Early versus delayed oral feeding after major gynaecologic surgery.

BACKGROUND: This is an updated and expanded version of the original Cochrane review, first published in 2014. Postoperative oral intake is traditionally withheld after major abdominal gynaecologic surgery until the return of bowel function. The concern is that early oral intake will result in vomiting and severe paralytic ileus, with subsequent aspiration pneumonia, wound dehiscence, and anastomotic leakage. However, clinical studies suggest that there may be benefits from early postoperative oral intake. Currently, gynaecologic surgery can be performed through various routes: open abdominal, vaginal, laparoscopic, robotic, or a combination. In this version, we included women undergoing major gynaecologic surgery through all of these routes, either alone or in combination. OBJECTIVES: To assess the effects of early versus delayed (traditional) initiation of oral intake of food and fluids after major gynaecologic surgery. SEARCH METHODS: On 13 June 2023, we searched the Cochrane Gynaecology and Fertility Group's Specialised Register, CENTRAL, MEDLINE, Embase, the citation lists of relevant publications, and two trial registries. We also contacted experts in the field for any additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared the effect of early versus delayed initiation of oral intake of food and fluids after major gynaecologic surgery, performed by abdominal, vaginal, laparoscopic, and robotic approaches. Early feeding was defined as oral intake of fluids or food within 24 hours post-surgery, regardless of the return of bowel function. Delayed feeding was defined as oral intake after 24 hours post-surgery, and only after signs of postoperative ileus resolution. Primary outcomes were: postoperative ileus, nausea, vomiting, cramping, abdominal pain, bloating, abdominal distension, need for postoperative nasogastric tube, time to the presence of bowel sounds, time to the first passage of flatus, time to the first passage of stool, time to the start of a regular diet, and length of postoperative hospital stay. Secondary outcomes were: infectious complications, wound complications, deep venous thrombosis, urinary tract infection, pneumonia, satisfaction, and quality of life. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed the risk of bias, and extracted the data. We calculated the risk ratio (RR) with a 95% confidence interval (CI) for dichotomous data. We examined continuous data using the mean difference (MD) and a 95% CI. We tested for heterogeneity between the results of different studies using a forest plot of the meta-analysis, the statistical tests of homogeneity of 2 x 2 tables, and the I² value. We assessed the certainty of the evidence using GRADE methods. MAIN RESULTS: We included seven randomised controlled trials (RCTs), randomising 902 women. We are uncertain whether early feeding compared to delayed feeding has an effect on postoperative ileus (RR 0.49, 95% CI 0.21 to 1.16; I² = 0%; 4 studies, 418 women; low-certainty evidence). We are uncertain whether early feeding affects nausea or vomiting, or both (RR 0.94, 95% CI 0.66 to 1.33; I² = 67%; random-effects model; 6 studies, 742 women; very low-certainty evidence); nausea (RR 1.24, 95% CI 0.51 to 3.03; I² = 74%; 3 studies, 453 women; low-certainty evidence); vomiting (RR 0.83, 95% CI 0.52 to 1.32; I² = 0%; 4 studies, 559 women; low-certainty evidence), abdominal distension (RR 0.99, 95% CI 0.75 to 1.31; I² = 0%; 4 studies, 559 women; low-certainty evidence); need for postoperative nasogastric tube placement (RR 0.46, 95% CI 0.14 to 1.55; 3 studies, 453 women; low-certainty evidence); or time to the presence of bowel sounds (MD -0.20 days, 95% CI -0.46 to 0.06; I² = 71%; random-effects model; 3 studies, 477 women; low-certainty evidence). There is probably no difference between the two feeding protocols for the onset of flatus (MD -0.11 days, 95% CI -0.23 to 0.02; I² = 9%; 5 studies, 702 women; moderate-certainty evidence). Early feeding probably results in a slight reduction in the time to the first passage of stool (MD -0.18 days, 95% CI -0.33 to -0.04; I² = 0%; 4 studies, 507 women; moderate-certainty evidence), and may lead to a slightly sooner resumption of a solid diet (MD -1.10 days, 95% CI -1.79 to -0.41; I² = 97%; random-effects model; 3 studies, 420 women; low-certainty evidence). Hospital stay may be slightly shorter in the early feeding group (MD -0.66 days, 95% CI -1.17 to -0.15; I² = 77%; random-effects model; 5 studies, 603 women; low-certainty evidence). The effect of the two feeding protocols on febrile morbidity is uncertain (RR 0.96, 95% CI 0.75 to 1.22; I² = 47%; 3 studies, 453 women; low-certainty evidence). However, infectious complications are probably less common in women with early feeding (RR 0.20, 95% CI 0.05 to 0.73; I² = 0%; 2 studies, 183 women; moderate-certainty evidence). There may be no difference between the two feeding protocols for wound complications (RR 0.82, 95% CI 0.50 to 1.35; I² = 0%; 4 studies, 474 women; low-certainty evidence), or pneumonia (RR 0.35, 95% CI 0.07 to 1.73; I² = 0%; 3 studies, 434 women; low-certainty evidence). Two studies measured participant satisfaction and quality of life. One study found satisfaction was probably higher in the early feeding group, while the other study found no difference. Neither study found a significant difference between the groups for quality of life (P > 0.05). AUTHORS' CONCLUSIONS: Despite some uncertainty, there is no evidence to indicate harmful effects of early feeding following major gynaecologic surgery, measured as postoperative ileus, nausea, vomiting, or abdominal distension. The potential benefits of early feeding include a slightly faster initiation of bowel movements, a slightly sooner resumption of a solid diet, a slightly shorter hospital stay, a lower rate of infectious complications, and a higher level of satisfaction.

A lmod1a mutation causes megacystis microcolon intestinal hypoperistalsis in a CRISPR/Cas9-modified zebrafish model.

PURPOSE: Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is defined as a congenital visceral myopathy with genetic mutations. However, the etiology and pathophysiology are not fully understood. We aimed to generate a gene leiomodin-1a (lmod1a) modification technique to establish a zebrafish model of MMIHS. METHODS: We targeted lmod1a in zebrafish using CRISPR/Cas9. After confirming the genotype, we measured the expression levels of the target gene and protein associated with MMIHS. A gut transit assay and spatiotemporal mapping were conducted to analyze the intestinal function. RESULTS: Genetic confirmation showed a 5-base-pair deletion in exon 1 of lmod1a, which caused a premature stop codon. We observed significant mRNA downregulation of lmod1a, myh11, myod1, and acta2 and the protein expression of Lmod1 and Acta2 in the mutant group. A functional analysis of the lmod1a mutant zebrafish showed that its intestinal peristalsis was fewer, slower, and shorter in comparison to the wild type. CONCLUSION: This study showed that targeted deletion of lmod1a in zebrafish resulted in depletion of MMIHS-related genes and proteins, resulting in intestinal hypoperistalsis. This model may have the potential to be utilized in future therapeutic approaches, such as drug discovery screening and gene repair therapy for MMIHS.

Antroduodenal manometry findings in children with suspected pediatric intestinal pseudo-obstruction.

BACKGROUND: In 2018 diagnostic criteria for pediatric intestinal pseudo-obstruction (PIPO) were established. Neuromuscular dysfunction of the gastrointestinal tract is one of these, and often examined through antroduodenal manometry (ADM). There is little data on antroduodenal manometries in children. Our objectives were to retrospectively apply these criteria to children evaluated for suspected motility disorder, to reevaluate the ADM patterns and compare children who did and did not meet the PIPO criteria and also with healthy adults. METHODS: Children with a suspected gastrointestinal motility disorder previously investigated with 24-h 8-lead ADM were reevaluated by applying the 2018 ESPGHAN/NASPGHAN PIPO diagnostic criteria and the 2018 ANMS-NASPGHAN guidelines. ADM findings were compared between children who retrospectively fulfilled a PIPO diagnosis, children who did not, and a control group of healthy adults. KEY RESULTS: Of 34 children (age 7.9 (±5.1) years, 18 males), 12 retrospectively fulfilled the 2018 PIPO diagnostic criteria. Twenty-five children (10 in the PIPO group) had abnormal diagnostic findings on ADM, whereas 9 (2 in the PIPO group) had no such findings. A PIPO diagnosis implied a significantly higher degree of abnormal ADM patterns (2.33 vs. 1.23, p = 0.02). There were no major differences in quantitative ADM measurements between the groups except higher pressures in children. CONCLUSIONS AND INFERENCES: Children who retrospectively fulfilled a PIPO diagnosis had a significantly higher abundance of abnormal ADM findings compared with symptomatic children without PIPO and healthy adults. Our data indicate a need for set criteria for evaluation of ADM in children with suspected PIPO.

Human HPSE2 gene transfer ameliorates bladder pathophysiology in a mutant mouse model of urofacial syndrome.

Rare early-onset lower urinary tract disorders include defects of functional maturation of the bladder. Current treatments do not target the primary pathobiology of these diseases. Some have a monogenic basis, such as urofacial, or Ochoa, syndrome (UFS). Here, the bladder does not empty fully because of incomplete relaxation of its outflow tract, and subsequent urosepsis can cause kidney failure. UFS is associated with biallelic variants of HPSE2, encoding heparanase-2. This protein is detected in pelvic ganglia, autonomic relay stations that innervate the bladder and control voiding. Bladder outflow tracts of Hpse2 mutant mice display impaired neurogenic relaxation. We hypothesized that HPSE2 gene transfer soon after birth would ameliorate this defect and explored an adeno-associated viral (AAV) vector-based approach. AAV9/HPSE2, carrying human HPSE2 driven by CAG, was administered intravenously into neonatal mice. In the third postnatal week, transgene transduction and expression were sought, and ex vivo myography was undertaken to measure bladder function. In mice administered AAV9/HPSE2, the viral genome was detected in pelvic ganglia. Human HPSE2 was expressed and heparanase-2 became detectable in pelvic ganglia of treated mutant mice. On autopsy, wild-type mice had empty bladders, whereas bladders were uniformly distended in mutant mice, a defect ameliorated by AAV9/HPSE2 treatment. Therapeutically, AAV9/HPSE2 significantly ameliorated impaired neurogenic relaxation of Hpse2 mutant bladder outflow tracts. Impaired neurogenic contractility of mutant detrusor smooth muscle was also significantly improved. These results constitute first steps towards curing UFS, a clinically devastating genetic disease featuring a bladder autonomic neuropathy.

Lysosomal dysfunction and overload of nucleosides in thymidine phosphorylase deficiency of MNGIE.

Inherited deficiency of thymidine phosphorylase (TP), encoded by TYMP, leads to a rare disease with multiple mitochondrial DNA (mtDNA) abnormalities, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). However, the impact of TP deficiency on lysosomes remains unclear, which are important for mitochondrial quality control and nucleic acid metabolism. Muscle biopsy tissue and skin fibroblasts from MNGIE patients, patients with m.3243 A > G mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and healthy controls (HC) were collected to perform mitochondrial and lysosomal functional analyses. In addition to mtDNA abnormalities, compared to controls distinctively reduced expression of LAMP1 and increased mitochondrial content were detected in the muscle tissue of MNGIE patients. Skin fibroblasts from MNGIE patients showed decreased expression of LAMP2, lowered lysosomal acidity, reduced enzyme activity and impaired protein degradation ability. TYMP knockout or TP inhibition in cells can also induce the similar lysosomal dysfunction. Using lysosome immunoprecipitation (Lyso- IP), increased mitochondrial proteins, decreased vesicular proteins and V-ATPase enzymes, and accumulation of various nucleosides were detected in lysosomes with TP deficiency. Treatment of cells with high concentrations of dThd and dUrd also triggers lysosomal dysfunction and disruption of mitochondrial homeostasis. Therefore, the results provided evidence that TP deficiency leads to nucleoside accumulation in lysosomes and lysosomal dysfunction, revealing the widespread disruption of organelles underlying MNGIE.

Molecular mechanisms linking missense ACTG2 mutations to visceral myopathy.

Visceral myopathy is a life-threatening disease characterized by muscle weakness in the bowel, bladder, and uterus. Mutations in smooth muscle γ-actin (ACTG2) are the most common cause of the disease, but the mechanisms by which the mutations alter muscle function are unknown. Here, we examined four prevalent ACTG2 mutations (R40C, R148C, R178C, and R257C) that cause different disease severity and are spread throughout the actin fold. R178C displayed premature degradation, R148C disrupted interactions with actin-binding proteins, R40C inhibited polymerization, and R257C destabilized filaments. Because these mutations are heterozygous, we also analyzed 50/50 mixtures with wild-type (WT) ACTG2. The WT/R40C mixture impaired filament nucleation by leiomodin 1, and WT/R257C produced filaments that were easily fragmented by smooth muscle myosin. Smooth muscle tropomyosin isoform Tpm1.4 partially rescued the defects of R40C and R257C. Cryo-electron microscopy structures of filaments formed by R40C and R257C revealed disrupted intersubunit contacts. The biochemical and structural properties of the mutants correlate with their genotype-specific disease severity.

Megacystis-microcolon-intestinal hypoperistalsis syndrome: don't forget the bladder.

PURPOSE: Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a well described clinical condition, but reports are focused on microcolon and intestinal hypoperistalsis, while data on bladder management are scant. Aim of the study is to present urological concerns in MMIHS. METHODS: Retrospective evaluation of clinical data on urological management of MMIHS patients treated in the last 10 years. RESULTS: Six patients were enrolled (3 male, 3 female). Three girls had prenatal diagnosis of megacystis (1 vesicoamniotic shunt was placed). All patients had genetic diagnosis: 5 had ACTG2 gene mutations and 1 MYH11 mutation. All patients were addressed to our attention for urinary symptoms, such as urinary retention, urinary tract infections, acute renal injury. Two patients presented frequent stoma prolapses. All children underwent a complete urological evaluation, and then started a bladder management protocol (clean intermittent catheterization, via urethra or cystostomy-tube placement), with improvement of urinary infections, upper urinary tract dilation and stoma prolapses, if present. All patients had good renal function at last follow-up. CONCLUSION: We believe that MMIHS patients must be addressed soon and before onset of symptoms for a multidisciplinary evaluation, including an early assessment by a pediatric urologist expert in functional disorder, to preserve renal function at its best.

Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS): challenges in diagnosis and management.

Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a rare, congenital functional intestinal obstruction, characterised by megacystis (bladder distention in the absence of mechanical obstruction), microcolon and intestinal hypoperistalsis (dysmotility).We are reporting a case of a female child with normal antenatal course who presented with recurrent episodes of abdominal distension since the second day of life and underwent negative exploratory laparotomy on multiple occasions. She also had urinary retention with a grossly distended bladder, requiring drainage by clean intermittent catheterisation. Surgical procedures for bowel decompression, including gastrostomy and ileostomy, were carried out without success. Genetic analysis revealed a mutation in the human smooth muscle (enteric) gamma-actin gene (ACTG2 gene), clinching the diagnosis of MMIHS. The patient was managed with parenteral nutrition and prokinetic medications and tolerated jejunostomy feeds for a brief period before she succumbed to the illness.Female neonates or infants presenting with abdominal distension and dilated urinary tract should be investigated for MMIHS early on. A timely diagnosis will enable the early involvement of a multidisciplinary team to provide the best options available for management.

Genome-wide analysis identifies MYH11 compound heterozygous variants leading to visceral myopathy corresponding to late-onset form of megacystis-microcolon-intestinal hypoperistalsis syndrome.

Megacystis-microcolon-hypoperistalsis-syndrome (MMIHS) is a rare and early-onset congenital disease characterized by massive abdominal distension due to a large non-obstructive bladder, a microcolon and decreased or absent intestinal peristalsis. While in most cases inheritance is autosomal dominant and associated with heterozygous variant in ACTG2 gene, an autosomal recessive transmission has also been described including pathogenic bialellic loss-of-function variants in MYH11. We report here a novel family with visceral myopathy related to MYH11 gene, confirmed by whole genome sequencing (WGS). WGS was performed in two siblings with unusual presentation of MMIHS and their two healthy parents. The 38 years-old brother had severe bladder dysfunction and intestinal obstruction, whereas the 30 years-old sister suffered from end-stage kidney disease with neurogenic bladder and recurrent sigmoid volvulus. WGS was completed by retrospective digestive pathological analyses. Compound heterozygous variants of MYH11 gene were identified, associating a deletion of 1.2 Mb encompassing MYH11 inherited from the father and an in-frame variant c.2578_2580del, p.Glu860del inherited from the mother. Pathology analyses of the colon and the rectum revealed structural changes which significance of which is discussed. Cardiac and vascular assessment of the mother was normal. This is the second report of a visceral myopathy corresponding to late-onset form of MMIHS related to compound heterozygosity in MYH11; with complete gene deletion and a hypomorphic allele in trans. The hypomorphic allele harbored by the mother raised the question of the risk of aortic disease in adults. This case shows the interest of WGS in deciphering complex phenotypes, allowing adapted diagnosis and genetic counselling.

Idiopathic chronic intestinal pseudo-obstruction syndrome is strongly associated with low serum levels of vitamin D.

Idiopathic chronic intestinal pseudo-obstruction (CIPO) is associated with intestinal inflammation and malabsorption and may cause serum vitamin D deficiency. We aimed to assess whether there is an association between idiopathic CIPO and serum levels of 25-hydroxy-vitamin D. Consecutive patients with confirmed diagnosis of idiopathic CIPO were prospectively enrolled and matched with healthy controls by gender, age, and BMI. Median serum level of 25-hydroxy-vitamin D of patients with CIPO was compared with that of healthy subjects using the Wilcoxon signed-rank test for matched samples. A total of 35 patients with CIPO and 35 matched healthy subjects were enrolled. All patients with CIPO had a 25-hydroxy-vitamin D deficiency with serum levels <12 ng/ml. The median serum level of vitamin D was significantly lower in patients with CIPO than in healthy controls (5.7 vs. 29.7 ng/ml, P  < 0.0001). Serum level of vitamin D was not associated with gender ( P  = 0.27), age ( P  = 0.22), BMI ( P  = 0.95), high (>10 000 × ml) WBC count ( P  = 0.08), or high (>5 mg/l) C-reactive protein ( P  = 0.87) among patients with CIPO. CIPO seems to be strongly associated with low serum levels of 25-hydroxy-vitamin D.

Exploring the complexities of megacystis-microcolon-intestinal hypoperistalsis syndrome: insights from genetic studies.

Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is an uncommon genetic disorder inherited in an autosomal recessive pattern that affects the muscles that line the bladder and intestines. The most common genes associated with MMIHS mutations are ACTG2, LMOD1, MYH11, MYL9, MYLK, and PDCL3. However, the complete genetic landscape of MMIHS still needs to be fully understood. The diagnosis of MMIHS can be challenging. However, advances in prenatal and diagnostic techniques, such as ultrasound and fetal urine analysis, have improved the ability to detect the syndrome early. Targeted next-generation sequencing (NGS) and other diagnostic tests can also diagnose MMIHS. The management of MMIHS involves addressing severe intestinal dysmotility, which often necessitates total parenteral nutrition (TPN), which can lead to complications such as hepatotoxicity and nutritional deficiencies. Multivisceral and intestinal transplantation has emerged as therapeutic options, offering the potential for improved outcomes and enteral autonomy. Understanding the genetic underpinnings of MMIHS is crucial for personalized care. While the prognosis varies, timely interventions and careful monitoring enhance patient outcomes. Genetic studies have given us valuable insights into the molecular mechanisms of MMIHS. These studies have identified mutations in genes involved in the development and function of smooth muscle cells. They have also shown that MMIHS is associated with defects in the signaling pathways that control muscle contraction. Continued research in the genetics of MMIHS holds promise for unraveling the complexities of MMIHS and improving the lives of affected individuals.

Pharmacologic prevention and therapy of postoperative paralytic ileus after gastrointestinal cancer surgery: systematic review and meta-analysis.

BACKGROUND: Postoperative paralytic ileus (POI) is a significant concern following gastrointestinal tumor surgery. Effective preventive and therapeutic strategies are crucial but remain elusive. Current evidence from randomized-controlled trials on pharmacological interventions for prevention or treatment of POI are systematically reviewed to guide clinical practice and future research. MATERIALS AND METHODS: Literature was systematically searched for prospective randomized-controlled trials testing pharmacological interventions for prevention or treatment of POI after gastrointestinal tumor surgery. Meta-analysis was performed using a random effects model to determine risk ratios and mean differences with 95% CI. Risk of bias and evidence quality were assessed. RESULTS: Results from 55 studies, involving 5078 patients who received experimental interventions, indicate that approaches of opioid-sparing analgesia, peripheral opioid antagonism, reduction of sympathetic hyperreactivity, and early use of laxatives effectively prevent POI. Perioperative oral Alvimopan or intravenous administration of Lidocaine or Dexmedetomidine, while safe regarding cardio-pulmonary complications, demonstrated effectiveness concerning various aspects of postoperative bowel recovery [Lidocaine: -5.97 (-7.20 to -4.74)h, P <0.0001; Dexmedetomidine: -13.00 (-24.87 to -1.14)h, P =0.03 for time to first defecation; Alvimopan: -15.33 (-21.22 to -9.44)h, P <0.0001 for time to GI-2 ] and length of hospitalization [Lidocaine: -0.67 (-1.24 to -0.09)d, P =0.02; Dexmedetomidine: -1.28 (-1.96 to -0.60)d, P =0.0002; Alvimopan: -0.58 (-0.84 to -0.32)d, P <0.0001] across wide ranges of evidence quality. Perioperative nonopioid analgesic use showed efficacy concerning bowel recovery as well as length of hospitalization [-1.29 (-1.95 to -0.62)d, P =0.0001]. Laxatives showed efficacy regarding bowel movements, but not food tolerance and hospitalization. Evidence supporting pharmacological treatment for clinically evident POI is limited. Results from one single study suggest that Neostigmine reduces time to flatus and accelerates bowel movements [-37.06 (-40.26 to -33.87)h, P <0.0001 and -42.97 (-47.60 to -38.35)h, P <0.0001, respectively] with low evidence quality. CONCLUSION: Current evidence concerning pharmacological prevention and treatment of POI following gastrointestinal tumor surgery is limited. Opioid-sparing concepts, reduction of sympathetic hyperreactivity, and laxatives should be implemented into multimodal perioperative approaches.

Enteric Nervous System Striped Patterning and Disease: Unexplored Pathophysiology.

The enteric nervous system (ENS) controls gastrointestinal (GI) motility, and defects in ENS development underlie pediatric GI motility disorders. In disorders such as Hirschsprung's disease (HSCR), pediatric intestinal pseudo-obstruction (PIPO), and intestinal neuronal dysplasia type B (INDB), ENS structure is altered with noted decreased neuronal density in HSCR and reports of increased neuronal density in PIPO and INDB. The developmental origin of these structural deficits is not fully understood. Here, we review the current understanding of ENS development and pediatric GI motility disorders incorporating new data on ENS structure. In particular, emerging evidence demonstrates that enteric neurons are patterned into circumferential stripes along the longitudinal axis of the intestine during mouse and human development. This novel understanding of ENS structure proposes new questions about the pathophysiology of pediatric GI motility disorders. If the ENS is organized into stripes, could the observed changes in enteric neuron density in HSCR, PIPO, and INDB represent differences in the distribution of enteric neuronal stripes? We review mechanisms of striped patterning from other biological systems and propose how defects in striped ENS patterning could explain structural deficits observed in pediatric GI motility disorders.

Bone marrow-derived mesenchymal stem cells mitigate chronic colitis and enteric neuropathy via anti-inflammatory and anti-oxidative mechanisms.

Current treatments for inflammatory bowel disease (IBD) are often inadequate due to limited efficacy and toxicity, leading to surgical resection in refractory cases. IBD's broad and complex pathogenesis involving the immune system, enteric nervous system, microbiome, and oxidative stress requires more effective therapeutic strategies. In this study, we investigated the therapeutic potential of bone marrow-derived mesenchymal stem cell (BM-MSC) treatments in spontaneous chronic colitis using the Winnie mouse model which closely replicates the presentation and inflammatory profile of ulcerative colitis. The 14-day BM-MSC treatment regimen reduced the severity of colitis, leading to the attenuation of diarrheal symptoms and recovery in body mass. Morphological and histological abnormalities in the colon were also alleviated. Transcriptomic analysis demonstrated that BM-MSC treatment led to alterations in gene expression profiles primarily downregulating genes related to inflammation, including pro-inflammatory cytokines, chemokines and other biomarkers of inflammation. Further evaluation of immune cell populations using immunohistochemistry revealed a reduction in leukocyte infiltration upon BM-MSC treatment. Notably, enteric neuronal gene signatures were the most impacted by BM-MSC treatment, which correlated with the restoration of neuronal density in the myenteric ganglia. Moreover, BM-MSCs exhibited neuroprotective effects against oxidative stress-induced neuronal loss through antioxidant mechanisms, including the reduction of mitochondrial-derived superoxide and attenuation of oxidative stress-induced HMGB1 translocation, potentially relying on MSC-derived SOD1. These findings suggest that BM-MSCs hold promise as a therapeutic intervention to mitigate chronic colitis by exerting anti-inflammatory effects and protecting the enteric nervous system from oxidative stress-induced damage.

Successful Sequential Liver and Isolated Intestine Transplantation for Mitochondrial Neurogastrointestinal Encephalopathy Syndrome: A Case Report.

BACKGROUND Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) is an autosomal recessive disease caused by thymidine phosphorylase deficiency leading to progressive gastrointestinal dysmotility, cachexia, ptosis, ophthalmoparesis, peripheral neuropathy and leukoencephalopathy. Although liver transplantation corrects thymidine phosphorylase deficiency, intestinal deficiency of the enzyme persists. Retrospective chart review was carried out to obtain clinical, biochemical, and pathological details. CASE REPORT We present a case of liver and subsequent intestine transplant in a 28-year-old man with MNGIE syndrome with gastrointestinal dysmotility, inability to walk, leukoencephalopathy, ptosis, cachexia, and elevated serum thymidine. To halt progression of neurologic deficit, he first received a left-lobe partial liver transplantation. Although his motor deficit improved, gastrointestinal dysmotility persisted, requiring total parenteral nutrition. After exhaustive intestinal rehabilitation, he was listed for intestine transplantation. Two-and-half years after liver transplantation, he received an intestine transplant. At 4 years after LT and 20 months after the intestine transplant, he remains off parenteral nutrition and is slowly gaining weight. CONCLUSIONS This is the first reported case of mitochondrial neurogastrointestinal encephalomyopathy to undergo successful sequential liver and intestine transplantation.

[Severe small bowel involvement and chronic intestinal pseudo-obstruction in systemic sclerosis (scleroderma): Pathophysiological, diagnostic and therapeutic basis, including parenteral nutrition]. / Atteinte sévère de l'intestin grêle et pseudo-obstruction intestinale chronique au cours de la sclérodermie systémique : bases physiopathologiques, diagnostiques et thérapeutiques, dont la nutrition parentérale.

Gastrointestinal involvement in systemic sclerosis can be severe, reaching the critical point of chronic intestinal pseudo-obstruction, secondary to major disorders of small bowel motility. It is associated with some clinical and biological characteristics, in particular the positivity of anti-fibrillarin/U3RNP antibodies. Chronic intestinal pseudo-obstruction (CIPO) is complicated by a small intestinal bacterial overgrowth that requires cyclic antibiotic therapy. CIPO leads to a reduction of the food intake, due to painful symptoms, nausea and vomiting caused by meals, and ultimately to severe malnutrition. Meal splitting is often transiently effective and patients require exogenous nutritional support, mostly parenteral. Systemic sclerosis is not an obstacle to initiation and long-term continuation of parenteral nutrition and central venous catheter implantation is not associated with an increased risk of cutaneous or infectious complications. However, continuation of long-term parenteral nutrition requires monitoring in an expert nutrition center in order to adapt nutritional volumes and intakes and to limit potentially fatal cardiac and hepatobiliary complications. In addition to nutrition, prokinetic treatments, whose side effects must be known, can be associated. Invasive procedures, whose risk-benefit ratio must be carefully assessed, can also be used to treat symptoms exclusively.

Chronic intestinal pseudo-obstruction: associations with gut microbiota and genes expression of intestinal serotonergic pathway.

BACKGROUND: Pediatric chronic intestinal pseudo-obstruction (PIPO) is a rare disease characterized by symptoms and radiological signs suggestive of intestinal obstruction, in the absence of lumen-occluding lesions. It results from an extremely severe impairment of propulsive motility. The intestinal endocrine system (IES) jointly with the enteric nervous system (ENS) regulates secreto-motor functions via different hormones and bioactive messengers/neurotransmitters. The neurotransmitter 5-hydroxytryptamine (5-HT) (or serotonin) is linked to intestinal peristalsis and secretory reflexes. Gut microbiota and its interplay with ENS affect 5-HT synthesis, release, and the subsequent serotonin receptor activation. To date, the interplay between 5-HT and gut microbiota in PIPO remains largely unclear. This study aimed to assess correlations between mucosa associated microbiota (MAM), intestinal serotonin-related genes expression in PIPO. To this purpose, biopsies of the colon, ileum and duodenum have been collected from 7 PIPO patients, and 7 age-/sex-matched healthy controls. After DNA extraction, the MAM was assessed by next generation sequencing (NGS) of the V3-V4 region of the bacterial RNA 16 S, on an Illumina Miseq platform. The expression of genes implicated in serotoninergic pathway (TPH1, SLC6A4, 5-HTR3 and 5-HTR4) was established by qPCR, and correlations with MAM and clinical parameters of PIPO have been evaluated. RESULTS: Our results revealed that PIPO patients exhibit a MAM with a different composition and with dysbiosis, i.e. with a lower biodiversity and fewer less connected species with a greater number of non-synergistic relationships, compared to controls. qPCR results revealed modifications in the expression of serotonin-related intestinal genes in PIPO patients, when compared to controls. Correlation analysis do not reveal any kind of connection. CONCLUSIONS: For the first time, we report in PIPO patients a specific MAM associated to underlying pathology and an altered intestinal serotonin pathway. A possible dysfunction of the serotonin pathway, possibly related to or triggered by an altered microbiota, may contribute to dysmotility in PIPO patients. The results of our pilot study provide the basis for new biomarkers and innovative therapies targeting the microbiota or serotonin pathways in PIPO patients.

Chronic intestinal pseudo-obstruction due to adult-onset acquired isolated hypoganglionosis with muscular atrophy in the small intestine: a case report and review of literature.

BACKGROUND: Chronic intestinal pseudo-obstruction (CIPO) is a rare intestinal disorder characterized by impaired propulsion of the digestive tract and associated with symptoms of intestinal obstruction, despite the absence of obstructive lesions. CIPO includes several diseases. However, definitive diagnosis of its etiology is difficult only with symptoms or imaging findings. CASE PRESENTATION: A 56-year-old man was referred to our hospital due to a 3-year history of continuous abdominal distention. Imaging, including computed tomography of the abdomen, and endoscopy revealed marked dilatation of the entire small intestine without any obstruction point. Therefore, he was diagnosed with CIPO. Since medical therapy didn't improve his symptoms, enterostomy and percutaneous endoscopic gastro-jejunostomy were performed. These procedures improved abdominal symptoms. However, he required home central venous nutrition due to dehydration. The pathological findings of full-thickness biopsies of the small intestine taken during surgery revealed decreased number and degeneration of ganglion cells in the normal plexus. These findings led to a final diagnosis of CIPO due to acquired isolated hypoganglionosis (AIHG). CONCLUSIONS: Here, we report the case of a patient with CIPO secondary to adult-onset AIHG of the small intestine. Since AIHG cannot be solely diagnosed using clinical findings, biopsy is important for its diagnosis.