Role of the gut microbiota in inflammatory bowel disease pathogenesis: What have we learnt in the past 10 years?

Our understanding of the microbial involvement in inflammatory bowel disease (IBD) pathogenesis has increased exponentially over the past decade. The development of newer molecular tools for the global assessment of the gut microbiome and the identification of nucleotide-binding oligomerization domain-containing protein 2 in 2001 and other susceptibility genes for Crohn’s disease in particular has led to better understanding of the aetiopathogenesis of IBD. The microbial studies have elaborated the normal composition of the gut microbiome and its perturbations in the setting of IBD. This altered microbiome or “dysbiosis” is a key player in the protracted course of inflammation in IBD. Numerous genome-wide association studies have identified further genes involved in gastrointestinal innate immunity (including polymorphisms in genes involved in autophagy: ATG16L1 and IGRM), which have helped elucidate the relationship of the local innate immunity with the adjacent luminal bacteria. These developments have also spurred the search for specific pathogens which may have a role in the metamorphosis of the gut microbiome from a symbiotic entity to a putative pathogenic one. Here we review advances in our understanding of microbial involvement in IBD pathogenesis over the past 10 years and offer insight into how this will shape our therapeutic management of the disease in the coming years.

The Gut Microbiota, Tumorigenesis, and Liver Diseases

In recent decades, diseases concerning the gut microbiota have presented some of the most serious public health problems worldwide. The human host＇s physiological status is influenced by the intestinal microbiome, thus integrating external factors, such as diet, with genetic and immune signals. The notion that chronic inflammation drives carcinogenesis has been widely established for various tissues. It is surprising that the role of the microbiota in tumorigenesis has only recently been recognized, given that the presence of bacteria at tumor sites was first described more than a century ago. Extensive epidemiological studies have revealed that there is a strong link between the gut microbiota and some common cancers. However, the exact molecular mechanisms linking the gut microbiota and cancer are not yet fully understood. Changes to the gut microbiota are instrumental in determining the occurrence and progression of hepatocarcinoma, chronic liver diseases related to alcohol, nonalcoholic fatty liver disease （NAFLD）, and cirrhosis. To be specific, the gut milieu may play an important role in systemic inflammation, endotoxemia, and vasodilation, which leads to complications such as spontaneous bacterial peritonitis and hepatic encephalopathy. Relevant animal studies involving gut microbiota manipulations, combined with observational studies on patients with NAFLD, have provided ample evidence pointing to the contribution of dysbiosis to the pathogenesis of NAFLD. Given the poor prognosis of these clinical events, their prevention and early management are essential. Studies of the composition and function of the gut microbiota could shed some light on understanding the prognosis because the microbiota serves as an essential component of the gut milieu that can impact the aforementioned clinical events. As far as disease management is concerned, probiotics may provide a novel direction for therapeutics for hepatocellular carcinoma （HCC） and NAFLD, given that probiotics function as a type of medicine that can improve human health by regulating the immune system. Here, we provide an overview of the relationships among the gut microbiota, tumors, and liver diseases. In addition, considering the significance of bacterial homeostasis, we discuss probiotics in this article in order to guide treatments for related diseases.

Gastrointestinal motility disorders in inflammatory bowel diseases

The relationship between motility and inflammatory gastrointestinal disorders is at the same time complex and intriguing since these conditions might share some genetic, environmental, immunological and microbial predisposing factors. In addition, significant symptom overlapping may occur, muddling the waters within the clinical context. Although on one hand this represents a challenge for the clinician for a potential under- or over-treatment and diagnostic delay, on the other hand it possibly represents an opportunity for the researcher to better disclose the intimate relationship between chronic (often low-grade) inflammation, motor disorders and deranged sensory function. The best example is probably represented by Crohn’s disease and ulcerative colitis. In fact, a number of gastrointestinal motor disorders have been described in association with these diseases, disorders which span from the esophagus to the anorectum, and which will be extensively covered in this review. It is conceivable that at least part of this derangement is strictly related to inflammatory cytokine trafficking and neuromuscular changes; however, given the high prevalence of functional gastrointestinal disorders in the general population, this overlap might also be serendipitous. However, it is worth noting that literature data on this topic are relatively scarce, sometimes quite outdated, and mostly focused on the interplay between irritable bowel syndrome and inflammatory bowel disease. Nevertheless, both researchers and clinicians must be aware that symptoms related to gastrointestinal motility disorders may be highly prevalent in both active and inactive inflammatory bowel disease, correlate with greater psychological comorbidity and poorer quality of life, and may negatively influence the therapeutic approaches.

Modulation of Gut Microbiota in Pathological States

The human microbiota is an aggregate of microorganisms residing in the human body, mostly in the gastrointestinal tract （GIT）. Our gut microbiota evolves with us and plays a pivotal role in human health and disease. In recent years, the microbiota has gained increasing attention due to its impact on host metabolism, physiology, and immune system development, but also because the perturbation of the microbiota may result in a number of diseases. The gut microbiota may be linked to malignancies such as gastric cancer and colorectal cancer. It may also be linked to disorders such as nonalcoholic fatty liver disease （NAFLD）; obesity and diabetes, which are characterized as ＂lifestyle diseases＂ of the industrial- ized world; coronary heart disease; and neurological disorders. Although the revolution in molecular technologies has provided us with the necessary tools to study the gut microbiota more accurately, we need to elucidate the relationships between the gut microbiota and several human pathologies more precisely, as understanding the impact that the microbiota plays in various diseases is fundamental for the development of novel therapeutic strategies. Therefore, the aim of this review is to provide the read- er with an updated overview of the importance of the gut microbiota for human health and the poten- tial to manipulate gut microbial composition for purposes such as the treatment of antibiotic-resistant Clostridium difficile （C difficile） infections. The concept of altering the gut community by microbial intervention in an effort to improve health is currently in its infancy. However, the therapeutic implications appear to be very great. Thus, the removal of harmful organisms and the enrichment of beneficial mi- crobes may protect our health, and such efforts will pave the way for the development of more rational treatment options in the future.