2018 Colloquium – Intestinal Microbiota and its host: Harmony or disagreement

Between the mouth and the anus, on a large surface of 400m2, about a hundred milliards of bacteria cohabit, without taking into account viruses and fungi. Microbiota, its functions as well as its abnormalities ‘characterization represent therefore  an important challenge and one of the main reasons for studying human physiology and pathologies.

The microbiota composition is conditioned by the nutrients and stress factors in the intestinal ecosystem. The composition changes during a lifetime and in response to recent environmental changes (role of food and antibiotics).

A growing number of Studies are seeking to identity cause and effect relations between microbiota and its host and their underlying mechanisms (immune system, carbohydrate and fat metabolism, the nervous system and on behavior).

Un nombre croissant d’études cherchent à établir des liens de cause à effet entre le microbiote et son hôte et identifier les mécanismes impliqués (système immunitaire et métabolisme glucido-lipidique, système nerveux et comportement).

The symbiotic microbiota of the intestine plays an important role in the ontogeny of the immune system after birth. When the cross-talk between microbiota and immune system is perturbed, the immune system develops a pathological imprinting that lasts into adulthood and increases the susceptibility to inflammatory pathology. We explore the components of the microbiota and the immune system that are required early in life to prevent pathological imprinting and inflammatory pathology later in life.

Alterations in the intestinal microbiota by antibiotics, diet, or genetic changes can contribute to metabolic and neurologic diseases, including obesity, diabetes, autism, multiple sclerosis, and Alzheimer’s disease.  Because of immature immune function in infancy as well as immunosenescence in the elderly, both early- and late-life represent windows in which people may be more vulnerable to microbiota alterations, and this may account for the initiation or progression of age-related metabolic and neurologic diseases. This presentation will demonstrate that manipulating the microbiota throughout life can influence chronic metabolic and neurologic diseases and provides therapeutic targets to maintain health.

The role of the intestinal microbiota [IM] in the individual susceptibility to liver disease has been the subject of recent studies. Alcoholic liver disease [ALD] and nonalcoholic liver disease [NAFLD] appear to be influenced by the composition of the IM, and dysbiosis is associated with ALD and NAFLD in rodent models and human patient cohorts.

Une dysbiose leur est associée dans des modèles de rongeurs et dans des cohortes de patients.

The development and progression of metabolic diseases are linked to changes in a myriad of environmental factors interacting with individuals’ genetic background and epigenetic factors. The gut microbiota is a key player at the interface between these environmental changes and host biology. Diseases are associated with reduced gut microbiota diversity and modified composition, with an aggravation of dysbiosis with the progression of the disease, particularly in the obesity context.  This presentation will examine whether modification of the microbiome can help in improving metabolic health and in which individuals.

The tumor microenvironment is influenced by anticancer therapies, and even more so by those affecting the gut homeostasis. We reported that a deviated repertoire of the intestinal microbiome called « dysbiosis », caused by broad spectrum antibiotics, compromised the efficacy of chemo- and immunotherapy. Our recent data suggest the importance of a healthy gut in the therapeutic efficacy of various anticancer therapies including immune checkpoint blockers, cyclophosphamide or platinum compounds. Modulation of the gut microbiome composition in cancer patients holds great promise in resetting the cancer-immune set point and circumventing primary resistance in advanced malignancies.

Human gut microbiota is considered as essential for controlling physiological key functions for its host, in particular the gut barrier function and immune system maturation.  The debate is open between skeptics   who only see a ‘microbiota mania’ which is transitory , expensive,  and  devoid of interest , and  the adepts  who see a  broken down paradigm inviting to revisit health monitoring, prevention and therapeutic approach, notably in the context of chronic diseases of which  uncontrolled incidence has continued to rise over  the last 60 years.

Patients with Inflammatory Bowel Disease (IBD) exhibit an altered gut microbiota composition with notably a decreased abundance of anti-inflammatory bacteria such as Faecalibacterium prausnitzii. We also observed alteration in the fungal microbiota composition in these patients. The association of several polymorphisms of innate immunity genes involved in microbial sensing with IBD is another argument for the involvement of the gut microbiota in the IBD pathogenesis. Some genetic factors involved in IBD might indeed act through a microbiota effect. We notably demonstrated that this is the case for the IBD susceptibility gene CARD9. Based on its demonstrated role in IBD pathogenesis, the gut microbiota is now considered as a potential therapeutic target and next generation probiotics as well as fecal microbiota transplantation are actively investigated.

The absence of F. prausnitzii is associated with several human dysbiotic diseases and can be thus considered as a biomarker of human health.

F. prausnitzii is thus now a major actor in novel preventive and curative strategies required to prevent and to treat gastrointestinal disorders and diseases.  We will present all our last results on F. prausnitzii and human health. All these recent results confirm the high potential of F. prausnitzii as a potential next-generation probiotic for both IBS and IBD patients. We will also present potential other next-generation probiotics which are lactobacilli able to produce Ahr agonists recently shown to be protective in murine colitis models.

The multidimensional analysis, thanks to a system biology approach, allows to isolate in a very complex crosstalk, such as the host to microbiota interplay, several metabolic activities and structural characteristics which are causal regulatory factors to be targeted for the development of a therapeutic solution. Studies concerning type 2 diabetes and cardiometabolic complications could be carried out to identify these causal factors.