Many chronic a inflammatory diseasesa are associated with disturbances in the composition of the gut microbiota. 1 Researchers have long been interested in flagellin, a bacterial protein that is the motor organ of so-called “motile” bacteria (that is, bacteria capable of moving). A characteristic feature of certain pathogenic bacteria, this motor system allows them to reach and then invade host cells.

Flagellin is a bacterial constituent that can be recognized by the immune system, but most motile bacteria in the gut microbiota are non-pathogenic and do not particularly alarm the immune system. More specifically, the immune system’s detection of flagellin helps control the level of motile bacteria.[2] This mechanism involves the secretion of immunoglobulin A (IgA) antibodies that bind to flagellin. This reaction then very quickly stops the production of flagellin by the targeted bacteria, thus reducing their motility. In particular, the immune system’s regulation of bacterial motility helps keep away bacteria that might attempt to get too close to the host’s intestinal cells. In this way, a balanced relationship can be established between the bacteria and the immune system, with the presence of one regulating the activity of the other and vice versa.

High quantities of flagellin are found and bacterial proximity to the host’s intestinal cells is observed in the intestines of patients with chronic inflammatory bowel disease (Crohn’s disease, ulcerative colitis) and metabolic b syndrome. , , [3],[4],[5]. Furthermore, experimental mouse models that are deficient in certain molecules that allow the immune system to recognize flagellin develop a metabolic syndrome and become overweight. [6] Studies have shown that, in humans, the proximity of motile bacteria to host cells is associated with intestinal inflammation. These bacteria penetrate the intestinal wall, which is covered by a protective layer of mucusc cthat is usually free of bacteria. Changes in the composition of the mucus and increased bacterial motility contribute to this, and factors in processed foods, such as emulsifying agents, facilitate these phenomena.[7]

 

A recent study has shown that the immune system can be trained to recognize flagellin in mice in order to prevent a failure to control motile bacteria in the gut. [8] The immune system then produces a significant amount of IgA antibodies to flagellin. The higher the level of anti-flagellin IgA antibodies produced, the lower the level of flagellin – and, consequently, of motile bacteria – in the mice’s intestines. Moreover, this research has shown that this specific anti-flagellin immunization prevents the convergence of bacteria and host, thus protecting against the development of chronic inflammatory bowel and metabolic diseases.

This study, carried out in experimental mouse models, opens up potential new pathways to preventing and treating chronic inflammatory diseases. Other studies in the past have used flagellin in combination with other microbial motifs as a tool to induce an immune response to these microbial motifs. [9], [10], [11][10],[11].

However, much research remains to be done before this work can be applied to humans. For instance, the vaccination protocol used needs to be optimized to increase the immune response against flagellin while minimizing potential side effects (fever, pain, etc.). Other research is attempting to understand why the immune system is, or becomes, defective in terms of its ability to control bacterial motility.

 

a: disease characterized by the persistence over time of a certain level of inflammation

b: combined alteration of several metabolic parameters (weight, abdominal circumference, blood pressure, blood lipids, fasting glycaemia, etc.), which are predisposing factors for the subsequent development of metabolic pathologies such as obesity and type 2 diabetes

c : a viscous substance that covers the wall of the digestive tract. Some cells in the intestines are specialized in its production. Mucins are the main components of mucus, responsible for its viscoelastic and gelling properties. The quantity and quality of mucus layers vary throughout the gastrointestinal tract

Bibliography

[1] Chassaing, « Microbiota Alterations in Inflammatory Bowel Diseases ».

[2] Cullender et al., « Innate and Adaptive Immunity Interact to Quench Microbiome Flagellar Motility in the Gut ».

[3] Lodes et al., « Bacterial Flagellin Is a Dominant Antigen in Crohn Disease ».

[4] Chassaing et al., « Colonic Microbiota Encroachment Correlates With Dysglycemia in Humans ».

[5] Johansson et al., « Bacteria Penetrate the Normally Impenetrable Inner Colon Mucus Layer in Both Murine Colitis Models and Patients with Ulcerative Colitis ».

[6] Vijay-Kumar et al., « Metabolic Syndrome and Altered Gut Microbiota in Mice Lacking Toll-like Receptor 5 ».

[7] Chassaing et al., « Dietary Emulsifiers Impact the Mouse Gut Microbiota Promoting Colitis and Metabolic Syndrome ».

[8] Tran et al., « Flagellin-Elicited Adaptive Immunity Suppresses Flagellated Microbiota and Vaccinates against Chronic Inflammatory Diseases ».

[9] Stocker et Newton, « Immune Responses to Epitopes Inserted in Salmonella Flagellin ».

[10] Newton et al., « Expression and Immunogenicity of an 18-Residue Epitope of HIV1 Gp41 Inserted in the Flagellar Protein of a Salmonella Live Vaccine ».

[11] Jeon, Ben-Yedidia, et Arnon, « Intranasal Immunization with Synthetic Recombinant Vaccine Containing Multiple Epitopes of Influenza Virus ».

Author

Dr. Emelyne LECUYER