Therapeutic Advances in Gastroenterology

Functional gastrointestinal disorders are very common in the Western world, but unfortunately the underlying mechanisms behind these disorders are incompletely understood. Treatment options are limited and the economic consequences for society are profound. Recent data suggest an involvement of bacteria in the pathogenesis of functional gastrointestinal disorders. Probiotics are promising new treatment alternatives, which will be reviewed in this supplement.

The human gastrointestinal tract comprises a series of complex and dynamic organs ranging from the stomach to the distal colon, which harbor immense microbial assemblages that are known to be vital for human health. Until recently, most of the details concerning our gut microbiota remained obscure. Over the past several years, however, a number of crucial technological and conceptual innovations have been introduced to shed more light on the composition and functionality of human gut microbiota. Recently developed high throughput approaches, including next-generation sequencing technologies and phylogenetic microarrays targeting ribosomal RNA gene sequences, allow for comprehensive analysis of the diversity and dynamics of the gut microbiota composition. Nevertheless, most of the microbes especially in the human large intestine still remain uncultured, and the in situ functions of distinct groups of the gut microbiota are therefore largely unknown, but pivotal to the understanding of their role in human physiology. Apart from functional and metagenomics approaches, stable isotope probing is a promising tool to link the metabolic activity and diversity of microbial communities, including yet uncultured microbes, in a complex environment. Advancements in current stable isotope probing approaches integrated with the application of high-throughput diagnostic microarray-based phylogenetic profiling and metabolic flux analysis should facilitate the understanding of human microbial ecology and will enable the development of innovative strategies to treat or prevent intestinal diseases of as yet unknown etiology.

The description of the de novo development of irritable bowel syndrome (IBS) following an episode of bacterial gastroenteritis (postinfectious IBS) illustrated the potential for a luminal factor (a bacterial pathogen) to cause this common gastrointestinal ailment. As a consequence of these and other observations as well as results of experiments involving animal models, the enteric flora and the immune response that it generates in the host have, somewhat surprisingly, come centre-stage in IBS research with their potential to induce the pathophysiological changes that are associated with IBS. While evidence for immune dysfunction both in the mucosa and systemically continues to accumulate, methodological limitations have hampered a full delineation of the nature of the microbiota in IBS. The latter is eagerly awaited and may yet provide a firm rationale for the use of certain probiotics and antibiotics in IBS, whose benefits have now been described with some consistency.

The digestive tract works through a complex net of integrative functions. At the level of the gut, this integration occurs between the immune, neuromotor and endocrine systems, the intestinal barrier and gut luminal contents. Gastrointestinal function is controlled and coordinated by the central nervous system to ensure effective motility, secretion, absorption and mucosal immunity. Thus, it is clear that the gut keeps a tightly regulated equilibrium between luminal stimuli, epithelium, immunity and neurotransmission in order to maintain homeostasis. It follows that perturbations of any of these systems may lead to gut dysfunction. While we acknowledge that the gut—brain axis is crucial in determining coordinated gut function, in this review we will focus on peripheral mechanisms that influence gastrointestinal physiology and pathophysiology. We will discuss the general hypothesis that the intestinal content is crucial in determining what we consider normal gastrointestinal physiology, and consequently that alteration in luminal content by dietary, antibiotic or probiotic manipulation can result in changes in gut function. This article focuses on lessons learned from animal models of gut dysfunction.

There is increasing evidence that inflammation or a disturbance of the flora within the gut might contribute to the pathogenesis of irritable bowel syndrome (IBS), at least in a proportion of cases. As a consequence it has been speculated that, as some probiotic bacteria have a range of anti-inflammatory and immunomodulatory properties, the administration of such organisms might prove to be beneficial in this condition. It has to be acknowledged that the quality and design of trials of probiotics in IBS has been somewhat variable but the majority have shown benefit, although some bacteria appear to be more effective than others. More recent studies using Bifidobacterium infantis 35624 and Bifidobacterium lactis DN-173-010 have given particularly encouraging results. Issues for the future include determining which organisms are most effective, defining optimal doses, comparing methods of delivery and assessing the role of mixtures or the addition of prebiotics.