Periodic Reporting for period 1 - MUCO-IMMUN (MUCOBIOME-MEDIATED IMMUNE PATHWAYS IN INFLAMMATORY BOWEL DISEASES)
Période du rapport: 2021-05-01 au 2023-04-30
Inflammatory Bowel Diseases (IBD) – including Crohn’s disease and ulcerative colitis – are chronic disorders affecting 2.5 to 3 million people in Europe and are steadily increasing in the worldwide population. IBD are
characterized by persistent ulcerations in the gastrointestinal tract, thereby drastically affecting the patient’s quality of life, and increasing mortality owing to associated complications such as cancer. For these reasons, IBD patients require intensive medical intervention, rendering this group of disorders a major health care issue. Despite IBD being a set of inflammatory diseases, the underlying host immune pathways are poorly understood, making it difficult to reliably treat and cure patients. The etiology of IBD is multi-factorial with both genetic and environmental components. Although polymorphisms in over 100 genes have been implicated in the pathogenesis of IBD, they seem to be poor predictors of disease development. Therefore, models of IBD require the combination of genetic and environmental risks. The gut microbiome and the dietary habits have been proposed as major environmental contributors of the disease. Although causal relationships are beginning to emerge, how the diet and the gut microbiome work together to induce gut inflammation is still poorly understood. Within the gut microbiome, here, we define mucobiomes as the microbial communities enzymatically geared to digest the host intestinal mucus layer, whose mucolytic activities are regulated by dietary fibres. The research hypothesis for the proposed MSCA application is that the mucobiomes catalyse important disease-promoting immune pathways in IBD. Objectives of this MSCA were to (1) highlight the role of mucobiomes in the fiber-deprivation-driven colitis in a genetically susceptible model of colitis (Il10-/- mice), and (2) characterize the mucobiome-associated immune pathways in this colitis model.
characterized by persistent ulcerations in the gastrointestinal tract, thereby drastically affecting the patient’s quality of life, and increasing mortality owing to associated complications such as cancer. For these reasons, IBD patients require intensive medical intervention, rendering this group of disorders a major health care issue. Despite IBD being a set of inflammatory diseases, the underlying host immune pathways are poorly understood, making it difficult to reliably treat and cure patients. The etiology of IBD is multi-factorial with both genetic and environmental components. Although polymorphisms in over 100 genes have been implicated in the pathogenesis of IBD, they seem to be poor predictors of disease development. Therefore, models of IBD require the combination of genetic and environmental risks. The gut microbiome and the dietary habits have been proposed as major environmental contributors of the disease. Although causal relationships are beginning to emerge, how the diet and the gut microbiome work together to induce gut inflammation is still poorly understood. Within the gut microbiome, here, we define mucobiomes as the microbial communities enzymatically geared to digest the host intestinal mucus layer, whose mucolytic activities are regulated by dietary fibres. The research hypothesis for the proposed MSCA application is that the mucobiomes catalyse important disease-promoting immune pathways in IBD. Objectives of this MSCA were to (1) highlight the role of mucobiomes in the fiber-deprivation-driven colitis in a genetically susceptible model of colitis (Il10-/- mice), and (2) characterize the mucobiome-associated immune pathways in this colitis model.
Dr Boudaud carried out this research fellowship under the supervision of Dr Mahesh S. Desai at the Luxembourg Institute of Health (LIH).
An animal model was used to mimick the multi-factorial requirement of IBD, by combining: (1) the genetic susceptibility of IL-10-deficient (Il10-/-)mice; (2) the dietary factor by feeding the animals a diet deprived of dietary fiber (Fiber-free, FF); (3) and the microbiome/mucobiome factor with the use of a tractable synthetic microbiota composed of 14 bacterial strains (14SM), 4 of which showing mucolytic activity in vitro. To evaluate the role of mucolytic bacteria in this model, the mice were colonized with either the 14SM or the 10 non-mucolytic strains (10SM).
This work showed that mice developped colitis only if the 3 required variables of the experimental model were combined: IL-10 deficiency (Il10-/-), fiber deprivation, and colonization with the 14SM. Importantly, the mice colonized with the 10 non-mucolytic strains (10SM) did not develop colitis. The immune characterization of the mice showed that the colitis in 14SM-colonized Il10-/- mice initiated with the expansion of NK cells, followed by a T cell response in both the cecum and colon. Fiber deprivation increased the expansion of NK and CD8+ T cells in the cecum and of Th1, Th17 and CD8+ T cells in the colon. Interestingly, 10SM-colonized mice had lower proportions of NK and T cells in the colon but not in the cecum. Furthermore, the 10SM-colonized mice did not show the FF-induced expansion of Th1 cells in the colon. These results were further supported by the high RNA levels of Th1 cytokines, IFNg and IL-12, in 14SM-colonized but not in 10SM-colonized FF-fed mice. Altogether, these data support that the mucobiome within the microbiome mediates FF-induced colitis via the pathological Th1 response in the colon.
These results have been presented in two international conferences by Dr Boudaud and compiled in a preprint publication that is currently under peer-review.
An animal model was used to mimick the multi-factorial requirement of IBD, by combining: (1) the genetic susceptibility of IL-10-deficient (Il10-/-)mice; (2) the dietary factor by feeding the animals a diet deprived of dietary fiber (Fiber-free, FF); (3) and the microbiome/mucobiome factor with the use of a tractable synthetic microbiota composed of 14 bacterial strains (14SM), 4 of which showing mucolytic activity in vitro. To evaluate the role of mucolytic bacteria in this model, the mice were colonized with either the 14SM or the 10 non-mucolytic strains (10SM).
This work showed that mice developped colitis only if the 3 required variables of the experimental model were combined: IL-10 deficiency (Il10-/-), fiber deprivation, and colonization with the 14SM. Importantly, the mice colonized with the 10 non-mucolytic strains (10SM) did not develop colitis. The immune characterization of the mice showed that the colitis in 14SM-colonized Il10-/- mice initiated with the expansion of NK cells, followed by a T cell response in both the cecum and colon. Fiber deprivation increased the expansion of NK and CD8+ T cells in the cecum and of Th1, Th17 and CD8+ T cells in the colon. Interestingly, 10SM-colonized mice had lower proportions of NK and T cells in the colon but not in the cecum. Furthermore, the 10SM-colonized mice did not show the FF-induced expansion of Th1 cells in the colon. These results were further supported by the high RNA levels of Th1 cytokines, IFNg and IL-12, in 14SM-colonized but not in 10SM-colonized FF-fed mice. Altogether, these data support that the mucobiome within the microbiome mediates FF-induced colitis via the pathological Th1 response in the colon.
These results have been presented in two international conferences by Dr Boudaud and compiled in a preprint publication that is currently under peer-review.
Overall, the in-depth immune profiling of the model of fiber-deprivation-induced colitis provides pioneering results for the understanding of the diet-mucobiome-immune axis, in an organ- and time-dependent manner.
This work provided strong bases for further research in the group and may allow to develop further animal models based on various genetic susceptibilities for the study of other multifactorial pathogenesis.
This work provided strong bases for further research in the group and may allow to develop further animal models based on various genetic susceptibilities for the study of other multifactorial pathogenesis.