The microbiota-gut-brain axis transmits bidirectional communication between the gut and the central nervous system and links the emotional and cognitive centers of the brain with peripheral gut functions. This communication occurs along the axis via local, paracrine, and endocrine mechanisms involving a variety of gut-derived peptide/amine produced by enteroendocrine cells. Neural networks, such as the enteric nervous system, and the central nervous system, including the autonomic nervous system, also transmit information through the microbiota-gut-brain axis. Recent advances in research have described the importance of the gut microbiota in influencing normal physiology and contributing to disease. We are only beginning to understand this bidirectional communication system. In this review, we summarize the available data supporting the existence of these interactions, highlighting data related to the contribution of enteroendocrine cells and the enteric nervous system as an interface between the gut microbiota and brain.

The clinical and pathologic characteristics of the murine polycystic kidney were examined in a mutant cy/cy mouse found in the KK strain, which is known to be a diabetic strain. This cy/cy mutant appeared to resemble human adult polycystic kidney disease in clinical course and morphology although inheritance was an autosomal recessive trait. Histologic studies of early postnatal animals suggested that cystic alterations might occur in any part of a collecting tubule or nephron. The cy/cy mutant might be a useful model animal for further investigation of early morphologic alterations and progression of cystic disease.

Xenin-25 is a neurotensin-like peptide that is secreted by enteroendocrine cells in the small intestine. Xenin-8 is reported to augment duodenal anion secretion by activating afferent neural pathways. The intrinsic neuronal circuits mediating the xenin-25-induced anion secretion were characterized using the Ussing-chambered, mucosa-submucosa preparation from the rat ileum. Serosal application of xenin-25 increased the short-circuit current in a concentration-dependent manner. The responses were abolished by the combination of Cl−-free and [Formula: see text]-free solutions. The responses were almost completely blocked by TTX (10−6 M) but not by atropine (10−5 M) or hexamethonium (10−4 M). The selective antagonists for neurotensin receptor 1 (NTSR1), neurokinin 1 (NK1), vasoactive intestinal polypeptide (VIP) receptors 1 and 2 (VPAC1 and VPAC2, respectively), and capsaicin, but not 5-hydroxyltryptamine receptors 3 and 4 (5-HT3 and 5-HT4), NTSR2, and A803467, inhibited the responses to xenin-25. The expression of VIP receptors ( Vipr) in rat ileum was examined using RT-PCR. The Vipr1 PCR products were detected in the submucosal plexus and mucosa. Immunohistochemical staining showed the colocalization of NTSR1 and NK1 with substance P (SP)- and calbindin-immunoreactive neurons in the submucosal plexus, respectively. In addition, NK1 was colocalized with noncholinergic VIP secretomotor neurons. Based on the results from the present study, xenin-25-induced Cl−/[Formula: see text] secretion is involved in NTSR1 activation on intrinsic and extrinsic afferent neurons, followed by the release of SP and subsequent activation of NK1 expressed on noncholinergic VIP secretomotor neurons. Finally, the secreted VIP may activate VPAC1 on epithelial cells to induce Cl−/[Formula: see text] secretion in the rat ileum. Activation of noncholinergic VIP secretomotor neurons by intrinsic primary afferent neurons and extrinsic afferent neurons by postprandially released xenin-25 may account for most of the neurogenic secretory response induced by xenin-25. NEW & NOTEWORTHY This study is the first to investigate the intrinsic neuronal circuit responsible for xenin-25-induced anion secretion in the rat small intestine. We have found that nutrient-stimulated xenin-25 release may activate noncholinergic vasoactive intestinal polypeptide (VIP) secretomotor neurons to promote Cl−/[Formula: see text] secretion through the activation of VIP receptor 1 on epithelial cells. Moreover, the xenin-25-induced secretory responses are mainly linked with intrinsic primary afferent neurons, which are involved in the activation of neurotensin receptor 1 and neurokinin 1 receptor.

The aim of the present study was to investigate the action of pituitary adenylate cyclase-activating polypeptide (PACAP) on ion transport in the guinea pig distal colon. Submucosal/mucosal segments from distal colon were mounted in Ussing flux chambers, and increases in short-circuit current (Isc) were used as an index of secretion. Serosal addition of PACAP-38 and PACAP-27 produced concentration-dependent (10(-10)-10(-6) M) increases in Isc. Furosemide and chloride-free solutions significantly reduced the PACAP-evoked responses. Tetrodotoxin (TTX) completely blocked PACAP-evoked responses. Atropine significantly reduced the PACAP-evoked responses but did not abolish the responses. The results suggest that PACAP evokes chloride secretion through cholinergic and noncholinergic neural mechanism. Vasoactive intestinal polypeptide (VIP), peptide histidine-isoleucine amide, and helodermin evoked Isc in a concentration-dependent manner. Atropine reduced but did not abolish the VIP- and related peptides-evoked responses. TTX also significantly decreased the responses to higher concentrations of VIP and related peptides but did not abolish the responses. The results suggest that VIP and related peptides act on both submucosal neurons and the epithelial cell itself. VIP tachyphylaxis significantly decreased PACAP-38- and PACAP-27-evoked responses. These results provide evidence that PACAP recognizes, in some part, VIP receptors in the submucosal neurons to evoke chloride secretion.

The diffuse chemosensory system (DCS) is well developed in the apparatuses of endodermal origin like gastrointestinal (GI) tract. The primary function of the GI tract is the extraction of nutrients from the diet. Therefore, the GI tract must possess an efficient surveillance system that continuously monitors the luminal contents for beneficial or harmful compounds. Recent studies have shown that specialized cells in the intestinal lining can sense changes in the luminal content. The chemosensory cells in the GI tract belong to the DCS which consists of enteroendocrine and related cells. These cells initiate various important local and remote reflexes. Although neural and hormonal involvements in ion transport in the GI tract are well documented, involvement of the DCS in the regulation of intestinal ion transport is much less understood. Since activation of luminal chemosensory receptors is a primary signal that elicits changes in intestinal ion transport and motility and failure of the system causes dysfunctions in host homeostasis, as well as functional GI disorders, study of the regulation of GI function by the DCS has become increasingly important. This review discusses the role of the DCS in epithelial ion transport, with particular emphasis on the involvement of free fatty acid receptor 2 (FFA2) and free fatty acid receptor 3 (FFA3).

The present study tried to clarify if mumefural would prevent hyperglycemia, one of the typical symptoms of type 2 diabetes mellitus (T2DM), since mumefural is an extract from Japanese apricots preventing hyperglycemia. To clarify if mumefural would prevent T2DM pathogenesis, we used Otsuka Long-Evans Tokushima fatty (OLETF) rats, T2DM model. Mumefural diminished hyperglycemia, HOMA-IR and plasma triglyceride concentration in OLETF rats under fasting conditions. In addition, mumefural elevated protein expression of sodium-coupled monocarboxylate transporter 1 (SMCT1) in the distal colon participating in absorption of weak organic acids, which behave as bases but not acids after absorption into the body. Mumefural also increased the interstitial fluid pH around the brain hippocampus lowered in OLETF rats compared with non-T2DM LETO rats used as control for OLETF rats. Amyloid-beta accumulation in the brain decreased in accordance with the pH elevation. On the one hand, mumefural didn't affect plasma concentrations of glucagon, GLP-1, GIP or PYY under fasting conditions. Taken together, these observations indicate that: 1) mumefural would be a useful functional food improving hyperglycemia, insulin resistance and the lowered interstitial fluid pH in T2DM; 2) the interstitial fluid pH would be one of key factors influencing the accumulation of amyloid-beta.

The effect of the newly developed 5-HT, and 5-HT4 receptor dual antagonist, FK1052 on short-circuit current was investigated using submucosa-mucosa sheets of guinea-pig distal colon. 5-Hydroxytryptamine (5-HT) evoked an increase in short-circuit current in a concentration-dependent manner. 5-Hydroxytryptamine (5-HT) is contained within enteric nervous system as well as within enteroendocrine cells of gastrointestinal tract (12). The presence of 5-HT in neurons or enteroendocrine cells suggests that 5-HT acts as a neurotransmitter and hormone/paracrine agent mediating enteric function (11, 21, 23). For example, addition of 5-HT to the serosal surface of flat sheets of guinea-pig small intestine and distal colon, rabbit ileum' and rat jejunum and colon in vitro results in a transient increase in short-circuit current (Isc) and transmural potential difference (PD) (5-7, 9, 14). The increase in Isc by 5-HT on the guinea-pig distal colon is primarily due to chloride secretion (7, 14). Since the responses were abolished by TTX, actions of 5-HT in intestinal mucosal ion transport appear to be mediated through the submucosal neurons. In pathological conditions, 5-HT is also believed to play a causal role in inducing diarrhea FK1052 inhibits the accelerated colonic transit induced by 5-HT in conscious rats and furthermore FK1052 prevents 5-HT-induced diarrhea. The same group has also reported that FK1052 inhibits

The inhibitory action of the secondary bile acid lithocholic acid (LCA) on neurally evoked Cl − / HCO 3 − secretion was investigated using the Ussing-chambered mucosal-submucosal preparation from the rat distal colon. Electrical field stimulation (EFS) evoked cholinergic and noncholinergic secretory responses in the rat distal colon. The responses were almost completely blocked by TTX (10 −6 M) but not atropine (10 −5 M) or hexamethonium (10 −4 M). The selective antagonist for VIP receptor 1 (VPAC1) greatly reduced the EFS-evoked response. Thus, the rat distal colon may be predominantly innervated by noncholinergic VIP secretomotor neurons. Basolateral addition of 6 × 10 −5 M LCA inhibited the EFS-evoked response. The inhibitory action of LCA was partly rescued by the Y2R antagonist BIIE0246. The bile acid receptor TGR5 agonist INT-777 mimicked the LCA-induced inhibitory action. Immunohistochemical staining showed the colocalization of TGR5 and PYY on L cells. TGR5 immunoreactivity was also found in VIP-immunoreactive submucosal neurons which also expressed the PYY receptor, Y2R. These results suggest that LCA inhibits neurally evoked Cl − /HCO 3 − secretion through the activation of TGR5 on L cells and cholinergic-and VIP-secretomotor neurons in the submucosal plexus. Furthermore, the inhibitory mechanism may involve TGR5-stimulated PYY release from L cells and Y2R activation in VIP-secretomotor neurons.