained from patients with ulcerative colitis or Crohn’s disease. Wallace added, “Previous studies performed in our laboratories have documented the profound beneficial effects of our hydrogen sulfide-releasing drugs in protecting intestinal cells from damage and promoting healing.”

 

“The findings…provide proof-of-principle evidence that a new H₂S-releasing anti-inflammatory drug can suppress iron intake in complex multispecies gut microbiota grown in their natural biofilm phenotype, hence reducing their virulence without modifying overall composition and survival. These are promising observations in our attempts to generate advances towards the development of a novel therapeutic for IBD that will help target both host inflammation and microbiota dysbiosis,” the article’s summary stated.