Seminar Title: Gut osmotic perturbation causes the loss of a keystone family of commensal bacteria, resulting in loss of pathogen colonization resistance
Abstract: The gastrointestinal microbiota is essential for host health and changes in response to perturbations. Increased intestinal osmolality is a perturbation prevalent in diverse pathologies such as inflammatory bowel disease and has been shown to deplete the highly abundant bacterial family Muribaculaceae (Mb). Mb is becoming a lost member in industrialized human microbiomes and many studies have correlated low Mb abundance with various disease states. We hypothesized that the depletion of Mb during osmotic diarrhea is due to a lack of genes required for osmotic stress response, and that its loss results in long-term detrimental effects on the host physiology and protection from pathogen infection. Our research aimed to 1) elucidate the mechanisms underlying Mb sensitivity to osmotic perturbation, 2) assess the impact of the loss of Mb on host physiology and 3) determine how Mb depletion and introduction may be connected to the onset and amelioration of pathogen infection. 1) To address our first aim, we compared the Mb genome to a closely related member of the Bacteroidaceae family (B. thetaiotaomicron), which is highly osmotic tolerant and genetically tractable. Through genome annotation and transcriptomics studies of gnotobiotic mice colonized with B. thetaiotaomicron, we identified and knocked out candidate osmotic stress tolerance genes in B. thetaiotaomicron that are not present in Mb. Growth curves and colonization experiments with these genetic knockout strains have begun to shed light on possible mechanisms required for osmotic stress survival that are missing in Mb. 2) To understand the impact of the loss of Mb, we developed two mouse models with complex microbiomes with and without Mb present (Mb positive and Mb naïve, respectively), and evaluated intestinal mucosal structure and the production of short-chain fatty acids (SCFAs) in these mice. We found that Mb naive mice lost colonic mucus striation and had a significant drop in the production of the SCFAs butyrate and acetate. We then re-introduced 16 characterized Mb isolates to Mb naïve mice and found that Mb is capable of superseding other bacterial colonizers to recover its original abundance, restoring the mucus layer but not SCFA production. 3) Lastly, we challenged the Mb positive and Mb naïve mice with Citrobacter rodentium and Salmonella enterica serovar Typhimurium infection models. Excitingly, Mb positive mice showed reduced colonization by both pathogens compared to mice lacking Mb. Together our results establish Mb as a model organism for studying bacterial sensitivities to common abiotic perturbations, such as osmotic stress, and highlight a potential use for this bacterium in microbiota-based therapies for disease prevention or amelioration.
Life Sciences Centre, LSC 3 - 2350 Health Sciences Mall MBIM itsupport@microbiology.ubc.ca America/Vancouver publicSeminar Title: Gut osmotic perturbation causes the loss of a keystone family of commensal bacteria, resulting in loss of pathogen colonization resistance
Abstract: The gastrointestinal microbiota is essential for host health and changes in response to perturbations. Increased intestinal osmolality is a perturbation prevalent in diverse pathologies such as inflammatory bowel disease and has been shown to deplete the highly abundant bacterial family Muribaculaceae (Mb). Mb is becoming a lost member in industrialized human microbiomes and many studies have correlated low Mb abundance with various disease states. We hypothesized that the depletion of Mb during osmotic diarrhea is due to a lack of genes required for osmotic stress response, and that its loss results in long-term detrimental effects on the host physiology and protection from pathogen infection. Our research aimed to 1) elucidate the mechanisms underlying Mb sensitivity to osmotic perturbation, 2) assess the impact of the loss of Mb on host physiology and 3) determine how Mb depletion and introduction may be connected to the onset and amelioration of pathogen infection. 1) To address our first aim, we compared the Mb genome to a closely related member of the Bacteroidaceae family (B. thetaiotaomicron), which is highly osmotic tolerant and genetically tractable. Through genome annotation and transcriptomics studies of gnotobiotic mice colonized with B. thetaiotaomicron, we identified and knocked out candidate osmotic stress tolerance genes in B. thetaiotaomicron that are not present in Mb. Growth curves and colonization experiments with these genetic knockout strains have begun to shed light on possible mechanisms required for osmotic stress survival that are missing in Mb. 2) To understand the impact of the loss of Mb, we developed two mouse models with complex microbiomes with and without Mb present (Mb positive and Mb naïve, respectively), and evaluated intestinal mucosal structure and the production of short-chain fatty acids (SCFAs) in these mice. We found that Mb naive mice lost colonic mucus striation and had a significant drop in the production of the SCFAs butyrate and acetate. We then re-introduced 16 characterized Mb isolates to Mb naïve mice and found that Mb is capable of superseding other bacterial colonizers to recover its original abundance, restoring the mucus layer but not SCFA production. 3) Lastly, we challenged the Mb positive and Mb naïve mice with Citrobacter rodentium and Salmonella enterica serovar Typhimurium infection models. Excitingly, Mb positive mice showed reduced colonization by both pathogens compared to mice lacking Mb. Together our results establish Mb as a model organism for studying bacterial sensitivities to common abiotic perturbations, such as osmotic stress, and highlight a potential use for this bacterium in microbiota-based therapies for disease prevention or amelioration.