By interacting directly with mucosal environment, the microbiota impacts intestinal mucosal functions and permeability, and influences local and systemic inflammatory activity [ 12 ] . In normal conditions neuromuscular apparatus is not in contact with the luminal content and quite inaccessible by the luminal microbes. However, dysbiotic conditions cause an increase in mucosal inflammation and intestinal paracellular permeability [ 17 , 18 ] (Figure 1 ) with possible translocation of pathogens, toxins, antigens and bacteria in the circulatory system [ 16 , 19 , 20 ] . GI motility might then be affected by microbiota essentially by two mechanisms: an indirect mechanism driven by the inflammatory mediators released by the mucosal immune system and a direct mechanism driven both by the release of end products of bacterial fermentation and bacterial substances.

On the other hand, both in vivo and in vitro evidence highlights that microbiota can affect GI motility [ 8 , 9 ] . In studies conducted on germ-free animals, impairment of neural and motor functions of the GI tract due to reduced expression of neurotransmitters and contractile proteins, were reversed by gut colonization [ 10 ] . Moreover, probiotics have been shown to affect GI motility in vivo and in vitro . Prebiotic or probiotic therapies are associated with a significant clinical improvement in irritable bowel syndrome (IBS) [ 11 , 12 ] and animal studies suggest that the neuromuscular apparatus could represent a target for probiotics [ 13 - 15 ] . Finally, dysbiosis is associated with significant alterations in intestinal transit time [ 16 ] .

Microbiota and gut motility are clearly associated, but it’s difficult to establish what plays the major role in influencing the other. According to the classical theory, gastrointestinal (GI) motility can affect the microbiota in terms of amount, location and diversity. This concept is mainly supported by the association between different GI motility disorders and small intestinal bacterial overgrowth (SIBO) [ 1 , 2 ] . GI motility disorders and alterations of migrating motor complex (MMC), that eliminates residual content through the GI tract during periods of fasting, predispose to SIBO because bacteria are not swept from the small bowel into the colon, as reported in experimental models and specific clinical conditions [ 3 - 5 ] . Neuropathic and myopathic diseases, such as scleroderma and polymyositis, seem to be associated with SIBO [ 1 , 6 ] as well as conditions associated to long-standing diabetes, such as gastroparesis [ 7 ] .

INDIRECT EFFECTS

The potential for the microbiota to produce inflammatory alterations in the gut microenvironment deranging gastrointestinal motor function prompts to a unifying hypothesis for the role of the microbiota in the pathogenesis of IBS. To support a role of the microbiota in IBD pathophysiology is the evidence that an acute episode of gastroenteritis precedes the onset of IBS, a specific condition called post-infectious IBS (PI-IBS)[11,21,22]. PI-IBS is characterized by persistent abdominal discomfort, bloating and diarrhea, despite the elimination of the causative pathogen. In this condition, the imbalance in microbiota composition leads to low-grade inflammation followed by alteration of the sensory and motor bowel functions. An increased amount of immune cells in the colonic, ileal, and jejunal mucosa of IBS patients has been largely reported[23,24]. The persistent inflammatory state is also characterized by increased mucosal interleukin 1β levels and mast cells count, as well as activation of entero-endocrine cells (EC), mainly those producing serotonin (5-HT)[25-28]. The interesting data is that most of these mucosal alterations persist for over a year and thus could contribute to the persistence of a PI-IBS. Therefore, the mucosal inflammation resulting from an acute infection can lead to a dysfunction of intestinal motility and 5-HT could play a pivotal role as its release increases motility and secretion, features which may explain diarrheal symptoms frequent in PI-IBS patients[29]. With an experimental model of primary infection with Trichinella spiralis, that causes hypercontractility of intestinal muscle persisting for over 20 d after the infection was cleared, it was shown that chronic immune response may extend to smooth muscle layers[30]. In this model, the levels of Th2 cytokines (interleukins 4, 5, and 13) resulted increased during the acute infection but not thereafter, whereas cyclooxygenase-2 (COX-2) and relative enzymatic activity localized to muscle remained significantly increased. These effects did not occur in athymic mice, suggesting a crucial role of T cells in the impairment of intestinal muscle function in post-infective disorders[30]. The role of COX-2 in muscle impairment during inflammation has been reported both in animal and humans. During severe mucosal inflammatory conditions, it has been shown in colonic muscle cells an altered expression of contractile key-signaling molecules and an increase in nuclear factor NF-κB DNA binding, which is low or absent in normal colonic muscle cells[31-33]. In human colonic smooth muscle, NF-κB activation leads to inflammatory gene expression of COX-2 and to production of prostaglandin E, both widely considered responsible for muscle cell impairment[34-37].

Mediators released by the colonic mucosa of IBS patients are able to activate aberrant responses in the enteric nervous system[38,39] and to impair contractility of human colonic smooth muscle likely through a receptor-dependent mechanism[40]. Histamine and proteases, two soluble inflammatory products obtained from IBS biopsy supernatants, are able to excite visceral afferents neurons and to cause hyperalgesia and allodynia when introduced into the colon of mice[41,42]. Beside increased visceral sensory activation, the soluble products found in supernatants derived from the colon of IBS patients have been shown to evoke excitatory cholinergic longitudinal muscle contractions in the guinea pig ileum[43]. This effect correlates with the number of mast cells and the activation of the nerve fibers appears to be mediated by the activation of different receptors, including transient receptor potential vanilloid subfamily member 1 (TRPV1), purinergic and prostanoids receptors[43].

Many studies have been conducted in attempt to identify a specific pattern of intestinal faecal microbiota in IBS patients and, although heterogeneity of IBS patients, qualitative and quantitative alterations in intestinal microflora have been found. Differently from traditional microbial culture-based techniques, studies using DNA-based techniques showed that specific fecal and mucosal microbiota composition are associated with different subgroups of IBS patients, even if these investigations have produced non univocal results. Some studies reported increased abundance of Proteobacteria and Firmicutes and reduction in Actinobacteria and Bacteroidetes in patients with IBS[11,44] while others reported a decreased amount of Lactobacilli and Bifidobacteria[45]. A very recent meta-analysis demonstrated that composition of IBS patients microbiota vary across geographical regions. The study reported a decreased numbers of Bifidobacteria and Lactobacillus and increased numbers of Escherichia coli and Enterobacterium in Chinese IBS patients with no significant differences in the abundance of Bacteroides and Enterococcus. On the other hand, a decreased numbers of Bifidobacteria and increased numbers of Bacteroides were found in IBS patients from other regions of the world[46]. The strict relationship between dysbiosis and GI motility in IBS need to be further elucidated as one of the major challenges in IBS is the absence of an animal model that fully represent this condition.