Research

We, humans, have been defined by the Nobel laureate Joshua Lederberg as “super organisms” consisting of the sum of the karyome (the host’s nuclear DNA genome), the chondriome (mitochondria), and the microbiome (“the menagerie of the body’s attendant microbes”). Despite the enormous importance of the host-microbiota interactions in all environments, the techniques and technologies capable of determining the composition of complex microbial populations have only recently become available. Metagenomics methods already provide the information necessary about bacterial community composition and function, and complement genetic analyses of known isolated strains including the best conditions for culturing, providing unprecedented information about the complexity of microbial communities.

My research program aims to understand the molecular mechanisms involved in modulation of microbial populations and their environment by probiotics and prebiotics. We have established next-generation sequencing and other culture-independent methods in our laboratory to analyze the microbiome of animal models and humans. Our studies are providing the information needed to modulate the immense intestinal bacterial ecosystem by introducing a carefully selected blend of beneficial organisms capable of survival, persistence, and delivery of a wide range of bioactive compounds with the objective of establishing direct molecular associations between components of the human microbiome and specific cells or systems in the gut.

Specific areas of research

Modulation of the intestinal microbiome by prebiotics

Prebiotics are “selectively fermented ingredients that result in specific changes in the composition and/or activity of the gastrointestinal microbiota thus conferring benefit(s) upon host health”. Prebiotics have been shown to decrease colon tumor incidence and incidence of aberrant crypt foci in rats treated with carcinogens, and to reduce recurrence rate of colon adenomas in humans. The most reported effect of prebiotics is the increase in beneficial bacterial populations of the gut, the probiome, specifically bifidobacteria and lactobacilli, with a concomitant increase in concentration of short chain fatty acids (SCFAs), specially butyrate, which have been extensively studied for their role in nutrition of the colonic epithelium, modulation of the colonic pH, intracellular pH and cell volume, and regulation of proliferation and gene expression. Additionally, modulation of intestinal inflammatory and anti-inflammatory modulators by prebiotics has been reported.

prebioticsGalactooligosaccharides (GOS) have been extensively studied and have a prebiotic status in the European Union. Our research aims to analyze the effects of GOS on colon microbiome, metabolome and immune system, and ultimately, evaluate GOS effects on the development of CRC tumors. We hypothesize that GOS will modulate the microbiome with direct and indirect immunomodulatory effects that will ultimately have a beneficial effect on inflammation and CRC. Our long term goal is to identify specific molecular targets of GOS as a bioactive food component that may have a role in cancer prevention.

Modulation of the intestinal microbiome and functional effects of probiotics on intestinal cells

characterization of probiotics

Probiotics are defined as “live microorganisms which, when administered in adequate amounts, confer a health benefit on the host”. Several selection criteria have been used for the selection of novel probiotic strains, which can be categorized in three groups: safety, functional and technological criteria. The objective of our project is to select and characterize human bacterial isolates of lactic acid bacteria in order to compare the functional effects of individual strains, or a combination of strains of probiotic bacteria of the lactic acid bacteria group with commensal (non-probiotic, non-pathogenic) bacteria in colon cancer cell lines, normal human intestinal epithelial cells, and the intestinal microbiota.

Perturbations of the intestinal microbiota

Crohn’s Disease (CD) and ulcerative colitis (UC) are two inflammatory bowel diseases (IBD), characterized by chronic inflammation of small bowel and/or colon (CD). Approximately 80% of CD patients will require surgical bowel resection in their lifetime. A common surgical intervention in CD involves the resection of the terminal ileum and cecum/proximal colon when medical therapies fail. In CD and necrotizing enterocolitis (NEC), ileocecal resection (ICR) can be required to remove regions of seriously inflamed, fibrotic or necrotic bowel, and the need for recurrent or more extensive resections poses a risk of intestinal failure. Complications that may be associated with ICR include the loss of ileum, which can reduce or prevent efficient reabsorption of bile acids, and the possibility that ICR may alter the microbiota in the jejunum or colon. Small intestinal bacterial overgrowth (SIBO) is common in CD, and more frequent in CD patients who had undergone surgery. This research project aims to elucidate the impact of ICR on the intestinal microbiota. We have characterized the impact of resection on conventionally raised C57BL6 wild type mice after ICR as the initial step to elucidate the impact of ICR on the microbiota in remnant jejunum and proximal colon without the influence of the genetic background of the host or ongoing disease.

network

We observed dramatic changes in jejunal and colonic microbiota induced by ICR and concomitant antibiotic injection which may therefore be considered as potential regulators of post-surgical adaptive growth or function, and in a setting of active IBD, potential contributors to post-surgical pathophysiology of disease recurrence. Future experiments will include characterization of the post-ICR microbiota of hosts with genetic susceptibility to IBD, given that current results suggest that ICR dramatically alters the intestinal microbiota, which may contribute to risk of postsurgical inflammation.