World Digestive Health Day WDHD – May 29, 2016 THE HUMAN GUT MICROBIOME, continued Figure 2: Mechanisms leading to loss of intestinal mucosal homeostasis: Under physiological circumstances a very tightly controlled antigen trafficking assure gut mucosal homeostasis, anergy and, therefore, state of health1. Functional loss of gut barrier function leads to inappropriate passage of undigested nutrients an/or endotoxins causing innate immune response or immune regulatory defects leading to the productions of po-inflammatory cytokines, including IFNγ and TNFα2. They in turn causes further increase in intestinal permeability causing a vicious circle3 that leads to massive dietary and microbial influx from gut lumen to submucosa, break of tolerance and, ultimately, to chronic inflammation.4 Adapted from P. Brandtzaeg. Beneficial Microbes 2010. derived peptides into the intestinal mucosal and eventually blood stream with subsequent increased interactions with immune cells leading to break of tolerance and, ultimately, onset of chronic inflammation (See Figure 2). Early in life, exposure to healthy and diverse commensal species promotes protection against chronic inflammation by those mechanisms, and therefore that pre-, peri-, and post-natal environmental factors (including physical, chemical, biological, behavioral, and social environmental factors) which strongly influence our gut ecosystems, thereby setting us up to be susceptible to or protected from the development of diseases throughout the entire lifespan (See Figure 1). Of all these factors, nutrition is by far the most influential one, suggesting that Western diet is indeed one of the key driving forces of the epidemics of these chronic diseases through changes in microbiota composition. ONGOING DISCOVERY IN COMMON GI CHRONIC DISEASES Research is blossoming in the area of the microbiome in nearly all human diseases. Here, we will discuss the current state of the field in three of the most common chronic GI diseases in which the microbiome is suspected to play a significant role in disease pathogenesis: IBD, CD, and IBS. Mechanistic discovery, ongoing prospective studies, interventions tried, and areas of promising future development will be highlighted. INFLAMMATORY BOWEL DISEASE The involvement of microorganisms in the pathogenesis of IBD has been postulated for many years. However, despite the great effort spent in search of the pathogen(s) triggering the chronic inflammatory process that characterizes IBD, the identification of microorganism(s) causing IBD has remained elusive. Now there is good evidence that the pathogenesis of IBD is the consequence of an inappropriate immune response to commensals rather than the consequence of infection with specific pathogens. This exaggerated response seems secondary to the combination of genetic mutations and imbalance of the gut microbiome.6 However, disparities in methodological approaches, including different techniques used to analyze gut microbiome, disease activity, site of inflammation, and different site of microbiota sampling (stools vs. mucosa), make comparison among the studies reported in literature very difficult. Nevertheless, a common theme emerges, suggesting that this dysbiosis is characterized by reduction in biodiversity (α-diversity) and altered representation of several taxa. Gut dysbiosis is often associated with specific dysfunctions of microbial metabolism and bacterial protein signaling, including involvement of oxidative stress pathways and decreased carbohydrate metabolism and amino acid biosynthesis counterbalanced by increase in nutrient transport and uptake.6 While these changes suggest a possible mechanistic link between modifications in microbiota composition and IBD pathogenesis, these studies remain mainly associative. CELIAC DISEASE CD is unique among autoimmune diseases in that there is a strong association with HLA DQ2 and/or DQ8(39), the environmental trigger (gluten) is known, and disease-specific autoantibodies have been identified and can be measured. Therefore, exposure to the environmental trigger can be carefully studied and frequent prospective screening against the autoantibody tissue transglutaminase (tTG) can determine precisely when the loss of tolerance to gluten occurs.7 Dysbiosis has been implicated in the development of CD. In vitro studies suggest that microbes can influence the digestion of gliadin, the production of cytokines in response to gliadin, and World Digestive Health Day WDHD May 29, 2016 WGO Handbook on DIET AND THE GUT 51
WGO Handbook on Diet and the Gut_2016_Final
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