Neutrophil-to-lymphocyte ratio (NLR) is a novel biomarker studied in several autoimmune diseases including inflammatory bowel disease (IBD) in adults but poorly characterized in pediatric IBD (pIBD). We aimed to primarily investigate the relationship between NLR and pIBD endoscopic disease severity. We also examined whether NLR predicted hospitalization, surgery, and therapy response by 52 weeks.

We used the Canadian Children IBD Network prospective inception cohort including patients < 18 years old with baseline data from 2013 to 2022. We excluded patients with concurrent diseases affecting NLR. Both Mayo endoscopic score (MES) and simple endoscopic scale for Crohn's disease (SES-CD) were dichotomized as low activity (quiescent-mild) and high activity (moderate-severe). For therapy responses, we examined year-1 steroid- and biologic-free remission. We used logistic regression for binary outcomes.

A total of 580 patients with ulcerative colitis and 1,081 patients with CD were included. High NLR was associated with high-activity MES and SES-CD in both univariate and multivariable analyses (odds ratio = 1.45, 95% CI = 1.07-1.97, P value = 0.016; and odds ratio = 1.42, 95% CI = 1.04-1.94, P value = 0.026, respectively). We also calculated the best NLR cutoff point to predict MES (1.90, sensitivity = 68%, specificity = 67%, area under the curve [AUC] = 0.67, AUC 95% CI = 0.59-0.74) and SES-CD (2.50, sensitivity = 63%, specificity = 69%, AUC = 0.66, AUC 95% CI = 0.59-0.75) high activity. NLR did not predict therapy response in either ulcerative colitis or CD.

Patients with pIBD with high baseline NLR are more probable to have worse endoscopic disease at diagnosis. This highlights NLR potential as a reliable noninvasive biomarker of disease activity. The predictive power of NLR is based mostly on neutrophils and the balance between neutrophils and lymphocytes.

The aim of this study was to identify, using proteomics, the molecular alterations caused by human serum exposure to Klebsiella pneumoniae ACH2. The analysis was performed under two different conditions, native serum from healthy donors and heat-inactivated serum (to inactivate the complement system), and at two different times, after 1 and 4 h of serum exposure. More than 1,000 bacterial proteins were identified at each time point. Enterobactin, a siderophore involved in iron uptake, and proteins involved in translation were upregulated at 1 h, while the chaperone ProQ and the glyoxylate cycle were identified after 4 h. Enzymes involved in the stress response were downregulated, and the SOD activity was validated using an enzymatic assay. In addition, an intricate metabolic adaptation was observed, with pyruvate and thiamine possibly involved in survival and virulence in the first hour of serum exposure. The addition of exogenous thiamine contributes to bacterial growth in human serum, corroborating this result. During 4 h of serum exposure, the glyoxylate cycle (GC) probably plays a central role, and the addition of exogenous succinate suppresses the GC, inducing a decrease in serum resistance. Therefore, serum exposure causes important changes in iron acquisition, the expression of virulence factors, and metabolic reprogramming, which could contribute to bacterial serum resistance.

The human gut microbiota, consisting of trillions of microorganisms, encodes diverse metabolic pathways that impact numerous aspects of host physiology. One key way in which gut bacteria interact with the host is through the production of small metabolites. Several of these microbiota-dependent metabolites, such as short-chain fatty acids, have been shown to modulate host diseases. In this review, we examine how disease-associated metabolic signatures are identified using metabolomic platforms, and where metabolomics is applied in gut microbiota-disease interactions. We further explore how integration of metagenomic and metabolomic data in human studies can facilitate biomarkers discoveries in precision medicine.

Despite numerous metabolomic studies on ulcerative colitis (UC), the results have been highly variable, making it challenging to identify key metabolic abnormalities in UC.

This study aims to uncover key metabolites and metabolic pathways in UC by analyzing existing metabolomics data.

A systematic review.

We conducted a comprehensive search in databases (PubMed, Cochrane Library, Embase, and Web of Science) and relevant study references for metabolomic research on UC up to 28 December 2022. Significant metabolite differences between UC patients and controls were identified, followed by an analysis of relevant metabolic pathways.

This review incorporated 78 studies, identifying 2868 differentially expressed metabolites between UC patients and controls. The metabolites were predominantly from 'lipids and lipid-like molecules' and 'organic acids and derivatives' superclasses. We found 101 metabolites consistently altered in multiple datasets within the same sample type and 78 metabolites common across different sample types. Of these, 62 metabolites exhibited consistent regulatory trends across various datasets or sample types. Pathway analysis revealed 22 significantly altered metabolic pathways, with 6 pathways being recurrently enriched across different sample types.

This study elucidates key metabolic characteristics in UC, offering insights into molecular mechanisms and biomarker discovery for the disease. Future research could focus on validating these findings and exploring their clinical applications.

Sphingosine-1-phosphate (S1P), a type of bioactive sphingolipid, can regulate various cellular functions of distinct cell types in the human body. S1P is generated intracellularly by the catalysis of sphingosine kinase 1/2 (SphK1/2). S1P is transferred to the extracellular environment via the S1P transporter, binds to cellular S1P receptors (S1PRs) and subsequently activates S1P-S1PR downstream signaling. Dysbiosis of the intestinal microbiota, immune dysregulation and damage to epithelial barriers are associated with inflammatory bowel disease (IBD). Generally, S1P mainly exerts a proinflammatory effect by binding to S1PR1 on lymphocytes to facilitate lymphocyte migration to inflamed tissues, and increased S1P was found in the intestinal mucosa of IBD patients. Notably, there is an interaction between the distribution of gut bacteria and SphK-S1P signaling in the intestinal epithelium. S1P-S1PR signaling can also regulate the functions of intestinal epithelial cells (IECs) in mucosa, including cell proliferation and apoptosis. Additionally, increased S1P in immune cells of the lamina propria aggravates the inflammatory response by increasing the production of proinflammatory cytokines. Several novel drugs targeted at S1PRs have recently been used for IBD treatment. This review provides an overview of the S1P-S1PR signaling pathway and, in particular, summarizes the various roles of S1P in the gut mucosal microenvironment to deeply explore the function of S1P-S1PR signaling during intestinal inflammation and, more importantly, to identify potential therapeutic targets for IBD in the SphK-S1P-S1PR axis.

Necrotizing enterocolitis (NEC) is the most prevalent gastrointestinal disorder that predominantly threatens preterm newborns. Succinate is an emerging metabolic signaling molecule that was recently studied in relation to the regulation of intestinal immunity and homeostasis. We aimed to investigate the relationship between NEC and gut luminal succinate and preliminarily explored the effect of succinate on NEC pathogenesis.

Fecal samples from human neonates and mouse pups were analyzed by HPLC - MS/MS and 16S rRNA gene sequencing. C57BL/6 mice were randomly divided into four groups: control, NEC, Lsuc, and Hsuc. The mortality, weight gain, and intestinal pathological changes in four mouse groups were observed. Inflammatory cytokines and markers of macrophages were identified by quantitative real-time PCR. Succinate receptor 1 (SUCNR1) localization was visualized by immunohistochemistry. The protein levels of SUCNR1 and hypoxia-inducible factor 1a (HIF-1a) were quantified by western blotting.

The levels of succinate in feces from NEC patients were higher than those in feces from non-NEC patients (P <0.05). In the murine models, succinate levels in intestinal content samples were also higher in the NEC group than in the control group (P <0.05). The change in succinate level was closely related to intestinal flora composition. In samples from human neonates, relative to the control group, the NEC group showed a higher abundance of Enterobacteriaceae and a lower abundance of Lactobacillaceae and Lactobacillus (P <0.05). In the murine models, relative to the control group, increased abundance was observed for Clostridiaceae, Enterococcaceae, Clostridium_sensu_stricto_1, and Enterococcus, whereas decreased abundance was observed for Lactobacillaceae and Lactobacillus (P <0.05). Increased succinate levels prevented mice from gaining weight, damaged their intestines, and increased their mortality; upregulated the gene expression of interleukin-1β (IL-1β), IL-6, IL-18 and tumor necrosis factor (TNF); and downregulated the gene expression of IL-10 and transforming growth factor (TGF)-β. Exogenous succinic acid increased inducible nitric oxide synthase (iNOS) gene expression but decreased Arginase-1 (Arg1) gene expression; and increased the protein expression of SUCNR1 and HIF-1a.

Succinate plays an important role in the development of necrotizing enterocolitis severity, and the activation of the HIF-1a signaling pathway may lead to disease progression.

Gut microbiota imbalances play an important role in inflammatory bowel disease (IBD), but no single pathogenic microorganism critical to IBD that is specific to the IBD terminal ileum mucosa or can invade intestinal epithelial cells has been found. Invasive Escherichia coli (E. coli) adhesion to macrophages is considered to be closely related to the pathogenesis of inflammatory bowel disease. Further study of the specific biological characteristics of adherent invasive E. coli (AIEC) may contribute to a further understanding of IBD pathogenesis. This review explores the relationship between AIEC and the intestinal immune system, discusses the prevalence and relevance of AIEC in Crohn's disease and ulcerative colitis patients, and describes the relationship between AIEC and the disease site, activity, and postoperative recurrence. Finally, we highlight potential therapeutic strategies to attenuate AIEC colonization in the intestinal mucosa, including the use of phage therapy, antibiotics, and anti-adhesion molecules. These strategies may open up new avenues for the prevention and treatment of IBD in the future.

The Crohn's disease (CD) exclusion diet (CDED) plus partial enteral nutrition (PEN) and exclusive enteral nutrition (EEN) both induce remission in pediatric CD. CDED+PEN is better tolerated and able to sustain remission. We characterized the changes in fecal metabolites induced by CDED+PEN and EEN and their relationship with remission.

A total of 216 fecal metabolites were measured in 80 fecal samples at week (W) 0, W6, and W12, of children with mild to moderate CD in a prospective randomized trial comparing CDED+PEN vs EEN. The metabolites were measured using liquid chromatography coupled to mass spectrometry. Metagenome Kyoto Encyclopedia of Genes and Genomes Orthology analysis was performed to investigate the differential functional gene abundance involved in specific metabolic pathways. Data were analyzed according to clinical outcome of remission (W6_rem), no remission (W6_nr), sustained remission (W12_sr), and nonsustained (W12_nsr) remission.

A decrease in kynurenine and succinate synthesis and an increase in N-α-acetyl-arginine characterized CDED+PEN W6_rem, whereas changes in lipid metabolism characterized EEN W6_rem, especially reflected by lower levels in ceramides. In contrast, fecal metabolites in EEN W6_nr were comparable to baseline/W0 samples. CDED+PEN W6_rem children maintained metabolome changes through W12. In contrast, W12_nsr children in the EEN group, who resumed a free diet after week 6, did not. The metabolome of CDED+PEN differed from EEN in the purine, pyrimidine, and sphingolipid pathways. A significant differential abundance in several genes involved in these pathways was detected.

CDED+PEN- and EEN-induced remission are associated with significant changes in inflammatory bowel disease-associated metabolites such as kynurenine, ceramides, amino acids, and others. Sustained remission with CDED+PEN, but not EEN, was associated with persistent changes in metabolites.

gov, Number NCT01728870.

As the microbiome plays an important role in instigating inflammation in ulcerative colitis (UC), strategies targeting the microbiome may offer an alternative therapeutic approach. The goal of the pilot trial was to evaluate the potential efficacy and feasibility of a novel UC exclusion diet (UCED) for clinical remission, as well as the potential of sequential antibiotics for diet-refractory patients to achieve remission without steroids.

This was a prospective, single-arm, multicenter, open-label pilot study in patients aged 8-19, with pediatric UC activity index (PUCAI) scores >10 on stable maintenance therapy. Patients failing to enter remission (PUCAI < 10) on the diet could receive a 14-day course of amoxycillin, metronidazole and doxycycline (AMD), and were re-assessed on day 21. The primary endpoint was intention-to-treat (ITT) remission at week 6, with UCED as the only intervention.

Twenty-four UCED treatment courses were given to 23 eligible children (mean age: 15.3 ± 2.9 years). The median PUCAI decreased from 35 (30-40) at baseline to 12.5 (5-30) at week 6 (p = 0.001). Clinical remission with UCED alone was achieved in 9/24 (37.5%). The median fecal calprotectin declined from 818 (630.0-1880.0) μg/g at baseline to 592.0 (140.7-1555.0) μg/g at week 6 (p > 0.05). Eight patients received treatment with antibiotics after failing on the diet; 4/8 (50.0%) subsequently entered remission 3 weeks later.

The UCED appears to be effective and feasible for the induction of remission in children with mild to moderate UC. The sequential use of UCED followed by antibiotic therapy needs to be evaluated as a microbiome-targeted, steroid-sparing strategy.

The gut metabolite composition determined by the microbiota has paramount impact on gastrointestinal physiology. However, the role that bacterial metabolites play in communicating with host cells during inflammatory diseases is poorly understood. Here, we aim to identify the microbiota-determined output of the pro-inflammatory metabolite, succinate, and to elucidate the pathways that control transepithelial succinate absorption and subsequent succinate delivery to macrophages. We show a significant increase of succinate uptake into pro-inflammatory macrophages, which is controlled by Na+-dependent succinate transporters in macrophages and epithelial cells. Furthermore, we find that fecal and serum succinate concentrations were markedly augmented in inflammatory bowel diseases (IBDs) and corresponded to changes in succinate-metabolizing gut bacteria. Together, our results describe a succinate production and transport pathway that controls the absorption of succinate generated by distinct gut bacteria and its delivery into macrophages. In IBD, this mechanism fails to protect against the succinate surge, which may result in chronic inflammation.