Targeting the Microbiota, from Irritable Bowel Syndrome to Mood Disorders: Focus on Probiotics and Prebiotics.

PURPOSE OF REVIEW: The crosstalk between the gut and the brain has revealed a complex communication system responsible for maintaining a proper gastrointestinal homeostasis as well as affect emotional mood and cognitive functions. Recent research has revealed that beneficial manipulation of the microbiota by probiotics and prebiotics represent an emerging and novel strategy for the treatment of a large spectrum of diseases ranging from visceral pain to mood disorders. The review critically evaluates current knowledge of the effects exerted by both probiotics and prebiotics in irritable bowel syndrome (IBS) and mood disorders such as anxiety and depression. RECENT FINDINGS: Relevant literature was identified through a search of MEDLINE via PubMed using the following words, "probiotics", "prebiotics", "microbiota", and "gut-brain axis" in combination with "stress", "depression", "IBS", and "anxiety". A number of trials have shown efficacy of probiotics and prebiotics in ameliorating both IBS related symptoms and emotional states. However, limitations have been found especially due to the small number of clinical studies, studies design, patient sample size, and placebo effect. SUMMARY: Nonetheless, current finding supports the view that beneficial manipulation of the microbiota through both probiotics and prebiotics intake represents a novel attractive strategy to treat gut-brain axis disorders such as IBS and depression.

Cognitive Function and the Microbiome.

There is increasing evidence that the composition of the resident bacteria within the gastrointestinal tract can influence the brain and behavior, particularly with respect to cognitive function. Cognitive function encompasses the life-long process of learning, both long- and short-term processes. Cognition was originally thought to be exclusively regulated by the central nervous system, with long-term potentiation and neurogenesis contributing to the creation and storage of memories, but now other systems, including, for example, the immune system and the intestinal microbiome may also be involved. Cognitive impairment has been identified in numerous disease states, both gastrointestinal and extraintestinal in nature, many of which have also been characterized as having a role for dysbiosis in disease pathogenesis. This includes, but is not limited to, inflammatory bowel diseases, irritable bowel syndrome, type 1 diabetes, obesity, major depressive disorder, and autism spectrum disorder. The role of cognition and the microbiome will be discussed in this chapter for all these diseases, as well as evidence for a role in maintaining overall human health and well being. Finally, evidence for a role for probiotics in beneficially modulating the microbiota and leading to improved cognition will be discussed.

TRPM8 on mucosal sensory nerves regulates colitogenic responses by innate immune cells via CGRP.

TRPM8 is the molecular sensor for cold; however, the physiological role of TRPM8+ neurons at mucosal surfaces is unclear. Here we evaluated the distribution and peptidergic properties of TRPM8+ fibers in naive and inflamed colons, as well as their role in mucosal inflammation. We found that Trpm8(-/-) mice were hypersusceptible to dextran sodium sulfate (DSS)-induced colitis, and that Trpm8(-/-) CD11c+ DCs (dendritic cells) showed hyperinflammatory responses to toll-like receptor (TLR) stimulation. This was phenocopied in calcitonin gene-related peptide (CGRP) receptor-deficient mice, but not in substance P receptor-deficient mice, suggesting a functional link between TRPM8 and CGRP. The DSS phenotype of CGRP receptor-deficient mice could be adoptively transferred to wild-type (WT) mice, suggesting that CGRP suppresses the colitogenic activity of bone marrow-derived cells. TRPM8+ mucosal fibers expressed CGRP in human and mouse colon. Furthermore, neuronal CGRP contents were increased in colons from naive and DSS-treated Trpm8(-/-) mice, suggesting deficient CGRP release in the absence of TRPM8 triggering. Finally, treatment of Trpm8(-/-) mice with CGRP reversed their hyperinflammatory phenotype. These results suggest that TRPM8 signaling in mucosal sensory neurons is indispensable for the regulation of innate inflammatory responses via the neuropeptide CGRP.

Prokineticin-1 evokes secretory and contractile activity in rat small intestine.

BACKGROUND: Prokineticins 1 and 2 (PROK1 and PROK2) are so named because they contract gastrointestinal smooth muscle, yet little else is known about their role in gastrointestinal function. Therefore, we used a combination of approaches to elucidate the mechanisms by which PROK1 alters ileal contractility and secretion in rats. METHODS: RT-PCR and immunofluorescence were used to determine PROK and receptor (PK-R) mRNA levels and PK-R1 localization, respectively. Upper GI transit and fluid secretion were determined in vivo. Contractility and intestinal epithelial ion transport were assessed in isolated ileal segments. KEY RESULTS: In the gastric fundus, PROK1 mRNA is highly expressed (70-fold >PROK2 mRNA) whereas the ileum has the highest mRNA expression of its receptor. PK-R1 immunoreactivity is visualized in ileal crypt cells, and in submucosal and myenteric neurons. In ileal segments, PROK1 evokes biphasic contractile responses consisting of an early, TTX-sensitive response (EC(50) = 87.8 nmol L(-1)) followed by a late, TTX-insensitive (EC(50) = 72.4 nmol L(-1)) component that is abolished in mucosa-free preparations. Oral administration of PROK1 enhances small bowel transit (111 +/- 3% of control) and fluid secretion (340 +/- 90% of control) and in muscle-stripped ileal preparations increases short-circuit current (EC(50) = 8.2 nmol L(-1)) in a TTX-insensitive manner. The PROK1-evoked Cl- secretion is reduced by piroxicam (non-selective cyclooxygenase inhibitor), and a prostaglandin EP(4) receptor antagonist (AH23848), but not a thromboxane receptor antagonist (GR32191B). CONCLUSIONS & INFERENCES: These results demonstrate that PROK1 has oral prokinetic and secretogogue activity and that it acts on the intestinal mucosa via PK-R1 and prostaglandin receptors to mediate these effects.