Faecalibacterium prausnitzii Strain HTF-F and Its Extracellular Polymeric Matrix Attenuate Clinical Parameters in DSS-Induced Colitis

Date of Acceptance: 26/02/2015 Funding: The authors received no specific funding for this work.Peer reviewedPublisher PD

Yap1-Driven Intestinal Repair Is Controlled by Group 3 Innate Lymphoid Cells

Intestinal repair is driven by epithelial stem cells, but how these stem cells are instructed to initiate repair was unknown. Here, Romera-Hernández et al. report that epithelial proliferation after damage is independent of the stem cell-protective signal IL-22 but requires ILC3-dependent amplification of regenerative YAP1 signaling in stem cells.Tissue repair requires temporal control of progenitor cell proliferation and differentiation to replenish damaged cells. In response to acute insult, group 3 innate lymphoid cells (ILC3s) regulate intestinal stem cell maintenance and subsequent tissue repair. ILC3-derived IL-22 is important for stem cell protection, but the mechanisms of ILC3-driven tissue regeneration remain incompletely defined. Here we report that ILC3-driven epithelial proliferation and tissue regeneration are independent of IL-22. In contrast, ILC3s amplify the magnitude of Hippo-Yap1 signaling in intestinal crypt cells, ensuring adequate initiation of tissue repair and preventing excessive pathology. Mechanistically, ILC3-driven tissue repair is Stat3 indepe

Management of Autoimmune Encephalitis in a 7-Year-Old Child With CTLA-4 Haploinsufficiency and AMPA Receptor Antibodies:A Case Report

OBJECTIVES: We report on the therapeutic management of early-onset severe neurologic symptoms in cytotoxic T lymphocyte antigen-4 haploinsufficiency (CTLA-4h) and the presence of antibodies to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) as an important finding. METHODS: This is a case report from a Dutch academic hospital. Repeated clinical examinations, repeated brain MRI and extended diagnostics on serum and CSF were performed. We used the CARE checklist. RESULTS: A 7-year-old boy was diagnosed with CTLA-4h based on family screening. On diagnosis, he had mild chronic diarrhea and autism spectrum disorder, but no abnormalities in extensive laboratory screening. Six months later, he presented with sudden-onset autoimmune encephalitis. Repeated brain MRI revealed no abnormalities, but immunohistochemistry analysis on serum and CSF showed the presence of AMPAR antibodies. Treatment was initially focused on immunomodulation and targeted CTLA-4 replacement therapy. Because of the persistent fluctuating cerebellar and neuropsychiatric symptoms and the potential clinical significance of the AMPAR antibodies, treatment was intensified with repetition of first-line immunomodulation and rituximab. This combined therapy resulted in sustained clinical improvement and served as a bridge to curative hematopoietic stem cell transplantation. DISCUSSION: This case illustrates the rare early onset of autoimmune encephalitis and presence of AMPAR antibodies in CTLA-4h. Targeted CTLA-4 replacement therapy resulted in a partial response. However, awaiting its optimal therapeutic effect, refractory CNS symptoms required intensification of immunomodulation. The identification of AMPAR antibodies guided our treatment decisions. CLASSIFICATION OF EVIDENCE: This provides Class IV evidence. It is a single observational study without controls.</p

Management of Autoimmune Encephalitis in a 7-Year-Old Child With CTLA-4 Haploinsufficiency and AMPA Receptor Antibodies:A Case Report

OBJECTIVES: We report on the therapeutic management of early-onset severe neurologic symptoms in cytotoxic T lymphocyte antigen-4 haploinsufficiency (CTLA-4h) and the presence of antibodies to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) as an important finding. METHODS: This is a case report from a Dutch academic hospital. Repeated clinical examinations, repeated brain MRI and extended diagnostics on serum and CSF were performed. We used the CARE checklist. RESULTS: A 7-year-old boy was diagnosed with CTLA-4h based on family screening. On diagnosis, he had mild chronic diarrhea and autism spectrum disorder, but no abnormalities in extensive laboratory screening. Six months later, he presented with sudden-onset autoimmune encephalitis. Repeated brain MRI revealed no abnormalities, but immunohistochemistry analysis on serum and CSF showed the presence of AMPAR antibodies. Treatment was initially focused on immunomodulation and targeted CTLA-4 replacement therapy. Because of the persistent fluctuating cerebellar and neuropsychiatric symptoms and the potential clinical significance of the AMPAR antibodies, treatment was intensified with repetition of first-line immunomodulation and rituximab. This combined therapy resulted in sustained clinical improvement and served as a bridge to curative hematopoietic stem cell transplantation. DISCUSSION: This case illustrates the rare early onset of autoimmune encephalitis and presence of AMPAR antibodies in CTLA-4h. Targeted CTLA-4 replacement therapy resulted in a partial response. However, awaiting its optimal therapeutic effect, refractory CNS symptoms required intensification of immunomodulation. The identification of AMPAR antibodies guided our treatment decisions. CLASSIFICATION OF EVIDENCE: This provides Class IV evidence. It is a single observational study without controls.</p

Local immune regulation of mucosal inflammation by tacrolimus

Purpose: Tacrolimus is a potent immunomodulator that is effective in the treatment of inflammatory bowel disease (IBD). However, potential toxicity and systemic effects with oral intake limit its use. Local tacrolimus treatment is effective in a subgrou

Faecalibacterium prausnitzii A2-165 has a high capacity to induce IL-10 in human and murine dendritic cells and modulates T cell responses

Acknowledgements This work was financially supported by the EC FP7 Cross-talk project (PITN-GA-2008-215553). The authors thank the Histology Platform from GABI research unit and especially Abdelhak Boukadiri for their technical support in the histology sample preparation and Marlène Héry, Charline Pontlevoy, Jerome Pottier and André Tiffoche (UE0907 IERP, Jouy en Josas) for their help during animal experiments. The authors thank Rafael Muñoz-Tamayo (INRA) for his help in performing the PCA.Peer reviewedPublisher PD

Proteomic analyses do not reveal subclinical inflammation in fatigued patients with quiescent Inflammatory Bowel Disease

BackgroundFatigue is a common and clinically challenging symptom in patients with inflammatory bowel diseases (IBD). While fatigue occurs most often in patients with active disease, up to 50% of patients with quiescent disease still report significant fatigue of unknown aetiology. Here, we aimed to investigate whether fatigue in patients with quiescent IBD is reflected by circulating inflammatory proteins, that in turn might reflect ongoing subclinical inflammation.MethodsNinety-two (92) different inflammation-related proteins were measured in plasma of 350 patients with quiescent IBD (188 Crohn’s disease [CD]; 162 ulcerative colitis [UC]). Quiescent IBD was defined as clinical (Harvey-Bradshaw Index [HBI] &lt;5 or Simple Clinical Colitis Activity Index [SCCAI] &lt;2.5) and biochemical remission (C-reactive protein [CRP] &lt;5 mg/L) at time of sampling. Fatigue severity was assessed on a visual analogue scale (VAS).ResultsNone of the analysed plasma proteins were differentially abundant between mildly (1st quartile, Q1) or severely (4th quartile, Q4) fatigued patients under a false discovery rate of 10%. Considering nominal significance (P&lt;0.05), however, leukemia inhibitory factor receptor (LIF-R) concentrations were inversely associated with severe fatigue, also after adjustment for confounding factors (P &lt;0.05) (Figure 1). Although solely LIF-R showed weak ability to discriminate between mild (Q1) and severe (Q4) fatigue (area under the curve [AUC]=0.61, 95% CI: 0.53–0.69, P&lt;0.05), a combined set of the top seven (7) fatigue-associated proteins (LIF-R, vascular endothelial growth factor-A [VEGF-A], glial-derived neurotrophic factor [GDNF], interleukin-20 receptor subunit alpha [IL-20RA], Delta and Notch-like epidermal growth factor-related receptor [DNER], T-cell surface glycoprotein CD5 [CD5], and extracellular newly identified receptor for advanced glycation end-products binding protein [EN-RAGE], also known as protein S100-A12, all P&lt;0.10) was observed to have reasonable discriminative performance (AUC=0.82 [95% CI: 0.74–0.91], P&lt;0.01).ConclusionFatigue in patients with IBD is not clearly reflected by distinct circulating inflammatory protein signatures, which suggests that subclinical immune activation as defined by the studied panel of inflammatory proteins could not be detected. Reduced shedding of the LIF-R protein could be related to fatigue in IBD through modification of the oncostatin-M (OSM) signaling pathway, or through induction of pro-inflammatory phenotypes of T-cells, macrophages, or neural cells. Future studies are warranted to investigate other proteomic or metabolic markers that may accurately reflect fatigue in quiescent IBD, which might represent alternative pathophysiological pathways

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) &lt; 0.05). Conversely, a Mediterranean-style pattern was associated with higher FGF-19 levels (FDR &lt; 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 &lt; 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

Sialylation of campylobacter jejuni lipo-oligosaccharides: impact on phagocytosis and cytokine production in mice

&lt;p&gt;Background: Guillain-Barré syndrome (GBS) is a post-infectious polyradiculoneuropathy, frequently associated with antecedent Campylobacter jejuni (C. jejuni) infection. The presence of sialic acid on C. jejuni lipo-oligosaccharide (LOS) is considered a risk factor for development of GBS as it crucially determines the structural homology between LOS and gangliosides, explaining the induction of cross-reactive neurotoxic antibodies. Sialylated C. jejuni are recognised by TLR4 and sialoadhesin; however, the functional implications of these interactions in vivo are unknown.&lt;/p&gt; &lt;p&gt;Methodology/Principal Findings: In this study we investigated the effects of bacterial sialylation on phagocytosis and cytokine secretion by mouse myeloid cells in vitro and in vivo. Using fluorescently labelled GM1a/GD1a ganglioside-mimicking C. jejuni strains and corresponding (Cst-II-mutant) control strains lacking sialic acid, we show that sialylated C. jejuni was more efficiently phagocytosed in vitro by BM-MΦ, but not by BM-DC. In addition, LOS sialylation increased the production of IL-10, IL-6 and IFN-β by both BM-MΦ and BM-DC. Subsequent in vivo experiments revealed that sialylation augmented the deposition of fluorescent bacteria in splenic DC, but not macrophages. In addition, sialylation significantly amplified the production of type I interferons, which was independent of pDC.&lt;/p&gt; &lt;p&gt;Conclusions/Significance: These results identify novel immune stimulatory effects of C. jejuni sialylation, which may be important in inducing cross-reactive humoral responses that cause GBS&lt;/p&gt