Gut Involvement Research Articles

Novelties on Neuroinflammation in Alzheimer's Disease-Focus on Gut and Oral Microbiota Involvement.

Recent studies underscore the role of gut and oral microbiota in influencing neuroinflammation through the microbiota-gut-brain axis, including in Alzheimer's disease (AD). This review aims to provide a comprehensive synthesis of recent findings on the involvement of gut and oral microbiota in the neuroinflammatory processes associated with AD, emphasizing novel insights and therapeutic implications. This review reveals that dysbiosis in AD patients' gut and oral microbiota is linked to heightened peripheral and central inflammatory responses. Specific bacterial taxa, such as Bacteroides and Firmicutes in the gut, as well as Porphyromonas gingivalis in the oral cavity, are notably altered in AD, leading to significant changes in microglial activation and cytokine production. Gut microbiota alterations are associated with increased intestinal permeability, facilitating the translocation of endotoxins like lipopolysaccharides (LPS) into the bloodstream and exacerbating neuroinflammation by activating the brain's toll-like receptor 4 (TLR4) pathways. Furthermore, microbiota-derived metabolites, including short-chain fatty acids (SCFAs) and amyloid peptides, can cross the blood-brain barrier and modulate neuroinflammatory responses. While microbial amyloids may contribute to amyloid-beta aggregation in the brain, certain SCFAs like butyrate exhibit anti-inflammatory properties, suggesting a potential therapeutic avenue to mitigate neuroinflammation. This review not only highlights the critical role of microbiota in AD pathology but also offers a ray of hope by suggesting that modulating gut and oral microbiota could represent a novel therapeutic strategy for reducing neuroinflammation and slowing disease progression.

A Complex Relationship between Clostridium Difficile Infection and Graft Versus Hoste Disease: Fundeni Clinical Institute Experience

Introduction: Clostridium difficile infection (CDI) is a common complication in patients who have undergone hematopoietic stem cell transplantation (HSCT) due to prolonged hospitalization, prolonged neutropenia, use of broad-spectrum antibiotics, mucosal damage, changes in gut microbiota and compromised immunity. The incidence of CDI in patients undergoing allogeneic HSCT varies between 12 and 34% in the literature and has gradually increased in recent years in Europe North America due to the NAP1 strain. In the patient who has experienced allogeneic HSCT, diagnostic testing for CDI should include both nucleic acid amplification test (NAAT) and enzyme immunoassays (EIA) for toxins A and B, because detection of toxins A and B tests have a sensitivity of 75-80%. 5 In HSCT patients, CDI appears to be strongly associated with graft versus host disease (GVHD), gut GVHD and/or severe GVHD, but this has not been universally demonstrated. The aim: For this reason, we wanted to see whether patients who developed a CDI between day 0 and day 100 were at higher risk for gut GVHD or for severe GVHD. Results: Between January 2017 and August 2022, we performed 290 of allogeneic hematopoietic stem cell transplant procedures, in the Fundeni Clinical Institute. 50/290 developed CDI within the first 100 days after HSCT and before the diagnosis of intestinal GVHD, and 240/290 did not develop CDI. 16/50 (32%) of those with CDI developed acute GVHD, respectively 402/240 (43%) of those without CDI. From these 13/16, respectively 50/102 hade gut involvement. Of the 118 patients with acute GVHD, 13/16 in the group with CDI, respectively 30/102 in the group without CDI were assigned to severe acute GVDH (grade III and IV). Mortality due to gut GVHD in the group with CDI was 46%, respectively 14% in the group without CDI. In conclusion: CDI is not a risk factor for GVHD, but gut damage is usually associated. CDI infection is associated with severe forms of GVHD, and the implication of the digestive tract in these patients increases mortality. Also, often in the patient with digestive GVHD, CDI can coexist, making them difficult to treat.

Lung protection of Chimonanthus nitens Oliv. essential oil driven by the control of intestinal disorders and dysbiosis through gut-lung crosstalk

This work aimed to investigate whether Chimonanthus nitens Oliv. essential oil (CEO)-mediated lung protection was implicated in gut-lung crosstalk. Results showed that CEO attenuated lung and intestinal impairment by improving histopathological changes and inhibiting TLR4/NF-κB signaling pathway in LPS-stimulated rats, suggesting that there might be a mechanism for its lung protection involved in gut-lung interaction through manipulating the overlap in pathological changes via the similar inflammatory response. Furthermore, CEO-triggered intestinal protection was in parallel with the mitigation of ROS production, apoptosis, Ca2+ transport and mitochondrial membrane potential loss in vivo, and its intestinal protection was confirmed in vitro through IEC-6 cells. Importantly, a combination with CEO and LPS significantly remodeled gut microbiota composition compared with LPS alone in rats, while no significant impact on lung microbiota. Therefore, CEO-exerted lung protection was linked to gut and lung interactions involvement with the control of intestinal disorders and dysbiosis.

Actin dynamics regulation by TTC7A/PI4KIIIα limits DNA damage and cell death under confinement

The actin cytoskeleton has a crucial role in the maintenance of the immune homeostasis by controlling various cellular processes, including cell migration. Mutations in TTC7A have been described as the cause of a primary immunodeficiency associated to different degrees of gut involvement and alterations in the actin cytoskeleton dynamics. This study investigates the impact of TTC7A deficiency in immune homeostasis. In particular, the role of the TTC7A/phosphatidylinositol 4 kinase type III α pathway in the control of leukocyte migration and actin dynamics. Microfabricated devices were leveraged to study cell migration and actin dynamics of murine and patient-derived leukocytes under confinement at the single-cell level. We show that TTC7A-deficient lymphocytes exhibit an altered cell migration and reduced capacity to deform through narrow gaps. Mechanistically, TTC7A-deficient phenotype resulted from impaired phosphoinositide signaling, leading to the downregulation of the phosphoinositide 3-kinase/AKT/RHOA regulatory axis and imbalanced actin cytoskeleton dynamics. TTC7A-associated phenotype resulted in impaired cell motility, accumulation of DNA damage, and increased cell death in dense 3-dimensional gels in the presence of chemokines. These results highlight a novel role of TTC7A as a critical regulator of lymphocyte migration. Impairment of this cellular function is likely to contribute to the pathophysiology underlying progressive immunodeficiency in patients.

Intestinal fatty acid binding protein is associated with cardiac function and gut dysbiosis in chronic heart failure.

The gut microbiota in patients with chronic heart failure (HF) is characterized by low bacterial diversity and reduced ability to synthesize beneficial metabolites. These changes may facilitate leakage of whole bacteria or bacterial products from the gut into the bloodstream, which may activate the innate immune system and contribute to the low-grade inflammation seen in HF. In this exploratory cross-sectional study, we aimed to investigate relationships between gut microbiota diversity, markers of gut barrier dysfunction, inflammatory markers, and cardiac function in chronic HF patients. In total, 151 adult patients with stable HF and left ventricular ejection fraction (LVEF) < 40% were enrolled. We measured lipopolysaccharide (LPS), LPS-binding protein (LBP), intestinal fatty acid binding protein (I-FABP), and soluble cluster of differentiation 14 (sCD14) as markers of gut barrier dysfunction. N-terminal pro-B-type natriuretic peptide (NT-proBNP) level above median was used as a marker of severe HF. LVEF was measured by 2D-echocardiography. Stool samples were sequenced using 16S ribosomal RNA gene amplification. Shannon diversity index was used as a measure of microbiota diversity. Patients with severe HF (NT-proBNP > 895 pg/ml) had increased I-FABP (p < 0.001) and LBP (p = 0.03) levels. ROC analysis for I-FABP yielded an AUC of 0.70 (95% CI 0.61-0.79, p < 0.001) for predicting severe HF. A multivariate logistic regression model showed increasing I-FABP levels across quartiles of NT-proBNP (OR 2.09, 95% CI 1.28-3.41, p = 0.003). I-FABP was negatively correlated with Shannon diversity index (rho = -0.30, p = <0.001), and the bacterial genera Ruminococcus gauvreauii group, Bifidobacterium, Clostridium sensu stricto, and Parasutterella, which were depleted in patients with severe HF. In patients with HF, I-FABP, a marker of enterocyte damage, is associated with HF severity and low microbial diversity as part of an altered gut microbiota composition. I-FABP may reflect dysbiosis and may be a marker of gut involvement in patients with HF.

Optimizing nutrition IN pediatric intestinal pseudo-obstruction syndrome.

Pediatric intestinal pseudo-obstruction (PIPO) encompasses a variety of rare, heterogeneous, and disabling disorders that severely affect gastrointestinal motility and are associated with high morbidity and mortality. PIPO management is complex and focuses on maintaining an optimal nutritional status, improving gut function, relieving symptoms, and treating complications. Nutritional issues prevail, and PIPO patients often experience severe undernutrition and faltering growth. Thus, nutritional management plays a pivotal role for achieving the most favorable clinical outcomes. The calorie and nutrient intake of each patient needs to be tailored to age, extent and severity of gut involvement and nutritional needs to support an optimal nutritional status. After defining the extent and severity of gut dysmotility, an experienced team should perform a careful nutritional assessment. An oral diet should always be encouraged and might include bite and dissolve solids, liquid diet or simple oral stimulation. If oral caloric intake is inadequate, liquid gastric feeds should provide the subsequent step. In the presence of severe gastric dysmotility, continuous post-pyloric feeding represents a viable option. In the most severe cases, parenteral nutrition (PN) is required to meet appropriate nutritional requirements. Pediatric data on this topic are scarce and mainly extrapolated from adult studies. In this review, we discuss current evidence and knowledge regarding nutritional options, implications of the use of different feed types, including a blended diet, and the use of PN. Moreover, based on our experience and the evidence from the literature, we propose a flow chart to guide the nutritional management of PIPO patients.

Gut microbiota composition during hospitalization is associated with 60-day mortality after severe COVID-19

BackgroundGut microbiota alterations have been reported in hospitalized COVID-19 patients, with reduced alpha diversity and altered microbiota composition related to respiratory failure. However, data regarding gut microbiota and mortality are scarce.MethodsRectal swabs for gut microbiota analyses were collected within 48 h after hospital admission (baseline; n = 123) and three-month post-admission (n = 50) in a subset of patients included in the Norwegian SARS-CoV2 cohort study. Samples were analysed by sequencing the 16S rRNA gene. Gut microbiota diversity and composition at baseline were assessed in relation to need for intensive care unit (ICU) admission during hospitalization. The primary objective was to investigate whether the ICU-related gut microbiota was associated with 60-day mortality.ResultsGut microbiota diversity (Shannon index) at baseline was lower in COVID-19 patients requiring ICU admission during hospitalization than in those managed in general wards. A dysbiosis index representing a balance of enriched and reduced taxa in ICU compared with ward patients, including decreased abundance of butyrate-producing microbes and enrichment of a partly oral bacterial flora, was associated with need of ICU admission independent of antibiotic use, dexamethasone use, chronic pulmonary disease, PO2/FiO2 ratio, C-reactive protein, neutrophil counts or creatinine levels (adjusted p < 0.001). The ICU-related dysbiosis index at baseline correlated with systemic inflammation and was associated with 60-day mortality in univariate analyses (Hazard ratio 3.70 [2.00–8.6], p < 0.001), as well as after separate adjustment for covariates. At the three-month follow-up, the dysbiosis index remained elevated in ICU patients compared with ward patients (adjusted p = 0.007).ConclusionsAlthough our data should be regarded as exploratory due to low number of clinical end points, they suggest that gut microbiota alterations during hospitalization could be related to poor prognosis after severe COVID-19. Larger studies of gut involvement during COVID-19 in relation to long-term clinical outcome are warranted.Trial registrationNCT04381819. Retrospectively registered May 11, 2020.

Relationship between Undernutrition and Anemia in Patients with Ulcerative Colitis

This study aimed to assess the relationship between malnutrition and anemia in patients with ulcerative colitis (UC). The cross-sectional retrospective study included 80 patients with UC. Body mass index and total body fat mass were derived retrospectively from bioimpedance measurements. Anemia was diagnosed retrospectively according to WHO criteria. A binary logistic regression was performed to study the relationship between nutritional status parameters and anemia, and adjusted for demographic and disease-associated characteristics. The prevalence of anemia in the study population was 40.0%. Among all included patients, 86.3% had acute disease corresponding to S1–S3 disease behavior. In the adjusted binary logistic model, total serum protein level below 64 g/L and low body fat percentage were associated with high odds for the of development of anemia, with odds ratios of 5.1 (95% CI 1.5; 17.8; p = 0.01) and 8.5 (95% CI 1.1; 63.6; p = 0.037), respectively. The adjusted model included sex, age, disease activity, extent of gut involvement, quantity of relapses from disease onset, and treatment with immunosuppressive drugs as confounders. Hypoproteinemia and low body fat percentage were associated with anemia in patients with UC. These results suggested that undernutrition may be involved as one of the causative factors of anemia in UC.

Application of Contrast-Enhanced Ultrasound in the Diagnosis of Gastrointestinal Acute Gvhd - Single Centre Experience

Introduction: Acute graft versus host disease (aGVHD) is one of the most common complications after allogeneic stem cell transplant, with gastro-intestinal (gut) involvement being associated with increased morbidity and mortality. The gastrointestinal symptoms are common and therefore pose differential diagnostic challenges. Biopsy with histopathological exam by endoscopy represent the gold standard for the diagnosis of gut aGVHD. In clinical practice, the endoscopy exam, a minimal invasive investigation, is difficult to tolerate by the patient and sometimes risky to perform due to the severe thrombocytopenia. For this reason, there is an urgent need to find some non-invasive diagnostic methods, such as standard ultrasound and contrast-enhanced ultrasound (CEUS), hoping that these investigations will help in the early diagnosis as well as in the follow-up response treatment. Aim: The aim of this study was to present our experience with CEUS in diagnosis of gut aGVHD after allogeneic stem cell transplantation Results: Between January 2019 and March 2022, in Fundeni Clinical Institute, 168 allogeneic stem cell transplants were performed. 20/168 were readmitted into the hospital with non-infectious diarrhea and with suspicion of gut aGVHD. All patients were investigated by classical GI tract ultrasound and CEUS. For 12 patients out of 20 we had histopathological confirmation of gut GVHD and could thus corelate with the CEUS findings. For all patients the bowel wall thickness was increased, and the most affected areas were ileal loops, followed by ileocecal region and ascending colon. The most common feature, contrast agent migration in the intestinal lumen (the penetration of microbubbles in the bowel lumen) was observed in 3/12 patients, but, 9/12 remaining patients performed CEUS after the first dose of treatment with corticotherapy. In conclusion, CEUS represent a noninvasive, simple and viable investigation for gut aGVHD, most valuable probably for ileal localization, where the endoscopic approach is difficult. Therefore, it is important to establish which is the exact period after the onset of symptoms when the microbubbles migrate in the bowel lumen and if this parameter can be used to monitor the response to treatment. Based on these results, we aim to introduce CEUS evaluation as standard investigation for aGVHD and monitor all the patients.

P1361: TREATMENT OF SEVERE STEROID-REFRACTORY ACUTE GVHD WITH MESENCHYMAL STROMAL CELLS: RESULTS OF THE PHASE III RANDOMIZED DOUBLE-BLIND MULTI-CENTER HOVON-113 TRIAL

Background: Severe steroid-refractory acute graft-versus-host disease (SR-aGvHD) following allogeneic stem cell transplantation (HSCT) is associated with a high mortality rate. Mesenchymal stromal cell (MSC) therapy has emerged as a promising treatment option for SR-aGvHD, yet its clinical efficacy has never been conclusively demonstrated. Aims: The randomized double-blind placebo-controlled HOVON-113 trial was designed as an international effort to evaluate whether addition of MSC to standardized second line treatment of SR-aGVHD improves clinical outcome. Patients developing aGvHD grade II to IV after alloSCT or donor lymphocyte infusions (DLI) with gut and/or liver involvement and stable or progressive disease or mixed response after 5 to 10 days of 2 mg/kg steroids or equivalent, were eligible for the study. Methods: Patients were randomized to receive 2 intravenous infusions at a 7-day interval of either MSC 2 x 106/kg body weight or placebo. In addition, all patients received mycophenolate mofetil (MMF) as standardized second line treatment. Patients who developed aGvHD while on prophylactic MMF were ineligible for inclusion. The trial’s primary endpoint was complete or partial response at 28 days following the 1st MSC or placebo infusion, reported as overall response (OR). Secondary endpoints included overall survival (OS), cumulative incidence of chronic GvHD, and adverse events. A sample size of 150 patients was calculated to detect an increase in the aGvHD response rate from 40% to 65% with a power of 0.80 and a 2-sided significance level of 0.05. Results: In the course of 5 years, 41 eligible patients were included in the Netherlands, Germany, Spain, Italy, and Belgium. 7 of these were < 18 years (age range 1-16). 20 patients were randomized to the MSC arm and 21 to the placebo arm. At diagnosis, 12% of patients had grade II aGvHD, 68% grade III, and 20% grade IV. In 63% of cases, aGvHD had been elicited by alloSCT and in 37% of cases by DLI. These variables were distributed evenly between the treatment arms. Of the 41 patients, 36 (85%) received both infusions. 3 did not receive any infusions and 2 received only 1 infusion due to refusal (1) or swift clinical deterioration and death (4). No infusion toxicity was observed. OR at day 28 was reached by 8 (38%) of patients in the placebo arm and by 12 (60%) in the MSC arm (odds ratio = 2.48, 95% confidence interval (CI) 0.65-9.51, p = 0.19). 7 patients died before day 28 and could not be evaluated, 6 (29%) in the placebo arm and 1 (5%) in the MSC arm, and were considered as non-responders in the primary analysis. OS at 1 year after randomization was 33% (95% CI 15-53) in the placebo arm and 45% (95% CI 23-65) in the MSC arm (HR = 0.81, 95% CI 0.37-1.77, p = 0.60). Infectious complications were comparable between treatments arms; placebo arm: 25% grade 3, 45% grade 4; MSC arm: 22% grade 3, 39% grade 4. The main causes of death were GvHD and infections. The median follow-up of the 15 patients still alive was 24.0 months (range 9.4 – 73.8 months). Summary/Conclusion: Due to regulatory issues and insufficient accrual, the trial could only include 41 patients and did not have sufficient power to detect the anticipated difference between the two treatment arms. No statistically significant effect of MSC infusions on aGvHD response on day 28, overall survival, or safety could be demonstrated. An extensive biomarker analysis, immunological monitoring, quality of life analysis, health technology assessment, and ethical examination are still ongoing.

Case Report: Liver as a Source of Hematopoietic Stem Cells After Liver Transplantation Following Hematopoietic Stem Cell Transplantation

We report a child with Fanconi anemia who, after hematopoietic stem cell transplantation (HSCT) complicated by acute graft-versus-host disease (GVHD), underwent orthotopic liver transplantation (OLT). Approximately 1 month after OLT, the presence of third-party genetic material from the liver donor was noted and in the next few weeks, the chimerism assessment revealed 100% liver donor leukocytes in the peripheral blood. The rapidly progressing GVHD with gut involvement resulted in patient’s death 6 months after OLT. The liver can act as a clinically significant source of hematopoietic stem cells, and the liver donor’s young age must be emphasized as potentially predisposing to this phenomenon. Transfer of OLT hematopoietic stem cells may not have clinical significance unless the patient is not immunocompetent or develops liver-transplantation associated GVHD, that can result in lymphocyte mediated elimination of original hematopoiesis. Patients with preexisting immunity disorder (such as primary or secondary immunodeficiency) might require intensified immunosuppressive therapy in peritransplant period as a prevention of liver-transplantation associated GVHD. Close monitoring of hematopoietic chimerism after OLT is warranted in patients at risk, because cytopenia or OLT hematopoiesis can reflect subclinical GVHD and further studies are necessary to elucidate this phenomenon.

Gut and liver involvement in pediatric hematolymphoid malignancies.

Hematolymphoid malignancies are common neoplasms in childhood. The involvement of the gastrointestinal (GI) tract, liver, biliary system, pancreas, and peritoneum are closely interlinked and commonly encountered. In leukemias, lymphomas, and Langerhans cell histiocytosis (LCH), the manifestations result from infiltration, compression, overwhelmed immune system, and chemotherapy-induced drug toxicities. In acute leukemias, major manifestations are infiltrative hepatitis, drug induced gastritis, neutropenic typhlitis and chemotherapy related pancreatitis. Chronic leukemias are rare. Additional presentation in lymphomas is cholestasis due to infiltration or biliary obstruction by lymph nodal masses. Presence of ascites needs a thorough workup for the underlying pathophysiology that may modify the therapy and affect the outcome. Uncommon hematolymphoid malignancies are primary hepatic, hepatosplenic, and GI lymphomas which have strict definitions. In advanced diseases with extensive spread, it may be impossible to distinguish these diseases from the primary site of origin. LCH produces biliary strictures that mimic as sclerosing cholangitis. Liver infiltration is associated with poor liver recovery even after chemotherapy. The heterogeneity of gut and liver manifestations in hematolymphoid malignancies has a clinical impact on their management. Though chemotherapy is the mainstay of therapy in all hematolymphoid malignancies, debulking surgery and radiotherapy have an adjuvant role in specific clinical scenarios. Rare situations presenting as liver failure or end-stage liver disease require liver transplantation. At their initial presentation to a primary care physician, given the ambiguity in clinical manifestations and the prognostic difference with time-bound management, it is vital to recognize them early for optimal outcomes. Pooled data from robust registries across the world is required for better understanding of these complications.

Prediction of outcomes after second-line treatment for acute graft-versus-host disease

AbstractAcute graft-versus-host disease (GVHD) requiring second-line treatment represents a highly morbid complication of allogenic hematopoietic cell transplantation (HCT). Recent studies have defined short-term outcomes after second-line treatment for acute GVHD, but longer-term outcomes have not been well defined. We examined overall survival (OS) and failure-free-survival (FFS) of 216 patient who had HCT who received second-line treatment for acute GVHD. Failure time for FFS was defined as the earliest of death, relapse, or implementation of third-line treatment. Multivariable Cox regression was used to identify risk factors for mortality and failure, and predictive models were derived for 6- and 12-month mortality. Point estimates of OS at 6 and 12 months were 59% (95% confidence interval [CI], 52-65) and 52% (95% CI, 45-68), respectively. Point estimates of FFS at 6 and 12 months were 42% (95% CI, 35-48) and 37% (95% CI, 31-43), respectively. Predictive models for both end points included serum albumin and total bilirubin concentrations at the onset of second-line treatment, patient age at onset of second-line therapy, and a combination of abdominal pain/stage 4 gut involvement. Optimism-corrected areas under the receiver-operator characteristic curve and Brier scores were 77.4 and 0.169 for 6-month mortality, respectively, and 80.0 and 0.169 for 12-month mortality. We identify risk factors associated with mortality and failure after second-line treatment of acute GVHD, provide historical benchmarks for assessment of FFS and OS in other studies, and propose predictive models for 6- and 12-month mortality that could be used to generate population-specific benchmarks.

Bowel wall thickness is a strong predictor of steroid-refractory acute graft-versus-host disease with gut involvement after allo-HSCT.

Acute graft-versus-host-disease (aGVHD) develops in 10-80% of allo-HSCT patients. More than half of all aGVHD cases are refractory to first-line therapy with steroids. We hypothesized that bowel wall thickness at the time of aGVHD diagnosis could be an early sign of steroid-refractory aGVHD with gut involvement. Our prospective study included 85 patients with hematological malignancies who had undergone allo-HSCT. We used an inexpensive, widespread and simple method of transabdominal ultrasonography to examine bowel wall thickness in patients suspected to have gut aGVHD. Descending colon wall thickness was significantly greater in patients with gut aGVHD later found to be steroid-refractory than in patients with steroid-sensitive gut aGVHD, with AUC-0.73 (95% CI 0.58-0.87, p = 0.013). We showed that bowel wall thickness could predict the steroid-refractoriness of aGVHD. Transabdominal ultrasonography could be used as a marker of steroid-refractory aGVHD with gut involvement after allo-HSCT.

The second brain in Parkinson's disease: fact or fantasy?

The second brain in Parkinson's disease: fact or fantasy?

Is Gut Involvement a Cause or Effect of COVID-19?

Digestive disorder symptoms in COVID-19 may be similar in form to post-infectious functional gastrointestinal disorder (PI-FGID). To cause clinical effects, SARS-CoV-2 must reach the bowels and gastric hypochlorhydria may facilitate such transit. Asian elderly are predisposed to greater infection rate and severity of COVID-19, and the high prevalence of gastric atrophy and intake of proton-pump inhibitor in this aged group might explain the risk. Persistence shedding of SARS-CoV-2 in stools indicates that faecal transmission should not be disregarded. Gut involvement in COVID-19 is mediated by angiotensin-converting enzyme 2 (ACE2) receptor, which serves as the entry point for SARS-CoV-2 in the small bowel. ACE2 dysregulation has an impact on the homeostasis of gut microbiota and altered inflammatory response. Liver injury is variable in COVID-19 and is likely a result of by-stander effects rather than actual viropathic process. Further research is needed to understand if gut involvement is a cause or effect of SARS-CoV-2.

Acute GvHD after HLA-Haploidentical Hematopoietic Cell Transplantation with Regulatory and Conventional T Cell Immunotherapy Does Not Adversely Affect Transplantation Outcomes

IntroductionAdoptive immunotherapy with CD4+CD25+FOXP3+ regulatory T cells (Tregs) and conventional T cells (Tcons) has been employed after allogeneic hematopoietic stem cell transplantation (HSCT) to prevent Graft-versus-Host Disease (GvHD) while mantaining Graft-versus-Leukemia effect in the absence of any further immune suppressive GvHD prophylaxis (Di Ianni, Blood 2011; Martelli, Blood 2014). A recent study of age-adapted haploidentical HSCT with Treg/Tcon adoptive immunotherapy (Treg/Tcon haplo-HSCT) resulted in an unprecedented 75% chronic GvHD (cGvHD)/leukemia-free survival (CRFS) in acute myeloid leukemia patients. Acute GvHD (aGvHD) occured in 33% of patients and was the most frequent complication of the procedure (Pierini, Blood Advances 2021). Here, we analyzed clinical and histological characteristics of aGvHD and evaluated its impact on outcomes in patients who received Treg/Tcon haplo-HSCT.MethodsWe retrieved data of patients who underwent Treg/Tcon haplo-HSCT at Perugia University Hospital and who were evaluable for aGvHD from January 2015 until June 2021 (clinicaltrials.gov: NCT03977103). Histological features and lymphoid infiltration by immunohistochemistry were analyzed in gut samples of patients who received diagnostic colonscopy and biopsy for gastrointestinal symptoms.ResultsA total of 105 patients engrafted after Treg/Tcon haplo-HSCT. Mean age at transplant was 48 years (range 18-70). Acute leukemia was the most frequent diagnosis (78/105 myeloid, 23/105 lymphoblastic), 4 patients had myelodisplastic syndrome and 2 multiple myeloma. Twenty-seven (26%) patients had active disease at the time of HSCT. Fourteen (13%) patients received Treg/Tcon haplo-HSCT as a second HSCT procedure. Thirty-one (29%) patients developed grade II-IV aGvHD. Four patients had grade II aGvHD, 23 grade III, and 4 grade IV. Almost all patients (90%) presented gut involvement, while skin was involved in 64% of them and liver in 35%. To explain why gut symptoms such as diarrhea and abdominal pain were more frequently present than symptoms of skin or liver involvement, we evaluated 40 histological samples from 34 patients who received colonoscopy for suspected aGvHD. Twenty-two of them (65%) received a clinical diagnosis of aGvHD and pharmacological immune suppression was promptly started. Clinical diagnosis did not always match histological findings: biopsies were suggestive of aGvHD in 20/22 patients who required treatment, but also in 8/12 patients who did not. We found no difference in median CD3+ cell infiltration among patients who did not need immune suppressive treatments and patients with aGvHD (460 cells/mmq vs 446 cells/mmq). However, FOXP3+ Tregs preferentially infiltrated gut mucosa of patients who resolved clinical symptoms with no need of immune suppressive treatments (120 cells/mmq vs 59 cells/mmq, p = 0.008; FOXP3/CD3 ratio: 0.27 vs 0.18, p = 0.004). This observation suggested Treg defective homing to gut mucosa of aGvHD patients. Indeed, we found infused Tregs expressed lower levels of gut homing receptor α4β7 in comparison with Tcons (p< .001).Despite severe presentation at diagnosis, aGvHD resolved in the majority of patients (71%), and immune suppressive therapy could be completely withdrawn after a relatively short-course (median: 98 days, range 48-404). Sixteen/31 patients (52%) were steroid refractory and required further treatments after first-line (e.g. Ruxolitinib). Only two of them developed moderate/severe cGvHD and one is alive and off-therapy.Indeed, aGvHD diagnosis did not result in higher incidence of non-relapse mortality (cumulative incidence of 29% in aGvHD patients vs 27% in controls; p=non significant, ns, Fig.1A), relapse (13% vs 20%; p=ns, Fig.1B), or cGvHD (6.5% vs 3%; p=ns, Fig.1C). In fact, CRFS of aGvHD patients was similar to CRFS of patients that did not develop aGvHD (Fig. 1D, p=ns, median follow up of live patients: 1246 days).ConclusionsTreg/Tcon haplo-HSCT is followed by low rates of relapse and cGvHD and results in good CRFS in high risk leukemia patients. aGvHD after Treg/Tcon haplo-HSCT preferentially involves the gut where Treg homing is defective. Strategies that enhance Treg homing in the gut (e.g. low-dose IL-2) may help reduce aGvHD after Treg/Tcon haplo-HSCT. In conclusion, despite aGvHD occurred in 29% of patients, it was responsive to treatments and it did not result in disease relapse or cGvHD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

S440 Clinical Characteristics and Endoscopic Features in Patients With Esophageal Graft versus Host Disease

Introduction: Graft versus host disease (GVHD) is an immunologic disorder most commonly following hematopoietic stem cell transplantation (HSCT) that frequently involves the gastrointestinal tract but not the esophagus. The aim of this study was to describe the clinical characteristics and endoscopic features in patients with esophageal GVHD. Methods: In this retrospective cohort study, we identified all patients with esophageal GVHD at Mayo Clinic between January 1, 2000 and June 3, 2021. Patients were included if they had a histologic diagnosis of GVHD from esophageal biopsies interpreted by an expert gastrointestinal pathologist (C.E.H). Retrospective chart review was performed to gather data on clinical characteristics and endoscopic features. Numerical and categorical data were reported as median (range) and proportions. Results: Forty-three patients with esophageal GVHD were included with median age 59 (5-75) years and 29 (67%) were men (Table 1). Forty-2 (98%) had received HSCT and 1 liver transplant. The median time from transplant to esophageal GVHD was 3 (0-39) months. Twenty-5 (58%) patients had known GVHD prior to esophageal involvement. Other organ involvement with GVHD was common at esophageal GVHD diagnosis, most commonly involving skin (72%). Clinical symptoms at esophageal GVHD diagnosis included nausea/vomiting (63%), anorexia (51%), diarrhea (44%), weight loss >5% (37%), and dysphagia (26%). Odynophagia (5%) and heartburn (5%) were less common. EGD showed no abnormalities in the esophagus in 13 (30%) patients. Where esophageal endoscopic abnormalities were present, 20 (67%) were diffuse and 10 (33%) were focal, and included erosive esophagitis in 10 (23%) patients, ulceration 7 (16%), desquamation 6 (14%), rings/furrows 6 (14%), and erythema/edema 5 (12%) (Figure 1). Concurrent endoscopic abnormalities were present in the stomach in 24 (56%) patients, duodenum 16 (37%), and colon 15 (35%). All patients were treated with steroids and 16 (37%) had recurrent gastrointestinal symptoms with steroid discontinuation. Twenty-one (49%) patients had a follow-up EGD at median 4.5 (0-29) months with 11 (52%) having persistent esophageal GVHD and 3 (14%) requiring dilation. Conclusion: As esophageal GVHD is associated with gut and other organ involvement and clinical and/or endoscopic findings are non-specific or absent, there should be a low threshold for biopsy when esophageal GVHD is suspected in the presence of other gastrointestinal involvement.Figure 1.: Endoscopic findings seen with esophageal graft versus host disease include A) erosive esophagitis, B) ulceration, C) desquamation, and D) rings.Table 1.: Clinical characteristics in patients with esophageal graft versus host disease.

S3689 Small Bowel Obstruction in COVID-19 Patient Without Risk Factors

Introduction: The documented gastrointestinal associations of COVID-19 infection include enteritis, colitis, ileus, and mesenteric thrombosis from associated coagulopathy. A direct link to small bowel obstruction (SBO) has yet to be proposed. Aside from isolated cases of bacterial enteritis, infection is not a widely accepted cause of SBO. SBO is mostly caused by adhesions formed after intra-abdominal surgery. Other causes include congenital adhesions, neoplasms, hernias, and stenosis from inflammatory bowel disease (IBD) or bowel ischemia. We report a unique case of acute SBO in a patient with COVID-19 symptoms but no known risk factors of SBO. Case Description/Methods: A 67-year-old man with history of HTN and TURP for BPH presented with intermittent fever and dry cough for 1 week. He had no history of abdominal surgery, hernia, malignancy, IBD, or bowel ischemia. He was febrile to 102.6F and O2 saturation was 100% on room air without respiratory distress. SARS-CoV-2 PCR assay was positive. After two days of remdesivir, he was hypoxic requiring nasal cannula and had abdominal pain with loose stool. On exam, abdomen was distended with guarding. CT abdomen showed 2 transition points, multiple dilated bowel loops, and fluid and stool in distal bowel consistent with partial SBO. Nasogastric tube drained gastric contents with bile. He was intubated for ex-lap which showed no transition points or congenital adhesions. Proximal two-thirds of bowel were dilated, thickened, and hyperemic but the distal third was normal caliber. Creeping fat and friable mesentery with ecchymosis were noted throughout. Abdomen was left open with plan for closure the following day. Closure was delayed by 4 days due to worsening hypoxia and new pressor requirements. Oxygen and pressor requirements improved after starting steroid and antibiotic treatment. Abdomen was then closed as bowel remained viable. He was extubated, weaned to room air, and able to tolerate food within 1 week followed by discharge to rehab. Discussion: In our patient who developed partial SBO in the setting of worsening COVID-19 respiratory symptoms with no history of intra-abdominal surgery or other risk factors of SBO, COVID-19 should be considered as a possible etiology. Ex-lap findings were non-specific and could indicate inflammatory or ischemic evidence of COVID-19 gut involvement. Further research is required to better understand this patient’s diagnosis and a possible relationship between COVID-19 enteritis and acute development of SBO.Figure 1:: CT Abdomen Showing Two Transition Points Image A: Transition point in left mid abdomen. Image B: Transition point in right mid abdomen.

Early constipation predicts faster dementia onset in Parkinson\u2019s disease

Constipation is a common but not a universal feature in early PD, suggesting that gut involvement is heterogeneous and may be part of a distinct PD subtype with prognostic implications. We analysed data from the Parkinson’s Incidence Cohorts Collaboration, composed of incident community-based cohorts of PD patients assessed longitudinally over 8 years. Constipation was assessed with the MDS-UPDRS constipation item or a comparable categorical scale. Primary PD outcomes of interest were dementia, postural instability and death. PD patients were stratified according to constipation severity at diagnosis: none (n = 313, 67.3%), minor (n = 97, 20.9%) and major (n = 55, 11.8%). Clinical progression to all three outcomes was more rapid in those with more severe constipation at baseline (Kaplan–Meier survival analysis). Cox regression analysis, adjusting for relevant confounders, confirmed a significant relationship between constipation severity and progression to dementia, but not postural instability or death. Early constipation may predict an accelerated progression of neurodegenerative pathology.