Milk fat globule-EGF factor 8 (MFG-E8)/lactadherin participates in several cell surface-mediated regulatory events. Although its mRNA is present in the gut, the physiological roles of MFG-E8 in the intestinal mucosa have not been explored. Here we show that MFG-E8 was expressed in intestinal lamina propria macrophages from mice. Using a wound-healing assay, MFG-E8 was shown to promote the migration of intestinal epithelial cells through a PKCε-dependent mechanism. MFG-E8 bound to phosphatidylserine and triggered reorientation of the actin cytoskeleton in intestinal epithelial cells at the wound edge. Depleting MFG-E8 in mice by administration of anti-MFG-E8 antibody or targeted deletion of the MFG-E8 gene resulted in a slowing of enterocyte migration along the crypt-villus axis and focal mucosal injury. Moreover, in septic mice, intestinal MFG-E8 expression was downregulated, which correlated with intestinal injury, interrupted enterocyte migration, and impaired restitution. Treatment with recombinant MFG-E8 restored enterocyte migration, whereas deletion of MFG-E8 impeded mucosal healing in mice with sepsis. These results suggest that a decrease in intestinal MFG-E8 impairs intestinal mucosal repair in sepsis. Together, our data indicate that MFG-E8 plays an important role in the maintenance of intestinal epithelial homeostasis and the promotion of mucosal healing and suggest that recombinant MFG-E8 may be beneficial for the treatment of bowel injuries.

Serum IgG antibody titres to some common foods increased in IBS and FD patients compared to controls. But there is no significant correlation between symptom severity and elevated serum food antigen-specific IgG antibodies in these patients.

The over-expressed colonic brain-derived neurotrophic factor (BDNF) has been reported to be associated with abdominal pain in patients with irritable bowel syndrome (IBS). However, the neuropathological mechanism is unclear. We here investigated the involvement of enteroglial cells (EGCs) and enteric nerves in IBS-like visceral hypersensitivity. We showed that glial fibrillary acidic protein (GFAP), tyrosine receptor kinase B (TrkB) and substance P (SP) were significantly increased in the colonic mucosa of IBS patients. The upregulation of those proteins was also observed in the colon of mice with visceral hypersensitivity, but not in the colon of BDNF+/− mice. Functionally, TrkB or EGC inhibitors, or BDNF knockdown significantly suppressed visceral hypersensitivity in mice. Using the EGC cell line, we found that recombinant human BDNF (r-HuBDNF) could directly activate EGCs via the TrkB-phospholipase Cγ1 pathway, thereby inducing a significant upregulation of SP. Moreover, supernatants from r-HuBDNF-activated EGC culture medium, rather than r-HuBDNF alone, triggered markedly augmented discharges in isolated intestinal mesenteric afferent nerves. r-HuBDNF alone could cause mesenteric afferent mechanical hypersensitivity independently, and this effect was synergistically enhanced by activated EGCs. We conclude that EGC-enteric nerve unit may be involved in IBS-like visceral hypersensitivity, and this process is likely initiated by BDNF-TrkB pathway activation.

The dysbiosis MS rat model and the post-inflammatory rat model captured some of the dysbiosis features of IBS patients. Fusobacterium, Clostridium XI and Porphyromonadaceae were identified as targets for future mechanistic research.

Severe sepsis is associated with dysfunction of the macrophage/monocyte, an important cellular effector of the innate immune system. Previous investigations suggested that probiotic components effectively enhance effector cell functions of the immune system in vivo. In this study, we produced bacteria-free, lysozyme-modified probiotic components (LzMPC) by treating the probiotic bacteria, Lactobacillus sp., with lysozyme. We showed that oral delivery of LzMPC effectively protected rats against lethality from polymicrobial sepsis induced by cecal ligation and puncture. We found that orally administrated LzMPC was engulfed by cells such as macrophages in the liver after crossing the intestinal barrier. Moreover, LzMPC-induced protection was associated with an increase in bacterial clearance in the liver. In vitro, LzMPC up-regulated the expression of cathelicidin-related antimicrobial peptide (CRAMP) in macrophages and enhanced bactericidal activity of these cells. Furthermore, we demonstrated that surgical stress or cecal ligation and puncture caused a decrease in CRAMP expression in the liver, whereas enteral administration of LzMPC restored CRAMP gene expression in these animals. Using a neutralizing Ab, we showed that protection against sepsis by LzMPC treatment required endogenous CRAMP. In addition, macrophages from LzMPC-treated rats had an enhanced capacity of cytokine production in response to LPS or LzMPC stimulation. Together, our data suggest that the protective effect of LzMPC in sepsis is related to an enhanced cathelicidin-related innate immunity in macrophages. Therefore, LzMPC, a novel probiotic product, is a potent immunomodulator for macrophages and may be beneficial for the treatment of sepsis.

In this study we aimed to compare the efficacy and safety of two personalized rescue therapies for Helicobacter pylori infection. Methods: An open-label, single-center, randomized controlled trial was conducted. Patients who had failed one or two regimens for H. pylori infection were randomized to receive a 14-day bismuth-containing quadruple therapy guided by antimicrobial susceptibility testing (AST) or personal medication history (PMH). In the AST group, either two of amoxicillin, clarithromycin, metronidazole or levofloxacin were prescribed according to the AST. In the PMH group, amoxicillin plus either levofloxacin or furazolidone were prescribed based on the patient's history of quinolone use. The primary outcomes were eradication rates confirmed by an urea breath test 6 weeks after treatment. The secondary outcomes were adherence, incidence of adverse events (AE) and cost-effectiveness. Results: Altogether 164 with a positive culture received AST-guided therapy and 192 received PMH-guided therapy, respectively. Both AST-and PMH-guided therapies achieved comparable eradication rate (intention-to-treat analysis: 78.10% vs 74.29%, P = 0.42; per-protocol analysis: 87.10% vs 88.64%, P = 0.80). The AST clarithromycin regimen had a lower per-protocol eradication rate than the levofloxacin (75.47% vs 96.30%, P = 0.03) or furazolidone-containing regimen (75.47% vs 92.75%, P = 0.02). Both groups had high compliance with low incidences of AE, and PMH-guided therapy had a lower medical cost. Conclusions: AST-guided therapy was not superior to PMH-guided therapy as a second-or third-line treatment for H. pylori infection. Considering the cost-effectiveness, PMH therapy is clinically more favorable.

The results indicated that cold water intake leads to lowered visceral perception thresholds in IBS patients that were inversely relevant to the abdominal symptoms in symptomatic diarrhea-predominant IBS patients. The alteration of rectal sensitivity and abdominal symptoms following cold water stimulation provided further objective evidence for visceral hypersensitivity in IBS patients.

Probiotic nutrients have shown promise in therapy for the treatment of gastrointestinal inflammation, infection, and atopic disease. Intestinal dendritic cells (DC) play a critical role in shaping the intestinal immune response. In this study, we tested the effect of a probiotic preparation (VSL#3) on DC distribution and phenotypes within the intestinal mucosa using a lineage depletion-based flow cytometric analysis. In naïve C57BL/10J mice, intestinal mucosal DC were composed of plasmacytoid DC (pDC) and myeloid DC (mDC). The pDC were the dominant form in lamina propria and Peyer's patches, whereas mDC were the prevailing type in the mesenteric lymph nodes. Additional characterization of pDC and mDC with flow cytometry revealed that they expressed heterogeneous phenotypes in the intestinal mucosa. In mice gavaged with the probiotic VSL#3 for 7 d, the proportion of pDC within the lamina propria was >60% lower, whereas the pDC subset in the mesenteric lymph nodes was more than 200% greater than in sham-treated controls (P < 0.01). Within pDC, the proportion of functionally unique CX3CR1(+) DC was greater than in controls in both the lamina propria and the Peyer's patches (P < 0.01). In contrast to pDC, the mDC number was greater than in controls in all intestinal lymphoid tissue compartments in VSL#3-treated mice (P < 0.01). In conclusion, this study suggests that phenotypically and functionally distinct DC subsets are localized to specific lymphoid tissues within the intestinal mucosa and that the VSL#3 probiotic nutritional supplement alters the distribution of the DC subsets within the intestinal mucosa. These changes may be important in the alteration of mucosal immunity following probiotic VSL#3 therapy.