Effect of different recumbent positions on postprandial gastroesophageal reflux in normal subjects

OBJECTIVE: Gastroesophageal reflux (GER) is increased in the right compared to the left recumbent position. Esophageal acid exposure is related to the acidity at the cardia, but the effect of body position on the acidity at the cardia has not yet been investigated. We aimed to investigate the mechanisms underlying increased esophageal acid exposure in the right recumbent position. METHODS: On 2 separate days a 4-h combined esophageal and lower esophageal sphincter (LES) manometry and pH recording of esophagus, gastric cardia, and corpus was performed in the right and left recumbent position after a high fat meal in 10 healthy subjects. RESULTS: In the right recumbent position a prolonged esophageal acid exposure (7.0% vs 2.0%, p < 0.03), a higher incidence of reflux episodes (3.8 vs 0.9/h, p < 0.03), more transient LES relaxations (TLESRs) (6.5 vs 3.2/h, p < 0.03), and higher percentage TLESRs associated with reflux (57.0% vs 22.4% p < 0.03) was recorded than in the left supine position. Acidity at gastric cardia and corpus was not affected by body position. CONCLUSIONS: Increased esophageal acid exposure in the right recumbent position relative to the left recumbent position is the result of a higher incidence of GER episodes caused by an increased incidence of TLESRs and higher percentage of TLESRs associated with GER. Body position does not affect the acidity at the gastric cardia and corpus.     

Siglec-7 specifically recognizes Campylobacter jejuni strains associated with oculomotor weakness in Guillain–Barré syndrome and Miller Fisher syndrome

Due to molecular mimicry, Campylobacter jejuni lipo-oligosaccharides can induce a cross-reactive antibody response to nerve gangliosides, which leads to Guillain–Barré syndrome (GBS). Cross-reactive antibodies to ganglioside GQ1b are strongly associated with oculomotor weakness in GBS and its variant, Miller Fisher syndrome (MFS). Antigen recognition is a crucial first step in the induction of a cross-reactive antibody response, and it has been shown that GQ1b-like epitopes expressed on the surface of C. jejuni are recognized by sialic acid-binding immunoglobulin-like lectin-7 (Siglec-7). We aimed to determine the epitope specificity of C. jejuni binding to Siglec-7, and correlate the outcome to disease symptoms in GBS and MFS patients. Using a well-defined GBS/MFS-associated C. jejuni strain collection, which included three sialic acid knockout strains, we found that Siglec-7 exclusively binds to C. jejuni strains that express terminal disialylated ganglioside mimics. When serological and diagnostic patient records were correlated with the Siglec-7-binding properties, we observed an association between Siglec-7 binding and the presence of anti-GQ1b antibodies in patient serum. In addition, Siglec-7 binding was associated with oculomotor weakness in GBS and MFS patients. Lipo-oligosaccharide-specific binding of C. jejuni to Siglec-7 may be an initiating event in immune recognition and presentation, and lead to anti-GQ1b antibody production and the development of ocular weakness in GBS or MFS.     

Acid and Non-Acid Reflux Patterns in Patients with Erosive Esophagitis and Non-Erosive Reflux Disease (NERD): A Study Using Intraluminal Impedance Monitoring

Background Non-erosive reflux disease (NERD) and erosive esophagitis (EE) are the most common phenotypic presentations of gastroesophageal reflux disease (GERD). Aim To assess acid and non-acid reflux patterns in patients with EE and NERD using combined esophageal pH-impedance monitoring. Methods A total of 26 GERD patients off acid-suppressive medication and ten healthy volunteers (HV) underwent upper endoscopy and 24-h pH-impedance monitoring. Analysis of the pH-impedance signals included total reflux time, number of reflux episodes according to gas–liquid composition, and pH (acid, non-acid). Results EE was identified in 13 patients and NERD in 13 patients. Pathologic acid reflux was found in 92.3 and 69.2% of patients with EE and NERD, respectively (P = 0.15). When compared to HV, EE patients and NERD patients showed a higher incidence of acid (P = 0.002 and P < 0.001, EE vs. HV and NERD vs. HV, respectively) and non-acid reflux episodes (P = 0.03 and P = 0.001, EE vs. HV and NERD vs. HV, respectively). Mean reflux times, as assessed by both pH-metry and impedance monitoring, and incidence of acid and non-acid reflux episodes were similar in EE and NERD patients. In the supine position, however, EE patients showed a higher incidence of acid (P = 0.048) and liquid reflux episodes (P = 0.07). Conclusion Whereas EE patients have more acid reflux episodes in the supine position than NERD patients, patients with EE and NERD have similar non-acid reflux patterns. This observation lends support to the notion that non-acid reflux is less damaging to the esophageal mucosa than acid reflux.     

Maintenance of small intestinal and colonic tolerance by IL-10-producing regulatory T cell subsets

The intestinal mucosa is continuously exposed to harmless exogenous antigens derived from food proteins and microbiota. Continuous surveillance by suppressive regulatory T cells prevents inflammatory responses to these antigens thereby maintaining intestinal homeostasis. The nature of the antigenic pressure varies at different locations of the intestinal tract. In agreement with this strong microenvironmental control, small intestinal and colonic regulatory T cell homeostasis varies considerably. In this review, we summarize the substantial advances that have been made in dissecting the phenotype and function of intestinal regulatory T cells, discuss how microbiota can modulate the intestinal regulatory T cell pool and review the crucial role of the immunoregulatory cytokine interleukin-10 (IL-10) in shaping and maintenance of mucosal tolerance.     

Characterization of the Specific Interaction between Sialoadhesin and Sialylated Campylobacter jejuni Lipooligosaccharides

In Campylobacter jejuni-induced Guillain-Barré syndrome (GBS), molecular mimicry between C. jejuni lipooligosaccharide (LOS) and host gangliosides leads to the production of cross-reactive antibodies directed against the peripheral nerves of the host. Currently, the presence of surface exposed sialylated LOS in C. jejuni is the single known bacterial pathogenesis factor associated with the development of GBS. Using a unique, well-characterized strain collection, we demonstrate that GBS-associated C. jejuni strains bind preferentially to sialoadhesin (Sn, Siglec-1, or CD169), a sialic acid receptor found on a subset of macrophages. In addition, using a whole-cell enzyme-linked immunosorbent assay (ELISA), C. jejuni strains with sialylated LOS bound exclusively to soluble Sn. Mass spectrometry revealed that binding was sialic acid-linkage specific with a preference for α(2,3)-linked sialic acid attached to the terminal galactose of the LOS chain as seen in the gangliosides GD1a, GM1b, and GM3. This molecular interaction was also related to functional consequences as a GBS-associated C. jejuni strain that bound Sn in a whole-cell ELISA adhered to surface-expressed Sn of Sn-transfected CHO cells but was unable to adhere to wild-type CHO cells. Moreover, a sialic acid-negative mutant of the same C. jejuni strain was unable to bind Sn-transfected CHO cells. This is the first report of the preferential binding of GBS-associated C. jejuni strains to the Sn immune receptor (P = 0.014). Moreover, because this binding is dependent on sialylated LOS, the main pathogenic factor in GBS progression, the present findings bring us closer to unraveling the mechanisms that lead to formation of cross-reactive antibodies in GBS disease.Campylobacter jejuni, a food-borne Gram-negative bacterium, is the major cause of bacterial gastroenteritis worldwide. In addition to enteritis, infection with C. jejuni may also lead to a neurological complication called the Guillain-Barré syndrome (GBS). GBS is an autoimmune disease affecting the peripheral nerves. Antibodies raised by the host during an infection with C. jejuni possess the capacity to cross-react with structures on human nerve tissue, resulting in neurological complications for the host (38). Further, high titers of anti-ganglioside antibodies are frequently found in the sera of GBS patients (24, 41). Gangliosides are glycosphingolipids with an extracellular sialylated oligosaccharide chain and a ceramide tail that is embedded in the outer leaflet of the plasma membrane. Although predominantly found in the nervous system, gangliosides are present on other cell surfaces as well.C. jejuni has lipooligosaccharide (LOS) structures on its outer membrane. Biochemical and structural analysis of LOS outer core oligosaccharides has identified sialylated moieties that are structurally similar to several gangliosides (6, 9, 30). During infection, the structural similarity between C. jejuni LOS and human gangliosides, also known as molecular mimicry, facilitates the induction of anti-ganglioside antibodies and the development of GBS (1, 29, 38, 40). The C. jejuni genes involved in ganglioside mimicry are located within the LOS biosynthesis locus, a gene cluster that is interchangeable between strains and is genetically highly diverse (18, 19). Therefore, several LOS classes (A through S) have been identified (31). LOS class, gene alterations, mutations, and mechanisms such as phase variation in the LOS locus contribute to structural variations in the ganglioside mimics produced (19). The presence of LOS biosynthesis locus-encoded genes responsible for synthesis, modification, and transfer of sialic acid, found in LOS classes A, B, and C, is crucial in the induction of anti-ganglioside antibodies and hence GBS (20, 36). Sialylated LOS is also involved in other aspects of C. jejuni pathogenesis. C. jejuni strains expressing sialylated LOS invade human epithelial intestinal cells significantly more frequently than strains expressing nonsialylated LOS (28). However, the receptor for C. jejuni attachment to human epithelial intestinal cells is unknown.Certain C. jejuni strains are known to bind to Siglec-7, a member of the sialic acid binding immunoglobulin-like lectin (Siglec) family (8). Siglecs are present on the cell surface of a range of immune-associated cells and are involved in cell to cell interactions and signaling. A subset of the Siglec family, the CD33-related Siglecs, can serve as regulators of the immune system through immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in their cytoplasmic tail (7, 11). In addition, several recently described human Siglecs, Siglecs-14, -15, and -16 can interact with the immunoreceptor tyrosine-based activation motif (ITAM) adaptor, DAP12 and therefore potentially mediate the activation of intracellular signaling (5, 10).Sialoadhesin (Sn, Siglec-1, or CD169) is a macrophage-restricted Siglec that has been associated with inflammatory and autoimmune diseases. For example, Sn levels are elevated on activated macrophages within the inflamed organs of several inflammatory disorders, including rheumatoid arthritis, experimental autoimmune encephalomyelitis (EAE), and experimental autoimmune uveoretinitis (EAU) (22, 32, 39). This elevated expression may have functional consequences since Sn-deficient mice show a reduced severity of EAE and EAU (25, 39). With a poorly conserved cytoplasmic tail and the absence of tyrosine-based signaling motifs, Sn seems to be more involved in cell-to-cell communication and ligand binding than intracellular immunoregulation. It has been shown that macrophages expressing Sn can bind and internalize sialylated Neisseria meningitidis in an Sn- and sialic acid-dependent manner (26). Further, HIV-1 can interact with Sn, probably via a sialic acid residue on gp120, with binding resulting in enhanced infectivity and facilitates transinfections in alpha interferon (IFN-α)-stimulated CD14⁺ monocytes. Furthermore, Sn gene expression is elevated in CD14⁺ monocytes from patients infected with HIV-1 (34).Each Siglec has a unique specificity for certain sialylated glycans, with Sn preferring sialic acid conjugates with an α(2,3)galactose (gal) linkage (12). This α(2,3)Gal linkage is often found on the LOS of GBS-associated C. jejuni strains.Because of the connection of C. jejuni infection with autoimmune disease such as GBS and its clinical variant Miller-Fisher syndrome (MFS), we investigated whether α(2,3)-linked sialic acid residues on the surface of C. jejuni strains could interact with Sn and whether this interaction was characteristic for GBS-associated strains.     

Anti-inflammatory actions of phosphatidylinositol

Chronic inflammatory T-cell-mediated diseases such as inflammatory bowel disease (IBD) are often treated with immunosuppressants including corticosteroids. In addition to the intended T-cell suppression, these farmacons give rise to many side effects. Recently, immunosuppressive phospholipids have been proposed as less-toxic alternatives. We aimed to investigate the immunoregulatory capacities of the naturally occurring phospholipid phosphatidylinositol (PI). Systemic PI treatment dramatically reduced disease severity and intestinal inflammation in murine 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis. Moreover, PI treatment inhibited the inflammatory T-cell response in these mice, as T cells derived from colon-draining LN of PI-treated mice secreted less IL-17 and IFN-γ upon polyclonal restimulation when compared to those of saline-treated mice. Further characterization of the suppressive capacity of PI revealed that the phospholipid suppressed Th cell differentiation in vitro irrespective of their cytokine profile by inhibiting proliferation and IL-2 release. In particular, PI diminished IL-2 mRNA expression and inhibited ERK1-, ERK-2-, p38- and JNK-phosphorylation. Crucially, PI did not ablate Treg differentiation or the antigen-presenting capacity of DCs in vitro. These data validate PI as a pluripotent inhibitor that can be applied mucosally as well as systemically. Its compelling functions render PI a promising novel physiological immune suppressant.     

Long-Term Dietary Patterns Are Reflected in the Plasma Inflammatory Proteome of Patients with Inflammatory Bowel Disease

Diet plays an important role in the development and progression of inflammatory bowel disease (IBD, comprising Crohn’s disease (CD) and ulcerative colitis (UC)). However, little is known about the extent to which different diets reflect inflammation in IBD beyond measures such as faecal calprotectin or C-reactive protein. In this study, we aimed to unravel associations between dietary patterns and circulating inflammatory proteins in patients with IBD. Plasma concentrations of 73 different inflammation-related proteins were measured in 454 patients with IBD by proximity extension assay (PEA) technology. Food frequency questionnaires (FFQ) were used to assess habitual diet. Principal component analysis (PCA) was performed to extract data-driven dietary patterns. To identify associations between dietary patterns and plasma proteins, we used general linear models adjusting for age, sex, BMI, plasma storage time, smoking, surgical history and medication use. Stratified analyses were performed for IBD type, disease activity and protein intake. A high-sugar diet was strongly inversely associated with fibroblast growth factor-19 (FGF-19) independent of IBD type, disease activity, surgical history and deviance from recommended protein intake (false discovery rate (FDR) < 0.05). Conversely, a Mediterranean-style pattern was associated with higher FGF-19 levels (FDR < 0.05). A pattern characterised by high alcohol and coffee intake was positively associated with CCL11 (eotaxin-1) levels and with lower levels of IL-12B (FDR < 0.05). All results were replicated in CD, whereas only the association with FGF-19 was significant in UC. Our study suggests that dietary habits influence distinct circulating inflammatory proteins implicated in IBD and supports the pro- and anti-inflammatory role of diet. Longitudinal measurements of inflammatory markers, also postprandial, are needed to further elucidate the diet–inflammation relationship.     

Endogenous secretory leukocyte protease inhibitor inhibits microbial-induced monocyte activation

In the intestine, epithelial factors condition incoming immune cells including monocytes to adapt their threshold of activation and prevent undesired inflammation. Colonic epithelial cells express Secretory Leukocyte Protease Inhibitor (SLPI), an inhibitor of NF kappa light chain enhancer of activated B cells (NF-κB) that mediates epithelial hyporesponsiveness to microbial stimuli. Uptake of extracellular SLPI by monocytes has been proposed to inhibit monocyte activation. We questioned whether monocytes can produce SLPI and whether endogenous SLPI can inhibit monocyte activation. We demonstrate that human THP-1 monocytic cells produce SLPI and that CD68⁺ SLPI-producing cells can be detected in human intestinal lamina propria. Knockdown of SLPI in human THP-1 cells significantly increased NF-κB activation and subsequent C-X-C motif chemokine ligand 8 (CXCL8) and TNF-α production in response to microbial stimulation. Reconstitution of SLPI-deficient cells with either full-length SLPI or SLPI lacking its signal peptide rescued inhibition of NF-κB activation and cytokine production, demonstrating that endogenous SLPI inhibits monocytic cell activation. Unexpectedly, exogenous SLPI did not inhibit CXCL8 or TNF-α production, despite efficient uptake. Our data argue that endogenous SLPI can regulate the threshold of activation in monocytes, thereby preventing activation by commensal bacteria in mucosal tissues.