Irf4-dependent CD103+CD11b+ dendritic cells and the intestinal microbiome regulate monocyte and macrophage activation and intestinal peristalsis in postoperative ileus.

OBJECTIVE: Postoperative ileus (POI), the most frequent complication after intestinal surgery, depends on dendritic cells (DCs) and macrophages. Here, we have investigated the mechanism that activates these cells and the contribution of the intestinal microbiota for POI induction. DESIGN: POI was induced by manipulating the intestine of mice, which selectively lack DCs, monocytes or macrophages. The disease severity in the small and large intestine was analysed by determining the distribution of orally applied fluorescein isothiocyanate-dextran and by measuring the excretion time of a retrogradely inserted glass ball. The impact of the microbiota on intestinal peristalsis was evaluated after oral antibiotic treatment. RESULTS: We found that Cd11c-Cre+ Irf4flox/flox mice lack CD103+CD11b+ DCs, a DC subset unique to the intestine whose function is poorly understood. Their absence in the intestinal muscularis reduced pathogenic inducible nitric oxide synthase (iNOS) production by monocytes and macrophages and ameliorated POI. Pathogenic iNOS was produced in the jejunum by resident Ly6C- macrophages and infiltrating chemokine receptor 2-dependent Ly6C+ monocytes, but in the colon only by the latter demonstrating differential tolerance mechanisms along the intestinal tract. Consistently, depletion of both cell subsets reduced small intestinal POI, whereas the depletion of Ly6C+ monocytes alone was sufficient to prevent large intestinal POI. The differential role of monocytes and macrophages in small and large intestinal POI suggested a potential role of the intestinal microbiota. Indeed, antibiotic treatment reduced iNOS levels and ameliorated POI. CONCLUSIONS: Our findings reveal that CD103+CD11b+ DCs and the intestinal microbiome are a prerequisite for the activation of intestinal monocytes and macrophages and for dysregulating intestinal motility in POI.

[IMMUNE RESPONSE IN PATIENTS WITH COLORECTAL CANCER IN POSTOPERATIVE PERIOD].

It was shown by the authors that changes of the level of cytokines reflected the degree of invasiveness of operative intervention. The endovideosurgical approach was less traumatic and provided a rapid rehabilitation of the patients in postoperative period. It is possible to consider the high levels of IL-10 as a predictor of development of local inflammatory process and as an indicator of probable infectious complications in postoperative period.

Suppression of ovalbumin-induced allergic diarrhea by diminished intestinal peristalsis in RAMP1-deficient mice.

Recent studies have revealed that various neurotransmitters regulate the immune system via their receptors expressed on the immune cells. Calcitonin gene-related peptide (CGRP), a sensory nerve C-fiber neuropeptide, is also known to have the ability to modulate the functions of immune cells in vitro. However, the contribution of CGRP to the immune regulation in vivo remains to be fully elucidated. Here we report that mice deficient in receptor activity-modifying protein 1 (RAMP1), which is a subunit of the CGRP receptor, showed a significantly lower incidence of diarrhea compared with wild-type (WT) mice in the ovalbumin (OVA)-induced food allergic model. Serum OVA-specific IgE levels and the differentiation of T helper cells was comparable in WT mice and RAMP1-deficient mice. Moreover, there were no significant differences between recruitment and degranulation of mast cells in the small intestine of these mice. In contrast, significantly diminished intestinal peristalsis was observed by the allergy induction in RAMP1-deficient mice compared with WT mice. These results suggest that this suppression of allergic diarrhea is due to the diminished intestinal peristalsis in RAMP1-deficient mice.

An autoantibody in narcolepsy disrupts colonic migrating motor complexes.

Despite strong circumstantial evidence for the autoimmune hypothesis of narcolepsy, conventional immunological methods have failed to detect an autoantibody. This study investigated the real-time effects of narcoleptic immunoglobulins on a spontaneous colonic migrating motor complex (CMMC) preparation. IgG from patients with narcolepsy with cataplexy or healthy controls was added directly to isolated mouse colons undergoing CMMC activity to test for autoantibodies that disrupt colonic motility. The effect of immunoglobulins prepared for clinical intravenous treatment (IVIg) on autoantibody-mediated colonic disruption was also assessed. Narcoleptic IgGs markedly reduced the frequency of CMMCs or irreversibly abolished them. Abrogation of CMMCs was followed by an increase in the resting tension of the colon preparation and appearance of atropine-sensitive phasic smooth muscle contractions. IVIg partially neutralized the inhibitory effect of narcoleptic IgG on the CMMCs. The dramatic effect of narcoleptic IgG on CMMC generation is consistent with an autoantibody-mediated disruption of enteric neural pathways. The ex vivo whole-organ approach allows real-time examination of the physiological effects of the narcoleptic autoantibody and offers a new avenue for exploring the autoimmune basis of narcolepsy. The neutralizing effect of IVIg on the autoantibody provides a rationale for the reported clinical improvement in cataplexy when IVIg are given at disease onset.

Parasitic suppression of feeding in the tobacco hornworm, Manduca sexta: parallels with feeding depression after an immune challenge.

The parasitic wasp, Cotesia congregata, suppresses feeding in its host Manduca sexta. Feeding suppression in the host coincides with the emergence of the wasps through the host's cuticle. During wasp emergence, host hemocyte number declined, suggesting that the host mounts a wound/immune response against the exiting parasitoids and/or resulting tissue damage. Eliciting a different type of immune response by injecting heat-killed Serratia marcescens also resulted in a decline in feeding and a reduction in hemocyte number. Both the emerging wasps and the bacteria induced an increase in hemolymph octopamine concentration and a decrease in foregut peristalsis in M. sexta. The emerging parasitoids produced the largest changes. The source of the additional octopamine appeared to be the host in both cases. S. marcescens was found to contain no detectable amounts of octopamine. The parasitoids had insufficient octopamine to account for the amount found in host hemolymph and they did not secrete octopamine in vitro. One cause for the high concentration of octopamine in parasitized M. sexta was that octopamine was removed from the hemolymph approximately 23 times more slowly after the wasps emerged than prior to wasp emergence. The striking similarity between the effects of parasitoids and bacteria on M. sexta feeding, hemocyte number, hemolymph octopamine concentration, and foregut peristalsis supports the possibility that the immune/wound reaction induced by the emerging wasps could play a role in the suppression of host feeding. These results also support the hypothesis that M. sexta exhibit an immune-activated anorexia.

Autoantibody profile in progressive systemic sclerosis as markers for esophageal involvement.

We investigated the relationship between the severity and extent of esophageal involvement in patients with progressive systemic sclerosis (PSS) and the autoantibody profile. We studied 37 consecutive patients with PSS and compared their results to 25 healthy volunteers. Patients with PSS were separated into three subgroups: group 1 (antinuclear antibody [ANA] [+/-], anti-Sc170 antibody [Scl70] [-], and anticentromere antibody [ACA] [-]), group 2 (ANA [+], Scl70 [+], and ACA [-]), and group 3 (ANA [+], Scl70 [-], and ACA [+]). The lower esophageal sphincter pressure and the mean proximal esophageal amplitude were significantly lower in group 3 when compared with group 1, group 2, and the healthy controls. Distal esophageal aperistalsis was noted in 85% of group 3, 40% of group 2, and 30% of group 1. An involvement of esophageal motility was found in 100% of the patients with ACA. Our results suggest that esophageal involvement is more pronounced in patients with PSS with ACA as compared with patients with only Sc170 or ANA.

Cirugía laparoscópica en el tratamiento del cáncer colorrectal / Laparoscopic surgery in the treatment of colorectal cancer

La introducción de las técnicas laparoscópicas ha supuesto un cambio en el tratamiento de la enfermedad colorrectal. Sin embargo, su aplicación no debe suponer un cambio en la naturaleza de la enfermedad, ya que la actitud del cirujano no debe modificarse, tanto si se emplean técnicas de cirugía laparoscópica como convencional. Los trabajos publicados sobre series prospectivas que comparan la cirugía laparoscópica y la convencional demuestran una serie de ventajas en el período postoperatorio de los pacientes intervenidos por laparoscopia. En el tratamiento de enfermedad colorrectal neoplásica existen una serie de controversias que deben responderse antes de considerar la cirugía laparoscópica como técnica de elección. Es fundamental poder garantizar una resección oncológica y, además, debemos conocer la influencia de esta técnica quirúrgica en la supervivencia de los pacientes ya que tras la introducción de la cirugía laparoscópica se ha observado un alarmante incremento de la aparición de implantes metastásicos en las puertas de entrada (port site metástasis). Se debe esperar los resultados de los estudios prospectivos aleatorizados que se están realizando para poder validar esta técnica quirúrgica en el tratamiento de la enfermedad colorrectal maligna (AU)

In vivo changes in the intestinal reflexes and the response to CCK in the inflamed small intestine of the rat.

Functional motor changes and morphological alterations have been associated with intestinal inflammation. The aim of our study was to evaluate functional alterations of intestinal reflexes and of the responses to CCK in the Trichinella spiralis model of intestinal inflammation. Rats were prepared with strain gauges and electrodes in the small intestine to evaluate spontaneous motor activity, the ascending contraction of the peristaltic reflex, and the motor responses to CCK-8 infusion. Infected animals showed increased motor activity at the duodenum and jejunum but not at the ileum. Ascending contraction was increased in both duodenum and ileum. Ascending excitation after N(omega)-nitro-L-arginine was still increased as well as the residual response after atropine. Response to CCK-8 during intestinal inflammation was changed in the jejunum, in which it turned from the inhibition shown in healthy animals to excitation. NADPH-diaphorase staining did not show any changes between distribution and density of positive neurons in either healthy or infected animals. In conclusion, intestinal inflammation induces functional changes in the motor activity that could explain the abnormal motor responses observed in inflammatory disorders.

Distribution of c-Kit immunopositive cells in normal human colon and in Hirschsprung's disease.

BACKGROUND: Subpopulations of c-Kit immunopositive cells in the muscle coat of the gastrointestinal tract are considered pacemaker cells and have been investigated in human tissue relating to motility disorder. However, the morphology of c-kit immunopositive cells in intact human tissue is still unclear. METHODS: The authors studied the distribution of c-Kit immunopositive cells in the normal human colon and their cellular configuration by confocal microscopy on whole-mount preparations. The authors then compared them with six cases of Hirschsprung's disease (HD; two of short segment aganglionosis, three of extensive aganglionosis, and one of total aganglionosis). RESULTS: In the normal colon regional differences were found in the distribution of c-Kit immunopositive cells. The population in the muscle layers and at the submucosal border was larger in the anal part than in the oral part. Accumulation of positive cells at the myenteric plexus level was prominent only at the descending colon. In the descending colon of HD the authors could not demonstrate any differences in c-Kit immunopositive cells on aganglionic segments compared with the corresponding area of intact tissue. CONCLUSION: More attention must be paid to these regional differences of distribution, and identical regions of affected and unaffected bowels must be compared when discussing the relation between the abnormality of c-Kit-positive cells and motility disorders including HD.