Understanding the Kynurenine Pathway: A Narrative Review on its Impact across Chronic Pain Conditions.

Chronic pain is a debilitating symptom with a significant negative impact on the quality of life and socioeconomic status, particularly among adults and the elderly. Major Depressive Disorder (MDD) stands out as one of the most important comorbid disorders accompanying chronic pain. The kynurenine pathway serves as the primary route for tryptophan degradation and holds critical significance in various biological processes, including the regulation of neurotransmitters, immune responses, cancer development, metabolism, and inflammation. This review encompasses key research studies related to the kynurenine pathway in the context of headache, neuropathic pain, gastrointestinal disorders, fibromyalgia, chronic fatigue syndrome, and MDD. Various metabolites produced in the kynurenine pathway, such as kynurenic acid and quinolinic acid, exhibit neuroprotective and neurotoxic effects, respectively. Recent studies have highlighted the significant involvement of kynurenine and its metabolites in the pathophysiology of pain. Moreover, pharmacological interventions targeting the regulation of the kynurenine pathway have shown therapeutic promise in pain management. Understanding the underlying mechanisms of this pathway presents an opportunity for developing personalized, innovative, and non-opioid approaches to pain treatment. Therefore, this narrative review explores the role of the kynurenine pathway in various chronic pain disorders and its association with depression and chronic pain.

Docosahexaenoic acid (DHA) alleviates inflammation and damage induced by experimental colitis.

PURPOSE: Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic gastrointestinal disorders associated with significant morbidity and complications. This study investigates the therapeutic potential of docosahexaenoic acid (DHA) in a trinitrobenzene sulfonic acid (TNBS) induced colitis model, focusing on inflammation, oxidative stress, and intestinal membrane permeability. METHODS: Wistar albino rats were divided into Control, Colitis, and Colitis + DHA groups (n = 8-10/group). The Colitis and Colitis + DHA groups received TNBS intrarectally, while the Control group received saline. DHA (600 mg/kg/day) or saline was administered via gavage for six weeks. Macroscopic and microscopic evaluations of colon tissues were conducted. Parameters including occludin and ZO-1 expressions, myeloperoxidase (MPO) activity, malondialdehyde (MDA), glutathione (GSH), total antioxidant status (TAS), total oxidant status (TOS), Interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) levels were measured in colon tissues. RESULTS: Colitis induction led to significantly higher macroscopic and microscopic damage scores, elevated TOS levels, reduced occludin and ZO-1 intensity, decreased mucosal thickness, and TAS levels compared to the Control group (p < 0.001). DHA administration significantly ameliorated these parameters (p < 0.001). MPO, MDA, TNF-α, and IL-6 levels were elevated in the Colitis group but significantly reduced in the DHA-treated group (p < 0.001 for MPO, MDA; p < 0.05 for TNF-α and IL-6). CONCLUSION: DHA demonstrated antioxidant and anti-inflammatory effects by reducing reactive oxygen species production, enhancing TAS capacity, preserving GSH content, decreasing proinflammatory cytokine levels, preventing neutrophil infiltration, reducing shedding in colon epithelium, and improving gland structure and mucosal membrane integrity. DHA also upregulated the expressions of occludin and ZO-1, critical for barrier function. Thus, DHA administration may offer a therapeutic strategy or supplement to mitigate colitis-induced adverse effects.

Intestinal biofilms: pathophysiological relevance, host defense, and therapeutic opportunities.

SUMMARYThe human intestinal tract harbors a profound variety of microorganisms that live in symbiosis with the host and each other. It is a complex and highly dynamic environment whose homeostasis directly relates to human health. Dysbiosis of the gut microbiota and polymicrobial biofilms have been associated with gastrointestinal diseases, including irritable bowel syndrome, inflammatory bowel diseases, and colorectal cancers. This review covers the molecular composition and organization of intestinal biofilms, mechanistic aspects of biofilm signaling networks for bacterial communication and behavior, and synergistic effects in polymicrobial biofilms. It further describes the clinical relevance and diseases associated with gut biofilms, the role of biofilms in antimicrobial resistance, and the intestinal host defense system and therapeutic strategies counteracting biofilms. Taken together, this review summarizes the latest knowledge and research on intestinal biofilms and their role in gut disorders and provides directions toward the development of biofilm-specific treatments.

The Effect of Protein Nutritional Support on Inflammatory Bowel Disease and Its Potential Mechanisms.

Inflammatory bowel disease (IBD), a complex chronic inflammatory bowel disorder that includes Crohn's disease (CD) and Ulcerative Colitis (UC), has become a globally increasing health concern. Nutrition, as an important factor influencing the occurrence and development of IBD, has attracted more and more attention. As the most important nutrient, protein can not only provide energy and nutrition required by patients, but also help repair damaged intestinal tissue, enhance immunity, and thus alleviate inflammation. Numerous studies have shown that protein nutritional support plays a significant role in the treatment and remission of IBD. This article presents a comprehensive review of the pathogenesis of IBD and analyzes and summarizes the potential mechanisms of protein nutritional support in IBD. Additionally, it provides an overview of the clinical effects of protein nutritional support in IBD and its impact on clinical complications. Research findings reveal that protein nutritional support demonstrates significant benefits in improving clinical symptoms, reducing the risk of complications, and improving quality of life in IBD patients. Therefore, protein nutritional support is expected to provide a new approach for the treatment of IBD.

Saffron as a Promising Therapy for Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory illness of the gastrointestinal tract (GI), characterized by recurrent episodes of inflammation and tissue destruction. It affects an increasing number of individuals worldwide who suffer from Crohn's disease (CD) or ulcerative colitis (UC). Despite substantial advances in understanding the underlying causes of IBD, the available treatments remain restricted and are sometimes accompanied by severe consequences. Consequently, there is an urgent need to study alternate therapeutic options. This review assesses the present drugs, identifies their limitations, and proposes the use of saffron, a natural plant with great therapeutic potential based on preclinical and clinical investigations. Saffron has gained attention for its potential therapeutic benefits in treating various ailments due to its established bioactive compounds possessing antioxidant and anti-inflammatory properties. This review covers how saffron impacts the levels of calprotectin, an inflammatory marker, for various inflammatory responses in multiple diseases including IBD. Data from clinical trials were assessed to determine the efficacy and safety of using saffron to counter inflammation in multiple diseases. Studies have shown that saffron may protect against inflammatory bowel disease (IBD) through several mechanisms by inhibiting pro-inflammatory cytokines (TNF-α, IL-1ß, and IL-6), reducing oxidative stress through antioxidant effects, enhancing mucosal barrier function by upregulating tight junction proteins, and modulating the gut microbiota composition to promote beneficial bacteria while suppressing pathogenic ones; these combined actions contribute to its therapeutic potential in managing and alleviating the symptoms of IBD. This will enable future research endeavors and expedite the translation of saffron-based interventions into clinical practice as a valuable adjunctive therapy or a potential alternative to conventional treatments, thereby enhancing the quality of life for individuals suffering from inflammatory diseases including IBD.

Causal Effects of Inflammatory Bowel Diseases on the Risk of Kidney Stone Disease.

BACKGROUND: Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, have been increasingly associated with kidney stone disease, posing significant health challenges globally. OBJECTIVE: This research sought to determine the causal relationship between kidney stone disease risk and inflammatory bowel disorders. METHODOLOGY: This retrospective cohort study included patients with IBDs, such as ulcerative colitis or Crohn's disease, who were diagnosed at least 18 years of age. Information was gathered with an emphasis on patients having comprehensive medical histories and confirmed cases of kidney stone disease from January to December 2022. Medical records were retrospectively evaluated by trained staff to extract treatment information and clinical, radiological, and demographic data. To evaluate relationships, statistical analysis was carried out in SPSS software version 23 using Chi-square tests and descriptive statistics. RESULTS: The study included 320 patients diagnosed with IBDs, among which 198 (61.87%) had Crohn's disease, and 122 (38.13%) were diagnosed with ulcerative colitis. The cohort consisted of 140 females (43.75%) and 180 men (56.25%), with a mean age of 45.5 years. Regarding smoking, 113 people (35.31%) reported being smokers, whereas 207 people (64.69%) did not smoke. Additionally, 18 (5.62%) of the population had an underweight BMI, 136 (42.50%) had a normal BMI, 119 (37.19%) had an overweight BMI, and 47 (14.69%) had an obese BMI. Of the patients, 86 (26.88%) had a prior history of kidney stone disease, while 194 (60.62%) did not. Aminosalicylates were the most often used therapy modality for IBD in 189 (58.97%) of cases, followed by corticosteroids in 117 (36.56%) and immunomodulators in 93 (28.94%). Radiological examinations showed that renal calculi were present in 60 (18.75%) of patients, and kidney stones occurred in 40 (12.50%) of patients throughout the research period. The smoking status (p=0.006) and prior history of kidney stones (p<0.001) were the corresponding p-values for the significant results. CONCLUSION: The study highlights an increased risk of kidney stone disease in IBD patients, particularly among smokers and those with a recurrent history of kidney stones. Of the 320 patients, 198 (61.87%) had Crohn's disease and 122 (38.13%) had ulcerative colitis, with a significant relationship found between kidney stones and both smoking (113 patients, 35.31%, p=0.006) and a prior history of kidney stones (86 patients, 26.88%, p<0.001). The findings emphasize the need for targeted preventive measures and close monitoring of these high-risk groups.

Circulating innate lymphoid cells (cILCs): Unconventional lymphocytes with hidden talents.

Innate lymphoid cells (ILCs) are a group of lymphocytes that are devoid of antigen-specific receptors and are mainly found in tissues. The subtypes ILC1, 2, and 3 mirror T-cell functionality in terms of cytokine production and expression of key transcription factors. Although the majority of ILCs are found in tissue (tILCs), they have also been described within the circulation (cILCs). As a result of their better accessibility and putative prognostic value, human cILCs are getting more and more attention in clinical research. However, cILCs are in many aspects functionally distinct from their tILC counterparts. In fact, from the 3 ILC subsets found within the circulation, only for cILC2s could a clear functional correspondence to their tissue counterparts be established. Indeed, cILC2s are emerging as a major driver of allergic reactions with a particular role in asthma. In contrast, recent studies revealed that cILC1s and cILC3s are predominantly in an immature state and constitute progenitors for natural killer cells and ILCs, respectively. We provide an overview about the phenotype and function of the different cILC subtypes compared to tILCs in health and disease, including transcriptomic signatures, frequency dynamics, and potential clinical value. Furthermore, we will highlight the dynamics of the NKp44+ ILC3 subset, which emerges as prognostic marker in peripheral blood for inflammatory bowel disease and leukemia.

Distal Cap-assisted Endoscopic Mucosal Resection allows the safe and effective resection of adherent, dysplastic lesions in the setting of inflammatory bowel disease: a multicenter, retrospective study with video.

BACKGROUND AND AIMS: Endoscopic mucosal resection (EMR) is established as the primary approach for large/complex dysplastic lesions. However, submucosal fibrosis caused by previous attempts at removal, biopsy, inflammation, or tattoo can cause a benign "negative lift sign" and create difficulty for EMR. Here, we present the use of distal-cap assisted EMR (EMR-DC) specifically for the use of resecting dysplastic colon lesions when submucosal fibrosis is present in IBD patients. METHODS: 16 IBD patients were retrospectively evaluated from two high volume centers. The patient demographics, lesion pathology and classification, outcomes including time and success of resection, SAEs within 30 days of the procedure, and efficacy were measured. RESULTS: 75% of patients treated with EMR-DC achieved complete resection with 0 serious adverse events within 30 days of the procedure. CONCLUSION: EMR-DC represents an attractive option for the resection of adherent dysplastic lesions in chronic IBD which is effective, safe, and inexpensive.

HucMSC-Ex alleviates DSS-induced colitis in mice by decreasing mast cell activation via the IL-33/ST2 axis.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic inflammatory disease that poses challenges in terms of treatment. The precise mechanism underlying the role of human umbilical cord mesenchymal stem cell-derived exosome (HucMSC-Ex) in the inflammatory repair process of IBD remains elusive. Mucosal mast cells accumulate within the intestinal tract and exert regulatory functions in IBD, thus presenting a novel target for addressing this intestinal disease. METHODS: A mouse model of Dextran Sulfate Sodium (DSS)-induced colitis was established and hucMSC-Ex were administered to investigate their impact on the regulation of intestinal mast cells. An in vitro co-culture model using the human clonal colorectal adenocarcinoma cell line (Caco-2) and human mast cell line (LAD2) was also established for further exploration of the effect of hucMSC-Ex. RESULTS: We observed the accumulation of mast cells in the intestines of patients with IBD as well as mice. In colitis mice, there was an upregulation of mast cell-related tryptase, interleukin-33 (IL-33), and suppression of tumorigenicity 2 receptor (ST2 or IL1RL1), and the function of the intestinal mucosal barrier related to intestinal tight junction protein was weakened. HucMSC-Ex treatment significantly reduced mast cell infiltration and intestinal damage. In the co-culture model, a substantial number of mast cells interact with the epithelial barrier, triggering activation of the IL-33/IL1RL1 (ST2) pathway and subsequent release of inflammatory factors and trypsin. This disruption leads to aberrant expression of tight junction proteins, which can be alleviated by supplementation with hucMSC-Ex. CONCLUSION: Our results suggest that hucMSC-Ex may reduce the release of mast cell mediators via the IL-33/IL1RL1 (ST2) axis, thereby mitigating its detrimental effects on intestinal barrier function.

Commensal microbiome and gastrointestinal mucosal immunity: Harmony and conflict with our closest neighbor.

BACKGROUND: The gastrointestinal tract contains a wide range of microorganisms that have evolved alongside the immune system of the host. The intestinal mucosa maintains balance within the intestines by utilizing the mucosal immune system, which is controlled by the complex gut mucosal immune network. OBJECTIVE: This review aims to comprehensively introduce current knowledge of the gut mucosal immune system, focusing on its interaction with commensal bacteria. RESULTS: The gut mucosal immune network includes gut-associated lymphoid tissue, mucosal immune cells, cytokines, and chemokines. The connection between microbiota and the immune system occurs through the engagement of bacterial components with pattern recognition receptors found in the intestinal epithelium and antigen-presenting cells. This interaction leads to the activation of both innate and adaptive immune responses. The interaction between the microbial community and the host is vital for maintaining the balance and health of the host's mucosal system. CONCLUSION: The gut mucosal immune network maintains a delicate equilibrium between active immunity, which defends against infections and damaging non-self antigens, and immunological tolerance, which allows for the presence of commensal microbiota and dietary antigens. This balance is crucial for the maintenance of intestinal health and homeostasis. Disturbance of gut homeostasis leads to enduring or severe gastrointestinal ailments, such as colorectal cancer and inflammatory bowel disease. Utilizing these factors can aid in the development of cutting-edge mucosal vaccines that have the ability to elicit strong protective immune responses at the primary sites of pathogen invasion.

Gut virome-wide association analysis identifies cross-population viral signatures for inflammatory bowel disease.

BACKGROUND: The gut virome has been implicated in inflammatory bowel disease (IBD), yet a full understanding of the gut virome in IBD patients, especially across diverse geographic populations, is lacking. RESULTS: In this study, we conducted a comprehensive gut virome-wide association study in a Chinese cohort of 71 IBD patients (15 with Crohn's disease and 56 with ulcerative colitis) and 77 healthy controls via viral-like particle (VLP) and bulk virome sequencing of their feces. By utilizing an integrated gut virus catalog tailored to the IBD virome, we revealed fundamental alterations in the gut virome in IBD patients. These characterized 139 differentially abundant viral signatures, including elevated phages predicted to infect Escherichia, Klebsiella, Enterococcus_B, Streptococcus, and Veillonella species, as well as IBD-depleted phages targeting Prevotella, Ruminococcus_E, Bifidobacterium, and Blautia species. Remarkably, these viral signatures demonstrated high consistency across diverse populations such as those in Europe and the USA, emphasizing their significance and broad relevance in the disease context. Furthermore, fecal virome transplantation experiments verified that the colonization of these IBD-characterized viruses can modulate experimental colitis in mouse models. CONCLUSIONS: Building upon these insights into the IBD gut virome, we identified potential biomarkers for prognosis and therapy in IBD patients, laying the foundation for further exploration of viromes in related conditions. Video Abstract.

CRIg+ macrophages deficiency enhanced inflammation damage in IBD due to gut extracellular vesicles containing microbial DNA.

Gut microbiota-derived extracellular vesicles (mEVs) are reported to regulate inflammatory response by delivering bacterial products into host cells. The complement receptor of the immunoglobulin superfamily macrophages (CRIg+ Mφ) could clear invading bacteria and their derivatives. Here, we investigate the role of CRIg+ Mφ and the mechanism by which mEVs regulate intestinal inflammation. We found that it is exacerbated in IBD patients and colitis mice by mEVs' leakage from disturbed gut microbiota, enriching microbial DNA in the intestinal mucosa. CRIg+ Mφ significantly decrease in IBD patients, allowing the spread of mEVs into the mucosa. The microbial DNA within mEVs is the key trigger for inflammation and barrier function damage. The cGAS/STING pathway is crucial in mEVs-mediated inflammatory injury. Blocking cGAS/STING signaling effectively alleviates inflammation caused by mEVs leakage and CRIg+ Mφ deficiency. Microbial DNA-containing mEVs, along with CRIg+ Mφ deficiency, stimulate inflammation in IBD, with the cGAS/STING pathway playing a crucial role.

Natural course of ulcerative colitis in China: Differences from the West?

BACKGROUND AND AIMS: Whether the natural course of ulcerative colitis (UC) in mainland China is similar or different from that in Western countries is unknown, and data on it is limited. We aimed to provide a comprehensive description of the natural course of UC in China and compare it with Western UC patients. METHODS: Based on a prospective Chinese nationwide registry of consecutive patients with inflammatory bowel diseases, the medical treatments and natural history of UC were described in detail, including disease extension, surgery, and neoplasia. The Cox regression model was used to identify factors associated with poor outcomes. RESULTS: A total of 1081 UC patients were included with a median follow-up duration of 5.3 years. The overall cumulative exposure was 99.1% to 5-aminosalicylic acids, 52.1% to corticosteroids, 25.6% to immunomodulators, and 15.4% to biologics. Disease extent at diagnosis was proctitis in 26.9%, left-sided colitis in 34.8%, and extensive colitis in 38.3%. Of 667 patients with proctitis and left-sided colitis, 380 (57.0%) experienced disease extent progression. A total of 58 (5.4%) UC patients underwent colectomy, demonstrating cumulative proportions of surgery at 1, 5, and 10 years after diagnosis of 0.6%, 3.4%, and 8.2%, respectively. In addition, 23 (2.1%) UC patients were diagnosed with neoplasia, demonstrating cumulative proportions of neoplasia at 1, 5, and 10 years after diagnosis of 0.5%, 1.0%, and 3.5%, respectively. CONCLUSIONS: Chinese UC patients had similar cumulative proportions of exposure to IBD-specific treatments but a lower surgical rate than patients in Western countries, indicating a different natural course, and close monitoring needs for UC in China. However, these results must be confirmed in population-based studies because the hospital-based cohort in our study might lead to selection bias.

Mucosal Single-Cell Profiling of Crohn's-Like Disease of the Pouch Reveals Unique Pathogenesis and Therapeutic Targets.

BACKGROUND & AIMS: The pathophysiology of Crohn's-like disease of the ileal pouch-anal anastomosis (CDP) in patients with a history of ulcerative colitis (UC) is unknown. We examined mucosal cells from patients with and without CDP using single cell analyses. METHODS: Endoscopic samples were collected from pouch body and pre-pouch ileum (pouch/ileum) of 50 patients with an IPAA. Single-cell RNA sequencing (scRNA-seq) was performed on pouch/ileal tissues of patients with normal pouch/ileum and CDP. Mass cytometry was performed on mucosal immune cells from patients with UC with normal pouch/ileum, CDP, pouchitis, as well as those with familial adenomatous polyposis (FAP) after pouch formation. Findings were independently validated using immunohistochemistry. RESULTS: The cell populations/states in pouch body differed from those in pre-pouch ileum, likely secondary to increased microbial burden. Compared to FAP pouch, UC pouch was enriched in colitogenic immune cells even without inflammation. CDP was characterized by increases in Th17 cells, inflammatory fibroblasts, inflammatory monocytes, TREM1+ monocytes, clonal expansion of effector T cells, and overexpression of Th17-inducing cytokine genes such as IL23, IL1B and IL6 by mononuclear phagocytes (MNPs). Ligand-receptor analysis further revealed a stromal-MNP-lymphocyte circuit in CDP. Integrated analysis showed that upregulated immune mediators in CDP were similar to those in CD and pouchitis, but not UC. Additionally, CDP pouch/ileum exhibited heightened endoplasmic reticulum (ER) stress across all major cell compartments. CONCLUSIONS: CDP likely represents a distinct entity of inflammatory bowel disease with heightened ER stress in both immune and non-immune cells, which may become a novel diagnostic biomarker and therapeutic target for CDP.

Association between mucosectomy and endoscopic outcomes in patients with ileal pouch-anal anastomosis.

Background: In patients with inflammatory bowel disease (IBD) for whom medical therapy is unsuccessful or who develop colitis-associated neoplasia, restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is often indicated. One consideration for surgeons performing this procedure is whether to create this anastomosis using a stapled technique without mucosectomy or using a hand-sewn technique with mucosectomy. This study tested the association between IPAA anastomosis technique and cuffitis and/or pouchitis, assessed endoscopically. Methods: This was a retrospective cohort study. We included consecutive adult patients with IBD who had undergone IPAA and had received index pouchoscopies at Columbia University Irving Medical Center between 2020 and 2022. Patients were then followed up from this index pouchoscopy for ≤12 months to a subsequent pouchoscopy. The primary exposure was mucosectomy vs non-mucosectomy and the primary outcome was cuffitis and/or pouchitis, defined as a Pouch Disease Activity Index endoscopy subscore of ≥1. Results: There were 76 patients who met study criteria including 49 (64%) who had undergone mucosectomy and 27 (36%) who had not. Rates of cuffitis and/or pouchitis were 49% among those with mucosectomy vs 41% among those without mucosectomy (P = 0.49). Time-to-event analysis affirmed these findings (log-rank P = 0.77). Stricture formation was more likely among patients with mucosectomy compared with those without mucosectomy (45% vs 19%, P = 0.02). Conclusions: There was no association between anastomosis technique and cuffitis and/or pouchitis among patients with IBD. These results may support the selection of stapled anastomosis over hand-sewn anastomosis with mucosectomy.

Life's essential 8, genetic susceptibility, and risk of inflammatory bowel diseases: a population-based cohort study.

BACKGROUND: Evidence has shown that the individual metrics in Life's Essential 8 (LE8), an updated cardiovascular health (CVH) concept proposed by the American Heart Association, play a role in the development of inflammatory bowel disease (IBD). However, epidemiological evidence on the overall LE8 on IBD risk remains limited. We aimed to assess the longitudinal associations of LE8-defined CVH and the risks of IBD and its subtypes, ulcerative colitis (UC) and Crohn's disease (CD). We also tested whether genetic susceptibility could modify these associations. METHODS: A total of 260,836 participants from the UK Biobank were included. LE8 scores were determined by 8 metrics (physical activity, diet, nicotine exposure, sleep, body mass index, blood pressure, blood glucose, and blood lipids), and were divided into three levels: low CVH (0-49), moderate CVH (50-79), and high CVH (80-100). Cox proportional hazards models were used to calculate the hazard ratios (HRs) and confidence intervals (CIs) of the risk of IBD in relation to CVH status. RESULTS: Over a median follow-up 12.3 years, we documented 1,500 IBD cases (including 1,070 UC and 502 CD). Compared to participants with low CVH, the HRs (95% CIs) of those with high CVH for IBD, UC, and CD were 0.67 (0.52, 0.83), 0.70 (0.52, 0.93), and 0.55 (0.38, 0.80), respectively. These associations were not modified by genetic susceptibility (all P for interactions > 0.05). The lowest HR (UC: 0.30, 95% CI: 0.20-0.45; CD: 0.33, 95% CI: 0.20-0.57) was observed in participants with both high CVH and low genetic risk. CONCLUSIONS: Better CVH, defined by LE8, was associated with significantly lower risks of IBD, UC, and CD, irrespective of genetic predisposition. Our results underscore the importance of adherence to LE8 guidelines for maintaining CVH as a potential strategy in the prevention of IBD.

Use of Biomarkers of Inflammation in the Differentiation of Iron Deficiency and Anaemia-Lessons from Inflammatory Bowel Disease.

Iron deficiency and iron deficiency anaemia are common in inflammatory bowel disease (IBD), to the detriment of the patients' quality of life. Since ferritin, as an acute-phase protein (APP), has limited diagnostic value in IBD, concurrent assessment of C-reactive protein (CRP) is recommended. The World Health Organization suggests using α1-acid glycoprotein (AGP) as an additional biomarker due to its differing half-life. This study aimed to evaluate ferritin levels in patients with IBD using CRP and AGP, individually and in combination. A total of 118 patients with IBD (mean age: 45.48 ± 15.25 years, 47.46% female) were recruited, including 38 with Crohn's disease, 47 with ulcerative colitis, and 33 controls. The results showed that while CRP alone detected an inflammatory increase in ferritin of 29.76%, this increased to 82.14% when AGP or both AGP and CRP were considered (p < 0.05). Elevated AGP levels were more prevalent in patients with ulcerative colitis. However, concordance between high CRP and AGP levels was confirmed in only 55% of cases. Correcting for inflammation using CRP and/or AGP significantly improved the diagnostic accuracy of ferritin levels in patients with IBD, highlighting the challenge posed by inflammation when assessing iron deficiency.

Exosomes derived from cancer cells relieve inflammatory bowel disease in mice.

Exosome therapy has garnered significant attention due to its natural delivery capabilities, low toxicity, high biocompatibility, and potential for personalised treatment through engineering modifications. Recent studies have highlighted the ability of tumour cell-derived exosomes (TDEs) to interact with immune cells or modify the immune microenvironment to suppress host immune responses, as well as their unique homing ability to parental cells. The core question of this study is whether this immunomodulatory property of TDEs can be utilised for the immunotherapy of inflammatory diseases. In our experiments, we prepared exosomes derived from murine colon cancer cells CT26 (CT26 exo) using ultracentrifugation, characterised them, and conducted proteomic analysis. The therapeutic potential of CT26 exo was evaluated in our dextran sulphate sodium salt (DSS)-induced inflammatory bowel disease (IBD) mouse model. Compared to the control and 293 T exo treatment groups, mice treated with CT26 exo showed a reduction in the disease activity index (DAI) and colon shortening rate, with no noticeable weight loss. Haematoxylin and eosin (H&E) staining of colon paraffin sections revealed reduced inflammatory infiltration and increased epithelial goblet cells in the colons of CT26 exo-treated group. Furthermore, we conducted preliminary mechanistic explorations by examining the phenotyping and function of CD4+ T cells and dendritic cells (DCs) in the colonic lamina propria of mice. The results indicated that the ameliorative effect of CT26 exosomes might be due to their inhibition of pro-inflammatory cytokine secretion by colonic DCs and selective suppression of Th17 cell differentiation in the colon. Additionally, CT26 exo exhibited good biosafety. Our findings propose a novel exosome-based therapeutic approach for IBD and suggest the potential application of TDEs in the treatment of inflammatory diseases.

Different infliximab induction dosing regimens do not affect remission rates up to 1 year in children with Crohn's disease.

OBJECTIVES: Multiple studies in patients with Crohn's disease (CD) treated with anti-tumor necrosis factor alpha agents have shown that proactive therapeutic drug monitoring (TDM) during the maintenance phase leads to improved outcomes. We aimed to assess whether accelerated infliximab administration during induction resulted in improved outcomes. METHODS: This retrospective study included CD patients aged 5-17.9 years that were treated with infliximab. We compared outcomes of patients treated during induction with 5-8 mg/kg dosing at Weeks 0, 2, 6, and 14 (Group 1), versus accelerated dosing (≥8 mg/kg and/or >4 infusions until Week 14, Group 2) of infliximab. Primary outcome was steroid-free clinical remission by Week 52. RESULTS: Sixty-eight patients were included, of whom seven discontinued infliximab before Week 14, due to infusion reactions, immunogenic failure, or primary nonresponse. Comparison of Group 1 (n = 25) and Group 2 (n = 36) showed similar clinical characteristics, as well as inflammatory markers, at infliximab initiation. Despite receiving significantly more infliximab, and reaching a higher trough level by Week 14 (10.3 ± 1.2 vs. 3.3 ± 0.7, p < 0.001), the median Pediatric Crohn's disease Activity Index (PCDAI) was slightly higher in Group 2 versus Group 1 (14 [5-20] vs. 5 [0-15], p = 0.02). However, at Weeks 26 and 52 the PCDAI and inflammatory markers were comparable between the groups. Moreover, about 70% in both groups achieved the desirable trough infliximab levels by Week 52. CONCLUSION: Accelerated infliximab dosing during induction did not result in improved outcomes up to 12 months follow-up. Prospective studies are required to determine the exact timing in which proactive TDM should be applied.

Probiotics in the Treatment of Inflammatory Bowel Diseases.

Inflammatory bowel diseases (IBD) are chronic, incurable inflammatory condition of the gut. They comprise Crohn's disease and ulcerative colitis. Crohn's disease (CD) may affect any tract of the gastrointestinal (GI) tract and is a transmural inflammatory condition; ulcerative colitis (UC), on the other hand, is limited to the mucosal layer of the rectum and colon. Treatment options available for both IBD are notoriously loaded with potentially serious side effects and risks. Although the pathogenesis of IBD involves a complex interaction between genetic, environmental, microbial and immunological factors, there is evidence that the interplay between the microbiota and the GI mucosa has a preponderant role. It is therefore no surprise that in recent years, a growing interest for effective and safer alternatives has focused on the potential role of prebiotics and-especially-probiotics.The mechanisms of action underlying the potential benefits of probiotics in IBD have been largely and quite extensively investigated in vitro and in vivo experiments. In terms of clinical evidence, the results of trials in the induction of remission of active CD or the maintenance of its remission with probiotics have been so far largely disappointing, to the point that their use in this disease cannot be at present recommended.On the contrary, for the treatment as well as for maintenance therapy of UC, there is clinical evidence of efficacy for some specific strains or multi-strain preparations.It is evident that this is a rapidly evolving and promising field; more data are very likely to yield a better understanding on what strains and in what doses should be used in different specific clinical settings, as we expect new and exciting developments of precision and even personalized therapy by the fast-growing field of probiogenomics.