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Nature Microbiology Jun 2022While gut microbiome and host gene regulation independently contribute to gastrointestinal disorders, it is unclear how the two may interact to influence host...
While gut microbiome and host gene regulation independently contribute to gastrointestinal disorders, it is unclear how the two may interact to influence host pathophysiology. Here we developed a machine learning-based framework to jointly analyse paired host transcriptomic (n = 208) and gut microbiome (n = 208) profiles from colonic mucosal samples of patients with colorectal cancer, inflammatory bowel disease and irritable bowel syndrome. We identified associations between gut microbes and host genes that depict shared as well as disease-specific patterns. We found that a common set of host genes and pathways implicated in gastrointestinal inflammation, gut barrier protection and energy metabolism are associated with disease-specific gut microbes. Additionally, we also found that mucosal gut microbes that have been implicated in all three diseases, such as Streptococcus, are associated with different host pathways in each disease, suggesting that similar microbes can affect host pathophysiology in a disease-specific manner through regulation of different host genes. Our framework can be applied to other diseases for the identification of host gene-microbiome associations that may influence disease outcomes.
Topics: Colon; Gastrointestinal Microbiome; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Microbiota
PubMed: 35577971
DOI: 10.1038/s41564-022-01121-z -
Gastroenterology Mar 2022Excessive shedding of apoptotic enterocytes into the intestinal lumen is observed in inflammatory bowel disease and is correlated with disease relapse. Based on their...
BACKGROUND & AIMS
Excessive shedding of apoptotic enterocytes into the intestinal lumen is observed in inflammatory bowel disease and is correlated with disease relapse. Based on their cytolytic capacity and surveillance behavior, we investigated whether intraepithelial lymphocytes expressing the γδ T cell receptor (γδ IELs) are actively involved in the shedding of enterocytes into the lumen.
METHODS
Intravital microscopy was performed on GFP γδ T cell reporter mice treated with intraperitoneal lipopolysaccharide (10 mg/kg) for 90 minutes to induce tumor necrosis factor-mediated apoptosis. Cell shedding in various knockout or transgenic mice in the presence or absence of blocking antibody was quantified by immunostaining for ZO-1 funnels and cleaved caspase-3 (CC3). Granzyme A and granzyme B release from ex vivo-stimulated γδ IELs was quantified by enzyme-linked immunosorbent assay. Immunostaining for γδ T cell receptor and CC3 was performed on duodenal and ileal biopsies from controls and patients with Crohn's disease.
RESULTS
Intravital microscopy of lipopolysaccharide-treated mice revealed that γδ IELs make extended contact with shedding enterocytes. These prolonged interactions require CD103 engagement by E-cadherin, and CD103 knockout or blockade significantly reduced lipopolysaccharide-induced shedding. Furthermore, we found that granzymes A and B, but not perforin, are required for cell shedding. These extracellular granzymes are released by γδ IELs both constitutively and after CD103/E-cadherin ligation. Moreover, we found that the frequency of γδ IEL localization to CC3-positive enterocytes is increased in Crohn's disease biopsies compared with healthy controls.
CONCLUSIONS
Our results uncover a previously unrecognized role for γδ IELs in facilitating tumor necrosis factor-mediated shedding of apoptotic enterocytes via CD103-mediated extracellular granzyme release.
Topics: Adolescent; Adult; Animals; Antigens, CD; Apoptosis; Cadherins; Caspase 3; Crohn Disease; Duodenum; Enterocytes; Female; Gene Knockdown Techniques; Granzymes; Humans; Ileum; Integrin alpha Chains; Intestinal Mucosa; Intraepithelial Lymphocytes; Intravital Microscopy; Jejunum; Lipopolysaccharides; Male; Mice; Mice, Knockout; Middle Aged; Receptors, Antigen, T-Cell, gamma-delta; Tumor Necrosis Factor-alpha; Young Adult
PubMed: 34861219
DOI: 10.1053/j.gastro.2021.11.028 -
The Journal of Experimental Medicine Nov 2022Group 3 innate lymphoid cells (ILC3s) are crucial for the maintenance of host-microbiota homeostasis in gastrointestinal mucosal tissues. The mechanisms that maintain...
Group 3 innate lymphoid cells (ILC3s) are crucial for the maintenance of host-microbiota homeostasis in gastrointestinal mucosal tissues. The mechanisms that maintain lineage identity of intestinal ILC3s and ILC3-mediated orchestration of microbiota and mucosal T cell immunity are elusive. Here, we identified BATF as a gatekeeper of ILC3 homeostasis in the gut. Depletion of BATF in ILC3s resulted in excessive interferon-γ production, dysbiosis, aberrant T cell immune responses, and spontaneous inflammatory bowel disease (IBD), which was considerably ameliorated by the removal of adaptive immunity, interferon-γ blockade, or antibiotic treatment. Mechanistically, BATF directly binds to the cis-regulatory elements of type 1 effector genes, restrains their chromatin accessibility, and inhibits their expression. Conversely, BATF promotes chromatin accessibility of genes involved in MHCII antigen processing and presentation pathways, which in turn directly promotes the transition of precursor ILC3s to MHCII+ ILC3s. Collectively, our findings reveal that BATF is a key transcription factor for maintaining ILC3 stability and coordinating ILC3-mediated control of intestinal homeostasis.
Topics: Animals; Basic-Leucine Zipper Transcription Factors; Chromatin; Homeostasis; Immunity, Innate; Interferon-gamma; Intestinal Mucosa; Lymphocytes; Mice
PubMed: 36048018
DOI: 10.1084/jem.20211861 -
Journal of Gastroenterology and... Jul 2022Human colonic spirochetosis (CS) is usually due toBrachyspira pilosicolior Brachyspira aalborgiinfection. While traditionally considered to be commensal bacteria, there... (Meta-Analysis)
Meta-Analysis Review
Human colonic spirochetosis (CS) is usually due toBrachyspira pilosicolior Brachyspira aalborgiinfection. While traditionally considered to be commensal bacteria, there are scattered case reports and case series of gastrointestinal (GI) symptoms in CS and reports of colonic polyps with adherent spirochetes. We performed a systematic review and meta-analysis investigating the association between CS and GI symptoms and conditions including the irritable bowel syndrome (IBS) and colonic polyps. Following PRISMA 2020 guidelines, a systematic search of Medline, CINAHL, EMBASE, and Web of Science was performed using specific keywords for CS and GI disease. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Of 75 studies identified in the search, 8 case-control studies met the inclusion criteria for meta-analysis and 67 case series studies met the inclusion criteria for pooled prevalence analysis. CS was significantly associated with diarrhea (n = 141/127, cases/controls, OR: 4.19, 95% CI: 1.72-10.21, P = 0.002) and abdominal pain (n = 64/65, OR: 3.66, 95% CI: 1.43-9.35, P = 0.007). CS cases were significantly more likely to have Rome III-diagnosed IBS (n = 79/48, OR: 3.84, 95% CI: 1.44-10.20, P = 0.007), but not colonic polyps (n = 127/843, OR: 8.78, 95% CI: 0.75-103.36, P = 0.084). In conclusion, we found evidence of associations between CS and both diarrhea and IBS, but not colonic polyps. CS is likely underestimated due to suboptimal diagnostic methods and may be an overlooked risk factor for a subset of IBS patients with diarrhea.
Topics: Bacterial Infections; Diarrhea; Humans; Intestines; Irritable Bowel Syndrome; Prevalence
PubMed: 35385602
DOI: 10.1111/jgh.15851 -
BMJ Open Gastroenterology Apr 2022Inflammatory bowel disease clinical nurse specialists (IBD-CNSs) face increasing pressures due to rising clinical and patient demands, advanced complexity of work role,... (Review)
Review
Scoping review with textual narrative synthesis of the literature reporting stress and burn-out in specialist nurses: making the case for inflammatory bowel disease nurse specialists.
OBJECTIVE
Inflammatory bowel disease clinical nurse specialists (IBD-CNSs) face increasing pressures due to rising clinical and patient demands, advanced complexity of work role, and minimal specialist management training and support. Stress and burn-out could undermine the stability of this workforce, disrupting clinical provision. We reviewed the literature on stress and burn-out to demonstrate the lack of evidence pertinent to IBD-CNSs and make the case for further research.
DESIGN
Following Levac 's scoping review framework, relevant databases were searched for publications reporting work-related stress and burn-out among specialist nurses. Following screening and consensus on selection of the final articles for review, all authors contributed to data charting. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Scoping Review extension guided reporting of the review.
RESULTS
Of 194 retrieved articles, eight were eligible for review. None focused on IBD-CNSs, were qualitative, or UK-based. Three core themes were identified: Rates of Burn-out, Mitigating and Alleviating Factors, and Preventing and Resolving Burn-out. Risk of burn-out is greatest in novice and mid-career CNSs. Age and duration in role appear protective. Personal achievement is also protective and can mitigate earlier episodes of burn-out; opportunities for career progression are limited. Promoting personal well-being is beneficial. Senior managers have poor understanding of the role and provide inadequate support. Commitment to patients remains high.
CONCLUSION
Burn-out arises in CNSs across clinical specialisms in the international literature and has a significant negative effect on the workforce. Further research is needed to address the dearth of evidence on burn-out in IBD-CNSs in the UK.
Topics: Burnout, Professional; Humans; Inflammatory Bowel Diseases; Nurse Clinicians; Nurse Specialists
PubMed: 35428670
DOI: 10.1136/bmjgast-2021-000852 -
Shock (Augusta, Ga.) Feb 2022Traumatic injuries, such as burn, are often complicated by ethanol intoxication at the time of injury. This leads to a myriad of complications and post-burn pathologies...
Traumatic injuries, such as burn, are often complicated by ethanol intoxication at the time of injury. This leads to a myriad of complications and post-burn pathologies exacerbated by aberrant immune responses. Recent findings suggest that immune cell dysfunction in the gastrointestinal system is particularly important in deleterious outcomes associated with burn injuries. In particular, intoxication at the time of burn injury leads to compromised intestinal T cell responses, which can diminish intestinal immunity and promote bacterial translocation, allowing for increased secondary infections in the injured host and associated sequelae, such as multiple organ failure and sepsis. Regulatory T cells (Treg) have been identified as important mediators of suppressing effector T cell function. Therefore, the goal of this study was to assess the effects of ethanol intoxication and burn injury on Treg populations in small intestinal immune organs. We also evaluated the suppressive capability of Tregs isolated from injured animals. Male C57BL/6 mice were gavaged with 2.9 g/kg ethanol before receiving a ∼12.5% total body surface area scald burn. One day after injury, we identified a significant increase in Tregs number in small intestine Peyer's patches (∼×1.5) and lamina propria (∼×2). Tregs-producing cytokine IL-10 were also increased in both tissues. Finally, Tregs isolated from ethanol and burn-injured mice were able to suppress proliferation of effector T cells to a greater degree than sham vehicle Tregs. This was accompanied by increased levels of IL-10 and decreased levels of pro-proliferative cytokine IL-2 in cultures containing ethanol + burn Tregs compared with sham Tregs. These findings suggest that Treg populations are increased in intestinal tissues 1 day following ethanol intoxication and burn injury. Tregs isolated from ethanol and burn-injured animals also exhibit a greater suppression of effector T cell proliferation, which may contribute to altered T cell responses following injury.
Topics: Alcoholic Intoxication; Animals; Burns; Intestine, Small; Male; Mice; Mice, Inbred C57BL; T-Lymphocytes, Regulatory
PubMed: 34482318
DOI: 10.1097/SHK.0000000000001853 -
Frontiers in Cellular and Infection... 2022Severe burn is a serious acute trauma that can lead to significant complications such as sepsis, multiple organ failure, and high mortality worldwide. The gut... (Review)
Review
Severe burn is a serious acute trauma that can lead to significant complications such as sepsis, multiple organ failure, and high mortality worldwide. The gut microbiome, the largest microbial reservoir in the human body, plays a significant role in this pathogenic process. Intestinal dysbiosis and disruption of the intestinal mucosal barrier are common after severe burn, leading to bacterial translocation to the bloodstream and other organs of the body, which is associated with many subsequent severe complications. The progression of some intestinal diseases can be improved by modulating the composition of gut microbiota and the levels of its metabolites, which also provides a promising direction for post-burn treatment. In this article, we summarised the studies describing changes in the gut microbiome after severe burn, as well as changes in the function of the intestinal mucosal barrier. Additionally, we presented the potential and challenges of microbial therapy, which may provide microbial therapy strategies for severe burn.
Topics: Humans; Gastrointestinal Microbiome; Bacterial Translocation; Intestinal Mucosa; Sepsis
PubMed: 36467727
DOI: 10.3389/fcimb.2022.974259 -
Journal of Clinical Medicine Jun 2019Inpatients are threatened by global malnutrition, but also by specific micronutrient (i.e., trace element and vitamins) deficiencies that frequently are overseen in the... (Review)
Review
Inpatients are threatened by global malnutrition, but also by specific micronutrient (i.e., trace element and vitamins) deficiencies that frequently are overseen in the differential diagnosis of major organ dysfunctions. Some of them are related to specific geographic risks (iodine, iron, selenium, zinc, vitamin A), while others are pathology related, and finally many are associated with specific feeding patterns, including low dose enteral feeding. Among the pathologies in which laboratory blood investigations should include a micronutrient outwork, anemia is in the front line, followed by obesity with bariatric surgery, chronic liver disease, kidney disease, inflammatory bowel disease, cardiomyopathies and heart failure. The micronutrients at the highest risk are iron, zinc, thiamine, vitamin B12 and vitamin C. Admission to hospital has been linked with an additional risk of malnutrition-feeding below 1500 kcal/day was frequent and has been associated with a structural additional risk of insufficient micronutrient intake to cover basal needs. Although not evidence based, systematic administration of liberal thiamine doses upon admission, and daily complementation of inpatients' food and enteral feeding solutions with multi-micronutrient tablets might be considered.
PubMed: 31261695
DOI: 10.3390/jcm8070931 -
Burns & Trauma 2023Inflammatory bowel disease (IBD) is a chronic, non-specific, recurrent inflammatory disease, majorly affecting the gastrointestinal tract. Due to its unclear... (Review)
Review
Inflammatory bowel disease (IBD) is a chronic, non-specific, recurrent inflammatory disease, majorly affecting the gastrointestinal tract. Due to its unclear pathogenesis, the current therapeutic strategy for IBD is focused on symptoms alleviation. Autophagy is a lysosome-mediated catabolic process for maintaining cellular homeostasis. Genome-wide association studies and subsequent functional studies have highlighted the critical role of autophagy in IBD via a number of mechanisms, including modulating macrophage function. Macrophages are the gatekeepers of intestinal immune homeostasis, especially involved in regulating inflammation remission and tissue repair. Interestingly, many autophagic proteins and IBD-related genes have been revealed to regulate macrophage function, suggesting that macrophage autophagy is a potentially important process implicated in IBD regulation. Here, we have summarized current understanding of macrophage autophagy function in pathogen and apoptotic cell clearance, inflammation remission and tissue repair regulation in IBD, and discuss how this knowledge can be used as a strategy for IBD treatment.
PubMed: 37152076
DOI: 10.1093/burnst/tkad004 -
Facts, Views & Vision in ObGyn May 2020Resectoscopic injuries to bowel and/or vessels, although rare, can be catastrophic, resulting in significant patient harm including death and can provoke medicolegal...
BACKGROUND
Resectoscopic injuries to bowel and/or vessels, although rare, can be catastrophic, resulting in significant patient harm including death and can provoke medicolegal litigation.
OBJECTIVE
To examine indications, preoperative risk factors, perioperative findings and intervention, and clinical outcomes of resectoscopic injuries.
MATERIALS AND METHODS
Eleven cases of resectoscopic complications were reviewed by one author (G.A.V.) for medicolegal purposes. After grouping of the complications, one case for each complication was selected, edited and reconstructed to reflect and highlight all potential complications associated with monopolar resectoscopes (26F, 9-mm) and nonconductive distending medium. Although these cases are reconstructed from actual complications, they do not reflect specific cases of medicolegal opinions and outcomes. Indications for resectoscopic surgery included abnormal uterine bleeding and/or infertility in premenopausal women.
RESULTS
Injuries were associated with uterine perforation resulting in hemorrhage or bowel injury; urinary bladder injury without uterine perforation; and thermal injuries to lower genital tract and dispersive electrode site.
CONCLUSIONS
Resectoscopic complications are associated with any one or a combination of trauma during uterine access or intra-operatively, excessive fluid intravasation of distending medium or thermal injuries from applied energy. Uterine perforation in the presence of distorted anatomy (e.g. uterine fibroids) may be considered as a known and accepted complication. Lower genital tract and dispersive electrode site burn occur due to inherent design of monopolar resectoscopes. Appropriate intra- and post-operative intervention minimizes adverse clinical and medicolegal outcomes. Lack of post-operative vigilance and inappropriate delay in investigation and intervention is associated with adverse clinical and, potentially, unfavourable legal outcomes.
WHAT IS NEW?
Reviewing resectoscopic complications raises awareness; provides insight for avoidance, recognition and timely intervention to minimise adverse clinical and medicolegal outcomes.
PubMed: 32696024
DOI: No ID Found