Demonstrating pharmacological effects in early-phase oncology clinical trials remains challenging, largely due to the lack of robust pharmacodynamic markers. Lipopolysaccharide (LPS) is used as an immune challenge agent in healthy participants to study drugs for autoimmune conditions. We hypothesized that the intravenous LPS challenge model could be implemented in oncology drug studies in healthy participants to evaluate in vivo pharmacodynamics of new drugs. This open-label study included 13 healthy males who received a single intravenous dose of 1 or 2 ng/kg LPS. Blood and bone marrow samples were collected pre- and post-LPS for bulk RNA sequencing, multiplex cytokine measurements, immunophenotyping, and immunohistochemistry of bone marrow biopsies. Differentially expressed genes were integrated with the OpenTargets Platform and the COSMIC database to assess their tractability and relation to cancer hallmarks. The LPS challenge and bone marrow sampling were safe and well tolerated. In peripheral blood, LPS induced a rapid, transient inflammatory response, with myeloid cell activation and enrichment of inflammation-related pathways. Conversely, bone marrow showed an attenuated cellular response and activation of hematopoietic and cell cycle-related transcriptional programs. We identified 91 LPS-induced oncology-relevant targets in blood and 24 targets in bone marrow. The oncogenic transcription factor MYC was upregulated in the bone marrow, which was confirmed at the protein level by a dose-dependent increase in c-Myc expression. Our findings highlight the potential of immune challenges in healthy participants to pharmacodynamically profile novel oncology agents, with the aim of generating early pharmacological data ahead of pivotal clinical trials in cancer patients.

Background: Prenatal and perinatal stress activates the maternal and fetal HPA axis, releasing biomarkers that can cross the placenta. In high concentrations, these substances may lead to congenital malformations, preterm labor, or intrauterine growth restriction (IUGR). Despite their potential, endogenous biomarkers are not yet part of standard gynecological diagnostics. Aim: This paper analyzes recent reports on hormonal and non-hormonal perinatal stress biomarkers to evaluate their application in assessing health risks for mothers and fetuses. Material and Methods: This literature review examines clinical trials and observational studies from the late 20th and early 21st centuries. It focuses on laboratory techniques such as ELI-SA, HPLC, and radioimmunoassay used to measure stress markers in maternal serum, cord blood, amniotic fluid, and urine. Results: Studies show that copeptin levels rise significantly during fetal hypoxia and IUGR, aiding ultrasonographic differentiation. Maternal cortisol levels correlate negatively with birth weight and increase the risk of infants being small for gestational age (SGA). ACTH and CRH serve as indicators of HPA axis maturity and predictors of preterm birth. Regarding non-hormonal markers, malondialdehyde and 8-isoprostane are sensitive indicators of oxidative stress linked to preeclampsia. Furthermore, elevated proinflammatory cytokines (IL-1, IL-6, IL-8, TNF-alpha) are closely associated with intrauterine infections and the onset of preterm labor. Conclusions: Perinatal stress biomarkers offer significant prognostic value for identifying risks of preterm labor and developmental pathologies. While cortisol currently has the greatest clinical utility, copeptin and malondialdehyde are noted for their stability and potential for routine screening. Further clinical trials are necessary to integrate these markers into standard obstetric care.

Maternal nutrition during late gestation is critical for fetal development, neonatal resilience, and postnatal adaptation in beef cattle. This study aimed to evaluate the effects of nutritional restriction and supplementation of hydroxytyrosol (HT) in late pregnancy on behavioural, circadian, stress-related, and inflammatory responses in cows and their restricted nursed offspring. Pregnant cows were allocated to a 2 × 2 factorial experimental design (feeding level: T100% vs. T60% of nutrient requirements; HT: 0 vs. 180 mg/kg of diet). Cow behaviours were recorded during meals (from week −12 prepartum to term), and calf activities, body temperature, and mother–offspring interactions were assessed at 5 weeks postpartum. Nutritional restriction accelerated feed intake in cows and increased stress-related behaviours, while HT partially mitigated these effects. Molecular analyses in blood samples revealed dynamic prepartum upregulation of glucocorticoid-receptor NR3C1 in week −6, and downregulation of circadian (BMAL1, PER1, CRY1) gene expression in week 5 after parturition, both in T60%-HT cows. In calves, maternal HT supplementation promoted active exploratory behaviour, and counteracted behavioural and circadian (CRY1 and PER1) and inflammatory markers (IL8) gene expression resulting from prenatal nutrient restriction, leading to behavioural profiles and blood gene expression comparable to those observed in calves born to adequately fed dams.

Diagnosing liver cirrhosis in patients with chronic hepatitis B (CHB) remains challenging due to the infrequent use of biopsy. In low-and-middle-income countries, access to transient elastography (TE), a recommended noninvasive imaging modality for cirrhosis assessment, is limited. It is against this backdrop that we investigated the diagnostic performance of several low-cost and readily accessible blood-based liver fibrosis markers among patients with CHB infection in Zambia. We performed a hospital-based cross-sectional study in Lusaka, Zambia, among consecutive treatment naive adults presenting at the university teaching hospital with CHB mono-infection (i.e., human immunodeficiency virus-negative). The reference test for cirrhosis was TE of ≥9.6 kilopascals. Low-cost markers were the aspartate transaminase-to-platelet ratio index (APRI) at the recommended threshold >2, as well as lower proposed alternative thresholds for Africa, >0.5 and >0.65, aspartate transaminase/alanine transferase ratio, and fibrosis 4 index (FIB-4 index) >3.25. We evaluated the performance of each marker versus TE. In a secondary analysis, we evaluated marker performance in participants with current alcohol use versus lifetime abstinence. A total of 239 adults with HBV mono-infection were included in this analysis. The mean age was 34.7 years. About 22.2% (n = 53) reported current alcohol use. The prevalence of cirrhosis by TE was 16.3% (95% confidence interval: 11.87–21.63). The area under the receiver operating characteristic curve was 0.83, 0.80, 0.79 and 0.73 for FIB-4, APRI >0.5, APRI >0.65, and APRI >2, respectively. Virtually all indices performed less well in people with current alcohol use. These findings suggest the use of a lower APRI threshold in African settings and the use of the FIB-4 index for diagnosing cirrhosis among patients with CHB. The currently recommended APRI threshold may fail to identify some individuals with cirrhosis who would benefit from antiviral treatment. Clinicians using these markers should routinely screen for alcohol use and consider reevaluating cirrhosis status following reductions in alcohol consumption.

Peripheral metabolic profiles in spinocerebellar ataxia type 3: Features and genotype-phenotype links.

Maternal dietary total antioxidant and oxygen radical absorption capacities and cord blood oxidative-inflammatory response in late-onset fetal growth restriction.

The purpose of this study is to determine the effects of 4-weeks dietary calorie restriction alone (CR) compared to CR with aerobic exercise (CR+E) on systemic inflammation and index knee pain in overweight and obese individuals with knee osteoarthritis (OA). Twenty-three individuals with knee OA completed a randomised controlled trial. Participants in the CR group (n=9, BMI: 30.0±2.4kg/m2, 56±5 years) were asked to reduce their habitual energy intake by 5000kcal/week for 4 weeks, and those randomised to the CR+E group (n=14, BMI: 32.3±4.8kg/m2, 57±5 years) were asked to follow the same dietary CR and perform five, 30-min bouts of moderate intensity cycling per week. Blood markers of inflammation, body composition, function, and pain were compared after a 4-week intervention period by ANCOVA, using pre-intervention value as a covariate. There was no difference in CRP between groups at post-intervention (p=0.517, d=0.31). IL-6 was lower (p<0.01; d=1.69) at post-intervention in the CR+E group (1.36mg/dL, 0.72 to 2.00) compared to CR group (2.98mg/dL, 2.22-3.73). Visual analogue scale (VAS) knee pain was lower (p<0.01; d=1.29) at post-intervention in the CR+E group (2, 1-3) compared to the CR group (4, 3-5). The time to complete the stair climb test was lower at post-intervention in the CR+E group compared to the CR group (p=0.016, d=1.17). Four weeks of moderate-intensity aerobic exercise training combined with CR led to a greater reduction in IL-6, but not CRP, compared to CR alone. The addition of exercise to CR led to greater reduction in knee pain compared to CR alone. ClinicalTrials.gov (ID: NCT05518890).

Vitamin K2 supplementation has emerged as a strategy to enhance recovery and modulate postexercise physiological responses. This study aimed to assess the effects of vitamin K2 on recovery from muscle-damaging exercise in young and older adults. Healthy young (18-40 yr) and older (65+ yr) adults were randomly assigned to either vitamin K2 (menaquinone-7, MK-7, 240 μg/d) or placebo (cellulose) for 12 wk in this double-blind randomized controlled trial. Before and after supplementation, knee extensor maximal torque, functional ability, muscle soreness, and systemic blood markers of muscle damage and inflammation were measured before (0 h) and 3, 24, 48, and 72-h postexercise. Data were analyzed using regression and mixed models. Seventy-one participants (35 young and 36 older) completed the study, with 12 wk of vitamin K2 supplementation increasing circulating MK-7 levels (P-value <0.001). There were no supplement × time effects for any variables. Significant supplement × time × older age interaction effects were noted for electromechanical delay (EMD) (P-value = 0.03), electromyography root mean square (RMS) (P-value = 0.01), interleukin-6 (IL-6) concentrations (P-value <0.001), and creatine kinase (CK) levels (P-value = 0.02). In older adults, after 12 wk, EMD appeared lower at all time points and RMS higher postexercise in the vitamin K2 group. No clear pattern in IL-6 or CK was observed, but at 72-h postexercise CK was lower in older adults in the vitamin K2 group. Vitamin K2 supplementation had no effect on muscle strength, physical function, muscle soreness, or inflammatory responses in the recovery period after a bout of resistance exercise. Effects of supplementation were observed on EMD, RMS, IL-6, and CK by age and warrant further investigation.

Strength training (ST) is commonly implemented to enhance soccer-related fitness qualities such as sprinting, jumping, and changes-of-direction while also contributing to injury risk reduction. It is traditionally emphasized in the pre-season period. In-season ST may confer these benefits, but it can also induce muscle damage and inflammation. To examine the effects of a 12-week in-season ST program on maximal dynamic strength, muscle damage biomarkers, and inflammatory biomarkers, 24 elite young female soccer players (Tier 4 according to the McKay et al. classification) aged 14.9 ± 0.8 years and a maturity offset of +2.6 ± 1.1 years were randomly allocated to an ST group (STG, n = 12) or an active control group (CG, n = 12). Both groups followed the same soccer training program. However, in the STG, two weekly soccer sessions were replaced with ST. Overall training volume was comparable between groups. Maximal dynamic strength (1-RM tests for bench press, lat pull-down, and leg press), blood biomarkers of muscle damage (creatine phosphokinase [CPK], lactate dehydrogenase [LDH]), and inflammation (interleukin-6 [IL-6], tumor necrosis factor-α [TNF-α]) were assessed before (T1) and after (T2) the interventions. Analyses showed significant increases for STG for the 1-RM bench press, the 1-RM lat pull-down, and the 1-RM leg press (p < 0.001). No significant interactions were detected for any blood marker of muscle damage (LDH and CPK) or inflammation (IL-6 and TNF-α) (all p > 0.05). Results support a 12-week in-season ST program improved maximal dynamic strength in elite young female soccer players without altering resting levels of muscle damage or inflammatory markers measured 48 h after training compared to regular soccer training. These findings suggest that ST can be safely implemented during the competitive season in young female soccer players without overreaching or overtraining.

Prolonged bed rest and immobilization have deleterious effects on skeletal muscle mass and function, especially in older adults. These can lead to reduced physical capacity and quality of life. Previous experiments in younger individuals show that exercise can mitigate these effects, but evidence remains scarce and inconclusive in older adults. Therefore, the aim of this study was to evaluate the effects of a mixed-exercise countermeasure on body composition, muscle volume, strength and quality in healthy, ageing adults during 2 weeks of head-down tilt bed rest and in the subsequent recovery period, and to explore the underlying mechanisms. Twenty-two participants (11male and 11female) aged 55-65 years completed the head-down tilt bed rest protocol. Participants were randomly assigned to either an exercise group (n=11) undertaking three daily exercise sessions or a passive-mobilization control group (n=11). Assessments of body composition, thigh muscle volume, muscle strength, blood markers and muscle biopsies were performed before, during and after bed rest, and after 4weeks and 4 months of recovery. Bed rest induced significant declines in total and lower-limb lean body mass, knee-extensor strength and muscle quality. The mixed-exercise intervention mitigated the loss of thigh muscle volume but did not prevent reductions in total or lower-limb lean mass, strength or muscle quality. All participants had recovered fully after 4weeks of recovery. In conclusion, daily participation in an exercise countermeasure preserves thigh muscle volume during 2 weeks of bed rest in healthy older adults but is insufficient to mitigate muscle strength and total lean mass.

The cortical cataract is the primary type of age-related cataract and can cause severe vision impairment in the early stage. To explore potential blood markers associated with individual physical conditions in cataract patients, we performed RNA sequencing to compare the differentially expressed genes (DEGs) between cortical and refractive cataract patients. Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and gene set enrichment analysis (GSEA) were conducted. ELISA was subsequently used to validate differences in the protein expression levels of the selected genes. A total of 311 upregulated and 268 downregulated genes were identified. After bioinformatics analysis, we identified three key DEGs (MPO, CXCL8, and FN1) and determined their possible molecular mechanisms. As determined by ELISA, the expression of these genes increased; among them, MPO was the most significant DEG, and it related to oxidative stress responses through peroxidase activity and the catabolism of hydrogen peroxide. In conclusion, MPO, CXCL8 and FN1 were regarded as potential blood markers in patients. However, owing to the small sample size, the above conclusions are hypothetical.

This study investigated the effects of a topical cannabidiol (CBD) gel compared to placebo on muscle function recovery, perceived muscle soreness, and blood marker of muscle damage following strenuous exercise designed to induce muscle damage. Fifteen physically active students (age: 21.4 ± 2.1 years; mass: 78.0 ± 9.5 kg; height: 181.7 ± 5.0 cm) participated in the study. To induce muscle damage, participants completed 10 sets of 10 drop jumps from a 0.6 m box, with 2 min of rest between sets. In a randomized crossover design, 2 g of either CBD gel or placebo gel were applied to the quadriceps and hamstrings immediately after exercise and over the following 72 h. Muscle function recovery was assessed by measuring isometric and concentric isokinetic peak torque of the knee extensors, plasma myoglobin (Myo) concentration, and Delayed Onset Muscle Soreness (DOMS), evaluated using a visual analogue scale (VAS) at baseline, immediately post-exercise, and at 24-, 48-, and 72-h intervals. The two-way ANOVA revealed no significant interaction between time and condition for concentric isokinetic peak torque (p > 0.05). No significant differences were observed between the CBD and placebo conditions for plasma Myo concentrations or DOMS scores. A significant interaction was observed for isometric torque (p = 0.02), with moderate effect sizes favoring CBD over placebo from 24 to 72 h post-exercise (ES = 0.85–1.0). The topical application of CBD gel does not appear to accelerate the recovery of muscle function or to reduce DOMS following muscle-damaging exercise. B200-2020–120.

Dengue virus (DENV) is a major burden to global public health, affecting hundreds of millions annually. Children represent the major proportion of global dengue cases, ranging from asymptomatic or subclinical presentation to dengue fever (DF) and severe dengue hemorrhagic fever or shock syndrome (DHF/DSS). The factors that distinguish this range of disease severity are still poorly understood. To identify biomarkers of severity, we analyzed the plasma proteome of acute DENV infected children including both subclinical and hospitalized cases. Proteins associated with the acute-phase response, innate immune and lysosomal activation, and components of the coagulation cascade showed marked differences between hospitalized and subclinical cases during early infection. Longitudinal profiling demonstrated that endothelial dysfunction emerges early, withPTX3showing the strongest and most rapid upregulation in hospitalized patients, supporting its potential role as a marker of imminent vascular involvement. When comparing severe (DHF/DSS) and classical DF hospitalized cases,CLEC11Adisplayed the highest fold change at hospital admittance. We used machine-learning analysis to predict disease severity at the acute phase of infection, distinguishing subclinical from hospitalized cases and patients that develop classical dengue fever or severe disease based on the identified complement regulators and inflammatory markers. The panel of identified plasma proteins shed light on the mechanisms of dengue related disease progression and may provide a handle to predict disease severity based on blood markers present during the acute phase of infection.

Trabecular bone score and bone metabolism markers in middle-aged and older female patients with distal radius fractures.

BackgroundThe prognostic evaluation of advanced CRC patients places increased importance on longitudinal peripheral blood immune status. This study aimed to identify prognosis associated longitudinal immune markers and construct dynamic prognostic models for advanced CRC patients with first-line chemotherapy.MethodsMetastatic CRC patients treated with standard first-line palliative chemotherapy were retrospectively collected at Shanghai General Hospital from May 2013 to May 2020. Lymphocyte subsets, inflammatory indices, and tumor markers in peripheral blood were repeatedly assessed before each chemotherapy cycle. Joint models were used to identify significant longitudinal prognostic markers. A dynamic prognostic model was established using random forests for time-dependent predictors, and internally validated using tenfold cross-validation.ResultsIncreased levels of CRP, CEA, CA199, and IL-6, as well as the CD4 + CD29 + cell proportion and the CD4 + CD45RO + /CD4 + ratio were identified as significant risk factors for overall survival (OS) in metastatic CRC patients. Conversely, the increased levels of CD3-CD19 + cell proportion and the CD4 + CD45RA + /CD4 + ratio were identified as favorable factors for OS. A dynamic prognostic model demonstrated good discriminative ability, with AUC values of 0.827, 0.787, 0.726, and 0.693 for 2-, 3-, 4-, and 5-year predictions, respectively. A high ratio of CD4 + CD45RA + /CD4 + before the third to fourth chemotherapy cycle was associated with significantly better OS. Normal CRP and IL-6 levels in the early phase of first-line chemotherapy indicated a good prognosis.ConclusionThis study highlights the prognostic significance of measuring longitudinal immune status in advanced CRC patients and develops an internally validated dynamic prediction model. External validation is needed before clinical implementation.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00262-025-04295-7.

Critical limb ischaemia (CLI), a severe peripheral artery disease, reduces blood flow, disrupting lipid metabolism and mitochondrial function. This leads to muscle loss, impaired repair, and greater limb loss risk. Standard diagnostics emphasise imaging and perfusion, often missing metabolic changes. The LIPID-CLI framework uses high-resolution mass spectrometry to analyse lipid shifts under mitochondrial stress. Biopsy limits shifted focus to blood markers reflecting tissue lipids. Altered ceramides and phospholipids indicate lipid–mitochondrial dysfunction and may serve as non-invasive biomarkers for early CLI detection and treatment. The method improves ceramides (400 mL), phospholipid ratio (1.5), acylcarnitines (6 L), OxPLs (300 mL), index score (<0.4), and mediator levels (200 mL). The reduction denotes decreased ceramide concentration (µmol/mL or ng/mL), normalised to total lipid content in affected tissues. This measure reflects how ceramide alterations disrupt lipid homeostasis and mitochondrial function in critical limb ischaemia (CLI).

Pyometra is a common and potentially life-threatening uterine infection in bitches, with severe local and systemic inflammation as symptoms. Studies exist on inflammatory markers in peripheral blood (PB), but little is known about their expression in uterine blood (UB). This study aimed to compare their concentrations simultaneously in UB and PB of bitches with pyometra, and to evaluate their diagnostic and prognostic potential. Twenty-two bitches with confirmed pyometra (13 closed-cervix and 9 open-cervix cases) and six healthy controls were enrolled. Blood samples were collected from the cephalic and uterine veins during ovariohysterectomy. The concentrations of IL-1α, IL-1β, IL-6 and IL-10 were measured using an ELISA validated for dogs, and C-reactive protein (CRP) was measured by an immunoturbidimetric assay. These five inflammatory markers were compared statistically between the three groups of dogs and two types of blood sample using the Mann-Whitney U and Wilcoxon tests. All markers were significantly elevated in affected bitches' UB and PB. The IL-6 concentrations were significantly higher in UB than in PB, suggesting local production of this cytokine. Conversely, the IL-10 levels were higher in PB, possibly reflecting a systemic regulatory response. The concentrations of IL-1α and IL-1β differed insignificantly from each other. Those of CRP were significantly higher in open-cervix than in closed-cervix pyometra, indicating a stronger acute-phase response. The results assign IL-6 and CRP a potential role as biomarkers for the diagnosis and prognosis of pyometra. Simultaneous analysis of uterine and systemic inflammatory responses provides insight into the disease's pathophysiology and may support more targeted therapeutic approaches.

Saliva is of great interest for diagnosing and monitoring various diseases, including cancer. Saliva contains a wide range of proteins, some of which are found in blood plasma, while others are unique. Despite the obvious advantages of using saliva for diagnostics and patient monitoring, difficulties in interpreting salivary values remain. Furthermore, the extent to which salivary results correlate with blood test results remains unclear. In this review, we have collected and analyzed all currently available parallel studies of saliva and blood on the nature of changes in biochemical parameters, cytokines, growth factors, hormones, and tumor markers in cancer patients. The most contradictory and divergent changes in saliva and blood were observed when measuring biochemical parameters. Cytokines, growth factors, hormones, and tumor markers in both saliva and blood have a higher reproducibility between independent studies. It is important to consider that the causes and mechanisms behind a particular indicator in saliva may differ from those underlying the same indicators in the blood. Furthermore, these indicators may not always be directly related to cancer. We suggest that comparing identical parameters in blood and saliva is useful in the context of "pathological process routing." The paper also provides interpretations and hypotheses regarding the causes and nature of changes in saliva and blood composition in cancer.

Background: Pancreatic ductal adenocarcinoma (PDAC) has one of the poorest prognoses among malignant tumors, mainly due to the difficulty of early diagnosis. Therefore, it is crucial to identify reliable blood markers for a highly sensitive diagnostic system. We previously developed a highly sensitive extracellular vesicle (EV)-counting system, which can quantify the absolute number of specific EVs in serum. In this study, a multiplex assay using lectins that recognize specific glycans on EVs in the serum of PDAC patients was performed to select the optimal lectin combination. Methods: The glycan alteration signature of serum EVs from patients with PDAC was analyzed using a lectin-based multiplex assay combined with the EV-counting system. The optimal lectin combination that recognizes PDAC-specific changes was selected using machine learning analyses (support vector machine) for high diagnostic performance across independent patient cohorts. Results: An optimal lectin combination, Jacalin and Agaricus bisporus agglutinin (ABA), for PDAC detection was identified using machine learning analysis. This lectin-based system, reflecting changes in Jacalin/ABA binding, showed significantly higher diagnostic performance (area under the curve [AUC] = 0.890 and 0.971) than that of the conventional diagnostic marker carbohydrate antigen 19-9 (CA19.9; AUC = 0.752). Notably, the system achieved an AUC of 0.870 in patients with the stage I disease. Conclusions: These findings highlight the potential of a serum EV-based diagnostic system leveraging Jacalin and ABA glycan recognition for the early detection of PDAC.

SummaryBackgroundThe irritable bowel syndrome (IBS) has long been considered a functional disorder, but recent work has demonstrated clear biological signatures in immune, microbiome and enteric nervous systems of patients with IBS. Despite this new knowledge, there is still no clear biological marker of IBS, with patient symptom reporting and exclusion of organic disease the main criteria for diagnosis. We aimed to perform a systematic review and meta-analysis to identify consistent biomarkers for IBS in serum and stool samples.MethodsWe searched Medline, EMBASE, Cochrane Library, Web of Science and Scopus to obtain all relevant publications published between 1992 and January 2026. Original, peer-reviewed research articles including adults with IBS and healthy or outpatient controls, and/or patients with organic gastrointestinal conditions (e.g. IBD) were included. All articles had quantification of blood and faecal markers between IBS and controls. Descriptive data presented as median and range or median (interquartile range) was converted to mean ± SD. To account for methodological assay differences between studies, standardised mean difference (SMD) with 95% confidence interval was used as the primary outcome measure for the meta-analyses, with a random effects model fitted to the data.FindingsThe search strategy identified 55,444 citations across all databases. 124 studies were included encompassing 14,930 patients with IBS, 7544 healthy/asymptomatic controls and 4317 patients with organic diseases. The top serum discriminators between IBS and healthy controls were TNF-⍺ (13 studies, 1025 controls and 1244 IBS, SMD = 2.74, 95% CI = 0.70, 4.70, p = 0.006), IL-6 (13 studies, 736 controls and 1022 IBS, SMD = 1.87, 95% CI = 0.13, 3.61, p = 0.035) and IFN-ɣ (4 studies, n = 195 controls, n = 372 IBS, SMD = 2.79, 95% CI = 1.07, 4.51, p = 0.002). For faecal markers calprotectin was significantly higher in patients with IBS over controls (11 studies, 1624 controls and 1383 IBS, SMD = 0.75, 95% CI = 0.30, 1.21, p = 0.001), while faecal valerate levels were lower in IBS versus controls (4 studies, 290 controls and 488 IBS, SMD = −0.79, 95% CI = −1.48, −0.11, p = 0.02). For discriminating IBS overall from organic diseases, serum albumin (4 studies, 282 IBS and 312 organic, SMD = 2.15, 95% CI = 0.20, 4.11, p = 0.031) and faecal calprotectin (16 studies, 1591 IBS and 1685 organic, SMD = −1.13, 95% CI = −1.51, −0.75, p < 0.0001) were significantly different. In discriminating IBS subtypes from controls, only diarrhoeal IBS (IBS-D) could be distinguished by albumin (3 studies, 248 controls and 219 IBS-D, SMD = −0.39, 95% CI = −0.68, −0.11, p = 0.007) and IL-6 (4 studies, 153 IBS-D and 169 controls, SMD = 2.53, 95% CI = 0.86, 4.21, p = 0.003). Heterogeneity across the studies ranged from moderate to high, but few overly influential studies were identified between comparisons.InterpretationPatients with IBS exhibit increased peripheral cytokine levels that are consistent with reports of increased epithelial permeability and may be important in distinguishing subgroups of IBS patients. Patients with IBS also demonstrated higher faecal calprotectin levels than healthy individuals, although these levels were still significantly lower than patients with organic diseases. Similarly, patients with IBS-D have lower serum albumin levels compared to healthy controls, while patients with organic disease had lower levels compared to patients with IBS, irrespective of subtype. There are clear biological signatures at play in IBS patients that may be useful clinically in establishing IBS diagnosis and may indicate the mechanisms of disease symptoms.Funding10.13039/501100000925National Health and Medical Research Council Centre for Research Excellence in Digestive Health (NJT, SK) G180219.