April 18, 2017

Microbiota and Clostridia Group

Daniel Paredes-Sabja

Associated Investigator  

Of the 56 million average annual global deaths, nearly 15 million are due to infectious diseases and many more due to secondary effects of infections. Nosocomial infections are hospital acquired, which include fungal and bacterial infections that are aggravated by the reduced immune response from the patient. An increasingly important group of nosocomial infections are the antibiotic associated diarrheas (AAD), which typically occur due to dysbiosis of the colonic microbiota and loss of colonization resistance after the patient is exposed to antibiotics. Nearly 15% of all hospitalized patients treated with antibiotics develop AAD. The most important etiological agent is c. difficile (30% of the cases). C. difficile infections (CDI) have become a major theme among healthcare systems world-wide and may cause severe outbreaks reaching mortality rates of up to 20%. Unlike other enteric infections, CDI has an outstandingly high rate of recurrence reaching 20, 40 and 50% after a first, second and third episode, respectively, and might easily progress into severe symptoms. C. difficile spores are considered the morphotype of persistence that contributes to relapsing episodes of CDI. Unfortunately, there is scares knowledge on how C. difficile spores interact with the host. In this context, we are interest in answering several research questions related to spore-host interactions:

i. How do difficile spores interact with the host´s immune system and impair adaptive immunity;

ii. How do difficile spores persist in the host´s colonic mucosa;

iii. How does the outermost exosporium-like layer of  difficile spores assembles, and contributes to spore-persistence.

The human gut microbiota is a diverse microbial environment consisting of mostly anaerobic bacteria containing up to more than 100 trillion commensal bacteria compromising more than 1,000 species. The intestinal tract provides the microbiota with a secure habitat and a constant source of nutrition. In turn, the gut microbiota helps our digestion and metabolism and protects us from intestinal intrusion by foreign pathogenic microorganisms via competition for space and nutrition. This host-microbiota interaction is mutually beneficial. To utilize the benefits of this relationship, the gut mucosa has evolved multi-component systems that co-exist with the microbiota which include intestinal epithelial cells that form a trans-epithelial barrier that constitutively secretes mucus gels, antimicrobials and regulatory cytokines to the colonic lumen. Specific commensal bacterial species induce accumulation of specific immune cell populations; therefore, dysbiosis of the microbiota results in disruption of the intestinal homeostasis and has implications in pathogenesis of several human disorders including inflammatory bowel diseases, obesity, cardiovascular diseases, antibiotic associated diarrheas and gastrointestinal infections. In this relatively new research line, our aim is to understand how the gut microbiota affects the pathogenesis of inflammation and immune colitis (inflammation of the colon or large intestine) and prevention of colitis-associated-cancer.