The myokine FGF21 associates with enhanced survival in ALS and mitigates stress-induced cytotoxicity.

Amyotrophic lateral sclerosis (ALS) is an age-related and fatal neurodegenerative disease characterized by progressive muscle weakness. There is marked heterogeneity in clinical presentation, progression, and pathophysiology with only modest treatments to slow disease progression. Molecular markers that provide insight into this heterogeneity are crucial for clinical management and identification of new therapeutic targets. In a prior muscle miRNA sequencing investigation, we identified altered FGF pathways in ALS muscle, leading us to investigate FGF21. We analyzed human ALS muscle biopsy samples and found a large increase in FGF21 expression with localization to atrophic myofibers and surrounding endomysium. A concomitant increase in FGF21 was detected in ALS spinal cords which correlated with muscle levels. FGF21 was increased in the SOD1 G93A mouse beginning in presymptomatic stages. In parallel, there was dysregulation of the co-receptor, ß-Klotho. Plasma FGF21 levels were increased and high levels correlated with slower disease progression, prolonged survival, and increased body mass index. In NSC-34 motor neurons and C2C12 muscle cells expressing SOD1 G93A or exposed to oxidative stress, ectopic FGF21 mitigated loss of cell viability. In summary, FGF21 is a novel biomarker in ALS that correlates with slower disease progression and exerts trophic effects under conditions of cellular stress.

Micro- and nano-plastics, intestinal inflammation, and inflammatory bowel disease: A review of the literature.

Plastics, encompassing a wide range of polymeric materials, and their downstream products (micro- and nanoplastics, MNPs) are accumulating in the environment at an alarming rate, and they are linked to adverse human health outcomes. Considering that ingestion is a main source of MNPs exposure, the impact of plastics is particularly relevant towards intestinal inflammation and inflammatory bowel disease (IBD). However, the study of MNPs has been limited by obstacles relating to sample collection, preparation, and microplastics analysis based on optical microscopy and chemical analysis, which we detail in this review alongside potential solutions. We summarize available data on human exposure to MNPs and overall health outcomes, with particular focus on data pertaining to intestinal inflammation, microbiome perturbations, and related outcomes. We include ecologic perspectives, and human, in vitro, and animal model studies. We discuss the way forward in MNPs and IBD research, including knowledge gaps and future research.

Emerging role of environmental pollutants in inflammatory bowel disease risk, outcomes and underlying mechanisms.

Epidemiological and translational data increasingly implicate environmental pollutants in inflammatory bowel disease (IBD). Indeed, the global incidence of IBD has been rising, particularly in developing countries, in parallel with the increased use of chemicals and synthetic materials in daily life and escalating pollution levels. Recent nationwide and ecological studies have reported associations between agricultural pesticides and IBD, particularly Crohn's disease. Exposure to other chemical categories has also been linked with an increased risk of IBD. To synthesise available data and identify knowledge gaps, we conducted a systematic review of human studies that reported on the impact of environmental pollutants on IBD risk and outcomes. Furthermore, we summarised in vitro data and animal studies investigating mechanisms underlying these associations. The 32 included human studies corroborate that heavy and transition metals, except zinc, air pollutants, per- and polyfluorinated substances, and pesticides are associated with an increased risk of IBD, with exposure to air pollutants being associated with disease-related adverse outcomes as well. The narrative review of preclinical studies suggests several overlapping mechanisms underlying these associations, including increased intestinal permeability, systemic inflammation and dysbiosis. A consolidated understanding of the impact of environmental exposures on IBD risk and outcomes is key to the identification of potentially modifiable risk factors and to inform strategies towards prediction, prevention and mitigation of IBD.

Impact of prenatal and postnatal maternal IBD status on offspring's risk of IBD: a population-based cohort study.

OBJECTIVE: In utero exposure to maternal inflammation may impact immune system development and subsequent risk of disease. We investigated whether a maternal diagnosis of IBD before childbirth is linked to a higher risk of IBD in offspring compared with a diagnosis after childbirth. Further, we analysed paternal IBD status for comparison. DESIGN: Using Danish health registers, we identified all individuals born in Denmark between 1997 and 2022 and their legal parents, as well as their IBD status. Cox proportional hazards regression analyses adjusted for calendar period and mode of delivery were used to estimate offspring IBD risk by maternal and paternal IBD status before and after childbirth. RESULTS: Of 1 290 358 children, 10 041 (0.8%) had mothers with IBD diagnosis before childbirth and 9985 (0.8%) had mothers with IBD diagnosis after childbirth. Over 18 370 420 person-years, 3537 individuals were diagnosed with IBD. Offspring of mothers with IBD before childbirth had an adjusted HR of IBD of 6.27 (95% CI 5.21, 7.54) compared with those without maternal IBD, while offspring of mothers with IBD after childbirth had an adjusted HR of 3.88 (95% CI 3.27, 4.60). Corresponding adjusted HRs were 5.26 (95% CI 4.22, 6.56) among offspring with paternal IBD before childbirth and 3.73 (95% CI 3.10, 4.50) for paternal IBD after childbirth. CONCLUSION: Offspring had a greater risk of IBD when either parent was diagnosed before childbirth rather than later, emphasising genetic predisposition and environmental risk factors rather than maternal inflammation in utero as risk factors for IBD.

Disruption of Core Stress Granule Protein Aggregates Promotes CNS Axon Regeneration.

Depletion or inhibition of core stress granule proteins, G3BP1 in mammals and TIAR-2 in C. elegans , increases axon regeneration in injured neurons that show spontaneous regeneration. Inhibition of G3BP1 by expression of its acidic or 'B-domain' accelerates axon regeneration after nerve injury bringing a potential therapeutic intervention to promote neural repair in the peripheral nervous system. Here, we asked if G3BP1 inhibition is a viable strategy to promote regeneration in the injured mammalian central nervous system where axons do not regenerate spontaneously. G3BP1 B-domain expression was found to promote axon regeneration in both the mammalian spinal cord and optic nerve. Moreover, a cell permeable peptide to a subregion of G3BP1's B-domain (rodent G3BP1 amino acids 190-208) accelerated axon regeneration after peripheral nerve injury and promoted the regrowth of reticulospinal axons into the distal transected spinal cord through a bridging peripheral nerve graft. The rodent and human G3BP1 peptides promoted axon growth from rodent and human neurons cultured on permissive substrates, and this function required alternating Glu/Asp-Pro repeats that impart a unique predicted tertiary structure. These studies point to G3BP1 granules as a critical impediment to CNS axon regeneration and indicate that G3BP1 granule disassembly represents a novel therapeutic strategy for promoting neural repair after CNS injury.

ECCO Guidelines on Therapeutics in Crohn's Disease: Surgical Treatment.

This article is the second in a series of two publications on the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the management of Crohn's disease. The first article covers medical management; the present article addresses surgical management, including preoperative aspects and drug management before surgery. It also provides technical advice for a variety of common clinical situations. Both articles together represent the evidence-based recommendations of the ECCO for Crohn's disease and an update of prior ECCO guidelines.

Breastfeeding Duration Is Not Associated With Offspring Inflammatory Bowel Disease Risk in Three Population-Based Birth Cohorts.

BACKGROUND & AIMS: Breastfeeding is critical for offspring health and development. Although many observational studies report a protective effect between breastfeeding and inflammatory bowel disease (IBD), the relationship is not well-understood. METHODS: We used prospectively collected data from 3 population-based birth cohorts (Danish National Birth Cohort, Norwegian Mother, Father, and Child Cohort, and All Babies in Southeast Sweden) and cross-linked national registers to ascertain the impact of breastfeeding duration on offspring IBD risk in each country, using adjusted Cox proportional regression analyses. We performed meta-analyses to determine pooled estimates. RESULTS: We included 148,737 offspring and 169,510 offspring in analyses of exclusive and any breastfeeding duration, respectively. During median follow-up of 16.3-22.3 years, between 1996 and 2021, 543 offspring were diagnosed with IBD. In each country, there was no association between exclusive breastfeeding duration and offspring IBD risk after adjusting for birth year (Denmark), offspring sex, parental IBD status, maternal education, smoking during pregnancy, age at delivery, mode of delivery, preterm birth, and small for gestational age. The pooled adjusted hazard ratio for IBD was 1.24 (95% confidence interval, 0.94-1.62; Q = 0.16, I2 = 0.0%) and 1.02 (95% confidence interval, 0.85-1.21; Q = 1.45, I 2= 0.0%) among offspring breastfed exclusively for ≥6 months and <4 months, respectively, compared with 4-5 months. Similarly, we found null associations in pooled analyses of any breastfeeding duration and IBD, subtypes Crohn's disease and ulcerative colitis, as well as in cohort-specific analyses. CONCLUSIONS: In prospectively collected data from 3 population-based birth cohorts, the duration of exclusive or any breastfeeding was not associated with offspring IBD risk.

Association between early life exposure to agriculture, biodiversity, and green space and risk of inflammatory bowel disease: a population-based cohort study.

Background: Specific pollutants and environmental exposures are implicated in modulating inflammatory bowel disease (IBD) risk. However, the role of environmental exposures, particularly during the early life period, towards IBD risk, has not been systematically evaluated. Methods: We conducted a nationwide population-based cohort study during the study period extending from January 1, 1995, to September 1, 2020, using cross-linked Danish registers, maps, and inventories to ascertain the impact of agricultural land use, biodiversity, green space, urban space, blue space, and normalized difference vegetation index during pregnancy and the first two years of life on IBD, Crohn's disease (CD), and ulcerative colitis (UC) risk, using adjusted Cox proportional hazards regression analyses. We adjusted for covariates sex, maternal age at delivery, calendar year of birth, municipal-level socioeconomic status, and first-degree relative with IBD. Findings: Of 1,438,487 individuals included in the study who were followed from age 2 years until a median (IQR) age of 14 (8-20) years, 3768 individuals were diagnosed with IBD. Exposure to the second, third and highest quartiles of agriculture land use during early life, relative to the lowest quartile, were associated with increased CD risk (aHR 1.12, 95% CI 1.01, 1.26, 1.19, 95% CI 1.05, 1.34 and, 1.24 95% CI 1.06, 1.46, respectively). There was no association of agriculture land use with UC risk. Conversely, exposure to the third quartile of biodiversity in early life, compared to the lowest quartile, were associated with a lower CD risk (aHR 0.86, 95% CI 0.75, 0.98). A protective effect of greenspace was noted in the highest quartile for CD (aHR 0.87, 95% CI 0.78, 0.98). Interpretation: In a nationwide cohort with long-term follow up data, early life environmental exposures were associated with modulation of CD risk, with a harmful effect of agriculture land use and protective effect of biodiversity and green space. Funding: Danish National Research Foundation, the International Organization for the Study of Inflammatory Bowel Disease, the National Institute of Diabetes and Digestive and Kidney Diseases.

Deciphering the different phases of preclinical inflammatory bowel disease.

Inflammatory bowel disease (IBD) is an immune-mediated inflammatory disease (IMID) of the gastrointestinal tract and includes two subtypes: Crohn's disease and ulcerative colitis. It is well-recognized that IBD is associated with a complex multifactorial aetiology that includes genetic predisposition and environmental exposures, with downstream dysregulation of systemic immune function and host-microbial interactions in the local environment in the gut. Evidence to support the notion of a multistage development of IBD is growing, as has been observed in other IMIDs such as rheumatoid arthritis and systemic lupus erythematosus. With the rising worldwide incidence of IBD, it is increasingly important to understand the complex interplay of pathological events during the different stages of disease development to enable IBD prediction and prevention strategies. In this article, we review comprehensively the current evidence pertaining to the preclinical phase of IBD, including at-risk, initiation and expansion phases. We also discuss the framework of preclinical IBD, expanding on underlying pathways in IBD development, future research directions and IBD development in the context of other IMIDs.

AGA Clinical Practice Guideline on the Management of Pouchitis and Inflammatory Pouch Disorders.

BACKGROUND & AIMS: Pouchitis is the most common complication after restorative proctocolectomy with ileal pouch-anal anastomosis for ulcerative colitis. This American Gastroenterological Association (AGA) guideline is intended to support practitioners in the management of pouchitis and inflammatory pouch disorders. METHODS: A multidisciplinary panel of content experts and guideline methodologists used the Grading of Recommendations Assessment, Development and Evaluation framework to prioritize clinical questions, identify patient-centered outcomes, conduct an evidence synthesis, and develop recommendations for the prevention and treatment of pouchitis, Crohn's-like disease of the pouch, and cuffitis. RESULTS: The AGA guideline panel made 9 conditional recommendations. In patients with ulcerative colitis who have undergone ileal pouch-anal anastomosis and experience intermittent symptoms of pouchitis, the AGA suggests using antibiotics for the treatment of pouchitis. In patients who experience recurrent episodes of pouchitis that respond to antibiotics, the AGA suggests using probiotics for the prevention of recurrent pouchitis. In patients who experience recurrent pouchitis that responds to antibiotics but relapses shortly after stopping antibiotics (also known as "chronic antibiotic-dependent pouchitis"), the AGA suggests using chronic antibiotic therapy to prevent recurrent pouchitis; however, in patients who are intolerant to antibiotics or who are concerned about the risks of long-term antibiotic therapy, the AGA suggests using advanced immunosuppressive therapies (eg, biologics and/or oral small molecule drugs) approved for treatment of inflammatory bowel disease. In patients who experience recurrent pouchitis with inadequate response to antibiotics (also known as "chronic antibiotic-refractory pouchitis"), the AGA suggests using advanced immunosuppressive therapies; corticosteroids can also be considered in these patients. In patients who develop symptoms due to Crohn's-like disease of the pouch, the AGA suggests using corticosteroids and advanced immunosuppressive therapies. In patients who experience symptoms due to cuffitis, the AGA suggests using therapies that have been approved for the treatment of ulcerative colitis, starting with topical mesalamine or topical corticosteroids. The panel also proposed key implementation considerations for optimal management of pouchitis and Crohn's-like disease of the pouch and identified several knowledge gaps and areas for future research. CONCLUSIONS: This guideline provides a comprehensive, patient-centered approach to the management of patients with pouchitis and other inflammatory conditions of the pouch.

Per- and Poly-Fluoroalkyl Substances Exposure Is Associated With Later Occurrence of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is an immune-mediated inflammatory disease of the intestinal tract of elusive etiology. Environmental chemical exposures are increasingly acknowledged as a potential IBD risk factor. Per- and poly-fluoroalkyl substances (PFASs), a large class of persistent fluorinated organic chemicals used in industrial applications and consumer products such as paints, food packaging, and nonstick cookware, for over 6 decades, may be implicated in IBD etiology. Yet, epidemiological evidence has so far been scarce. Exposures to a few legacy PFASs, including perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorodecanoic (PFDA), and perfluorohexane sulfonate (PFHxS), have been associated with immunotoxicity and increased risk of other immune-mediated diseases,1 but data for their potential association with IBD are conflicting.2,3 Further, the impact of more recently emerging PFAS chemicals on IBD risk has not been studied.

Early-life exposures and the microbiome: implications for IBD prevention.

The early-life period is one of microbiome establishment and immune maturation. Early-life exposures are increasingly being recognised to play an important role in IBD risk. The composition of functions of the gut microbiome in the prenatal, perinatal, and postnatal period may be crucial towards development of health or disease, including IBD, later in life. We herein present a comprehensive summary of the interplay between early-life factors and microbiome perturbations, and their association with risk of IBD. In addition, we provide an overview of host and external factors in early life that are known to impact gut microbiome maturation and exposures implicated in IBD risk. Considering the emerging concept of IBD prevention, we propose strategies to minimise maternal and offspring exposure to potentially harmful variables and recommend protective measures during pregnancy and the postpartum period. This holistic view of early-life factors and microbiome signatures among mothers and their offspring will help frame our current understanding of their importance towards IBD pathogenesis and frame the roadmap for preventive strategies.

Sensorineural Hearing Loss in Patients With Chronic Kidney Disease: A Comprehensive Review.

This article aims to ascertain the prevalence of loss of hearing in patients with chronic kidney disease (CKD) and also to examine potential causes of sensorineural hearing loss (SNHL) in patients suffering from CKD. It has been discovered in recent years that there is a relationship between the occurrence of SNHL and CKD. Nowadays many people are suffering from CKD. These patients deal with several otorhinolaryngological issues, such as SNHL, candidiasis, epistaxis, halitosis, dysgeusia, xerostomia, and lip and thyroid malignancies. One of the most frequent otorhinolaryngological complications is audiovestibular system impairment. There are various proposed mechanisms for the appearance of loss of hearing in people suffering from CKD. The kidney and the inner ear have multiple functional and structural similarities, which may be the cause of these problems in CKD patients. In addition, changes in the homeostasis of water and electrolytes can affect the endolymphatic fluid and result in endolymphatic hydrops. Finally, some medications, like aminoglycosides and loop diuretics, are well known for their ototoxicity and are utilized to treat patients with CKD. Only a small number of population-based research have so far been able to show a connection between CKD and audiovestibular system impairment. Some investigation has shown that CKD patients are more likely than healthy people to experience vestibular impairment. The quality of life of a patient can be reduced by hearing loss. People with hearing loss experience communication issues in daily life, which negatively affects their cognitive and psychosocial functioning. Social isolation and a poor quality of life in terms of health can all result from hearing loss. In addition, decreased renal function has also been linked to poor quality of life, hospitalization, and cognitive dysfunction.

Aberrant splicing exonizes C9ORF72 repeat expansion in ALS/FTD.

A nucleotide repeat expansion (NRE) in the first annotated intron of the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While C9 NRE-containing RNAs can be translated into several toxic dipeptide repeat proteins, how an intronic NRE can assess the translation machinery in the cytoplasm remains unclear. By capturing and sequencing NRE-containing RNAs from patient-derived cells, we found that C9 NRE was exonized by the usage of downstream 5' splice sites and exported from the nucleus in a variety of spliced mRNA isoforms. C9ORF72 aberrant splicing was substantially elevated in both C9 NRE+ motor neurons and human brain tissues. Furthermore, NREs above the pathological threshold were sufficient to activate cryptic splice sites in reporter mRNAs. In summary, our results revealed a crucial and potentially widespread role of repeat-induced aberrant splicing in the biogenesis, localization, and translation of NRE-containing RNAs.

Medication-Wide Study: Exploring Medication Use 10 Years Before a Diagnosis of Inflammatory Bowel Disease.

INTRODUCTION: There is growing interest in the prediagnostic phase of inflammatory bowel disease (IBD) and in the overlap of IBD with other diseases. We described and compared use of any prescription medication between individuals with and without IBD in a 10-year period preceding diagnosis. METHODS: Based on cross-linked nationwide registers, we identified 29,219 individuals diagnosed with IBD in Denmark between 2005 and 2018 and matched to 292,190 IBD-free individuals. The primary outcome was use of any prescription medication in years 1-10 before IBD diagnosis/matching date. Participants were considered as medication users if they redeemed ≥1 prescription for any medication in the World Health Organization Anatomical Therapeutic Chemical (ATC) main groups or subgroups before diagnosis/matching. RESULTS: The IBD population had a universally increased use of medications compared with the matched population before IBD diagnosis. At 10 years before diagnosis, the proportion of users was 1.1-fold to 1.8-fold higher in the IBD population in 12 of 14 ATC main groups of medication ( P -value < 0.0001). This applied across age, sex, and IBD subtypes, although it was the most pronounced for Crohn's disease (CD). Two years before diagnosis, the IBD population had a steep increase in medication use for several organ systems. When analyzing therapeutic subgroups of medication, the CD population exhibited 2.7, 2.3, 1.9, and 1.9 times more users of immunosuppressants, antianemic preparations, analgesics, and psycholeptics, respectively, than the matched population 10 years before diagnosis ( P -value < 0.0001). DISCUSSION: Our findings demonstrate universally increased medication use years before IBD, especially CD, diagnosis and indicates multiorgan involvement in IBD.

Early Ileocecal Resection for Crohn's Disease Is Associated With Improved Long-term Outcomes Compared With Anti-Tumor Necrosis Factor Therapy: A Population-Based Cohort Study.

BACKGROUND & AIMS: Early Crohn's disease (CD) treatment involves anti-tumor necrosis factor (TNF) agents, whereas ileocecal resection (ICR) is reserved for complicated CD or treatment failure. We compared long-term outcomes of primary ICR and anti-TNF therapy for ileocecal CD. METHODS: Using cross-linked nationwide registers, we identified all individuals diagnosed with ileal or ileocecal CD between 2003 and 2018 and treated with ICR or anti-TNF agents within 1 year of diagnosis. The primary outcome was a composite of ≥1 of the following: CD-related hospitalization, systemic corticosteroid exposure, CD-related surgery, and perianal CD. We conducted adjusted Cox's proportional hazards regression analyses and determined the cumulative risk of different treatments after primary ICR or anti-TNF therapy. RESULTS: Of 16,443 individuals diagnosed with CD, 1279 individuals fulfilled the inclusion criteria. Of these, 45.4% underwent ICR and 54.6% received anti-TNF. The composite outcome occurred in 273 individuals (incidence rate, 110/1000 person-years) in the ICR group and in 318 individuals (incidence rate, 202/1000 person-years) in the anti-TNF group. The risk of the composite outcome was 33% lower with ICR compared with anti-TNF (adjusted hazard ratio, 0.67; 95% confidence interval, 0.54-0.83). ICR was associated with reduced risk of systemic corticosteroid exposure and CD-related surgery, but not other secondary outcomes. The proportion of individuals on immunomodulator, anti-TNF, who underwent subsequent resection, or were on no therapy 5 years post-ICR was 46.3%, 16.8%, 1.8%, and 49.7%, respectively. CONCLUSION: These data suggest that ICR may have a role as first-line therapy in CD management and challenge the current paradigm of reserving surgery for complicated CD refractory or intolerant to medications. Yet, given inherent biases associated with observational data, our findings should be interpreted and applied cautiously in clinical decision making.

The appendix and ulcerative colitis - an unsolved connection.

The appendix is thought to have a role in the pathogenesis of ulcerative colitis, but the nature and basis of this association remains unclear. In this Perspective, we consider the biology of the appendix with respect to its immunological function and the microbiome, and how this relates to evidence that supports the involvement of the appendix in ulcerative colitis. In experimental models, removal of the inflamed appendix prevents colitis, and in human observational studies, appendectomy is associated with protection against ulcerative colitis. Further, among people who develop ulcerative colitis, appendectomy before diagnosis might influence the course and outcomes of the disease - some evidence suggests that it protects against colectomy but could increase the risk of colorectal cancer. Appendectomy after onset of ulcerative colitis seems to have disparate consequences. Clinical trials to understand whether appendectomy has a role in the treatment of ulcerative colitis are ongoing. Major questions about the role of the appendix in the pathogenesis of ulcerative colitis remain unanswered, and further research is needed to establish whether the connection is clinically relevant.

Mild Crohn's Disease: Definition and Management.

PURPOSE OF REVIEW: Crohn's Disease (CD) is a chronic inflammatory disease that can lead to progressive damage to the gastrointestinal tract and significant disability. Early, "top-down" biologic therapy is recommended in moderate-to-severe CD to induce remission and to prevent hospitalization and complications. However, an estimated 20-30% of patients with CD have a mild disease course and may not garner sufficient benefit from expensive, immunosuppressing agents to justify their risks. Herein, we review characteristics of patients with mild CD, the available options for disease treatment and monitoring, and future directions of research. RECENT FINDINGS: For ambulatory outpatients with low-risk, mild, ileal or ileocolonic CD, induction of remission with budesonide is recommended. For colonic CD, sulfasalazine is a reasonable choice, although other aminosalicylates have no role in the treatment of CD. No large, randomized trial has supported the use of antibiotics or antimycobacterials in the treatment of CD. Partial Enteral Nutrition and Crohn's Disease Exclusion Diets may be appropriate for inducing remission in some adult patients, with trials ongoing. Select patients with mild-to-moderate CD may benefit from maintenance therapy with azathioprines or gut specific biologics, such as vedolizumab. The role of complementary and alternative medicine is not well defined. The identification, risk stratification, and monitoring of patients with mild CD can be a challenging clinical scenario. Some patients with low risk of disease progression may be appropriate for initial induction of remission with budesonide or sulfasalazine, followed by close clinical monitoring. Future research should focus on pre-clinical biomarkers to stratify disease, novel therapies with minimal systemic immune suppression, and validation of rigorous clinical monitoring algorithms.