The potential of FimH as a novel therapeutic target for the treatment of Crohn’s disease

ABSTRACT

Introduction: Crohn’s disease (CD) is a life-long chronic disorder characterized by intestinal inflammation. Current treatments for CD are directed towards abnormal immune responses rather than the intestinal bacteria that trigger intestinal inflammation.

Areas covered: Adherent-Invasive Escherichia coli (AIEC) bacteria abnormally colonize the ileal mucosa in a subgroup of CD patients. They can promote or perpetuate chronic inflammation and are therefore an interesting therapeutic target. Various strategies that target these E. coli strains have been developed to promote their intestinal clearance. Here, we review current AIEC-targeted strategies, especially anti-adhesive strategies, that are based on the development of FimH antagonists. We discuss their potential as personalized microbiota-targeted treatments for CD patients abnormally colonized by AIEC.

Expert opinion: A large panel of mannose-derived FimH antagonists were tested for their ability to inhibit E. coli adhesion to host cells. Documented reports suggest that monovalent mannosides are promising candidates that could represent a complementary therapeutic strategy to prevent intestinal inflammation in the E. coli-colonized CD patient subgroup. Ongoing research continues to improve the pharmacokinetic properties of mannosides, and hopefully, clinical trials will be performed in CD patients in the near future.

KEYWORDS:

• FimH antagonists
• personalized therapy
• microbiota-targeting therapy
• mannosides
• Escherichia coli

Article highlights

• Adherent-Invasive E. coli (AIEC) bacteria are a possible trigger of intestinal inflammation, and strategies to eradicate them from the digestive tract of CD patients could be effective in decreasing intestinal inflammation.

• Novel therapies for Crohn’s disease (CD) include biologic agents that target various mechanisms of action in inflammatory pathways, but they do not target the origin of the inflammation. Thus, the use of FimH antagonists to effectively block the interaction between AIEC bacteria and mannosylated proteins expressed on the ileal mucosa is a more personalized therapeutic strategy to manage CD.

• Various mannosides (monovalent and multivalent heptyl mannosides and thiazolylamino-mannosides) are very potent inhibitors of AIEC adhesion. However, further studies are needed to evaluate the pharmacokinetic behaviour of these molecules in the gut environment and in the presence of the intestinal microbiota.

• FimH antagonists are promising candidates for the treatment of CD patients colonized by AIEC. Efforts must be made to identify easily measurable biomarkers in patient cohorts to identify patients who should be treated with mannosides.

This box summarizes key points contained in the article.

Acknowledgments

Figure 1 was kindly prepared by Dr. E.-M. Krammer for the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 750280.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by the Ministère de la Recherche et de la Technologie, Inserm (U1071), INRA (USC-2018).