Search

Background: Malabsorption syndrome is an umbrella term for manifestations consisting of diarrhea, steatorrhea, malnutrition, unexplained weight loss, persistent or recurrent abdominal pain, and anemia. Celiac disease and Tropical sprue remain the two important causes among many more. Materials and Methods: The objectives of this study were to assess the spectrum of histological features of malabsorption at a tertiary care center and to correlate the clinical, endoscopic, and histological features between the various etiologies. Biopsy specimens of 547 subjects formed the sample for this institutional-based, retrospective research. All subjects who had a clinical diagnosis of malabsorption and underwent subsequent endoscopic evaluation along with biopsy were considered. The hematoxylin and eosin-stained sections were analyzed for villous architecture and intraepithelial lymphocytes (IELs). The histopathological findings were further correlated with the endoscopic findings. Data thus obtained were statistically analyzed using Microsoft Excel for Windows (2010). Results: The mean age of the subjects was 46.65 ± 17.31 years and with 330 males (60.33%) and 217 female (39.63%) subjects. Chronic diarrhea was the major presenting symptom in 95% of the subjects (n = 520). Normal villous architecture was noted in 68.19%, while the remaining cases showed varying degrees of atrophy ranging from mild in 27.61% (n = 151) to moderate in 2.56% (n = 14) to severe in 1.65% (n = 9). IELs were noted in 70.78% of cases. Conclusion: Histopathological findings, when analyzed, showed intraepithelial lymphocytosis as the major diagnosis in 34.19% of cases (n = 187), followed by tropical sprue in 19.56% (n = 107) cases. The pathology was nonspecific in about 13.89% (n = 76).

Background: Malabsorption syndrome is an umbrella term for manifestations consisting of diarrhea, steatorrhea, malnutrition, unexplained weight loss, persistent or recurrent abdominal pain, and anemia. Celiac disease and Tropical sprue remain the two important causes among many more. Materials and Methods: The objectives of this study were to assess the spectrum of histological features of malabsorption at a tertiary care center and to correlate the clinical, endoscopic, and histological features between the various etiologies. Biopsy specimens of 547 subjects formed the sample for this institutional-based, retrospective research. All subjects who had a clinical diagnosis of malabsorption and underwent subsequent endoscopic evaluation along with biopsy were considered. The hematoxylin and eosin-stained sections were analyzed for villous architecture and intraepithelial lymphocytes (IELs). The histopathological findings were further correlated with the endoscopic findings. Data thus obtained were statistically analyzed using Microsoft Excel for Windows (2010). Results: The mean age of the subjects was 46.65 ± 17.31 years and with 330 males (60.33%) and 217 female (39.63%) subjects. Chronic diarrhea was the major presenting symptom in 95% of the subjects (n = 520). Normal villous architecture was noted in 68.19%, while the remaining cases showed varying degrees of atrophy ranging from mild in 27.61% (n = 151) to moderate in 2.56% (n = 14) to severe in 1.65% (n = 9). IELs were noted in 70.78% of cases. Conclusion: Histopathological findings, when analyzed, showed intraepithelial lymphocytosis as the major diagnosis in 34.19% of cases (n = 187), followed by tropical sprue in 19.56% (n = 107) cases. The pathology was nonspecific in about 13.89% (n = 76). [ABSTRACT FROM AUTHOR]

Pseudomelanosis duodeni is characterized by endoscopic findings of black or black-brown speckled pigmentation in the duodenal mucosa, usually diagnosed via biopsy. This report presents a case of a 75-year-old male presented with left lower abdominal pain, change in bowel habits, and decreased appetite. Gastroduodenoscopy and biopsies of the duodenum and antrum lead to the diagnosis of pseudomelanosis duodeni. [ABSTRACT FROM AUTHOR]

Summary: Background: The prevalence of coeliac disease doubled in Finland from 1980 to 2000. Aims: To investigate whether this increase is continuing and if there are specific patient‐related factors predicting the development of coeliac disease at a population level. Methods: We elicited comprehensive health data in the nationwide Health 2000 and Health 2011 surveys. Serum samples were taken for the measurement of tissue transglutaminase antibodies (TGA); subjects who were seropositive were tested for endomysial antibodies (EmA). Coeliac disease was defined either as a reported diagnosis or as positive TGA and EmA. The surveys comprised, respectively, 6379 and 4056 individuals, forming representative samples for 2,946,057 and 2,079,438 Finnish adults. Altogether 3254 individuals participating in both surveys comprised a prospective follow‐up cohort. Results: Prevalence of coeliac disease was 2.12% in 2000 and 2.40% in 2011 (p = 0.156). In the prospective cohort, 16 out of the 3254 (0.49%) subjects developed coeliac disease during follow‐up from 2000 to 2011, with an annual incidence rate of 45 per 100,000 persons. Positive TGA without EmA (OR: 133, 95% CI: 30.3–584), TGA values in the upper normal range (51.1, 16.0–163), and after adjusting for TGA, previous autoimmune co‐morbidity (8.39, 4.98–35.9) in 2000 increased the likelihood of subsequent coeliac disease. Conclusions: The nationwide prevalence of coeliac disease kept on rising from 2.12% in 2000 to 2.40% in 2011 in Finland. Positive TGA without EmA, TGA titres in the upper normal range and a pre‐existing autoimmune disease predisposed to coeliac disease during the 10‐year follow‐up. [ABSTRACT FROM AUTHOR]

Celiac disease (CD) a complex immune disease that affects duodenal mucosa. Identification of tissue specific biomarkers is expected to improve the existing biopsy based CD diagnosis. To investigate the differentially expressed genes (DEGs) in duodenal mucosa tissue to identify clinically relevant gene expression pattern in CD. Whole RNA extracted from the duodenal biopsies of three CD patients and four non-CD controls were sequenced. Significant DEGs were identified. Prioritized DEGs were validated using qRT-PCR in an independent group (CD=23; Control=26). Enriched pathways were analyzed, protein-protein interaction networks were evaluated. 923 DEGs comprising of 135 up-regulated, and 788 down-regulated genes, with p -value≤0.05; log2FC>2 or <-2 were identified. A novel down-regulated gene CDH18 (p = 0.03; log2FC=−0.74) was identified. Previously known CXCL9 was replicated. CDH18, a trans-membrane protein was found to interact with other CDH proteins, α/β catenins, and other membrane transporters such as SLC and ABCB. Pathways and protein networks contributing in channel activity (p = 2.15E-12), membrane transporters (p = 2.15E-12), and cellular adhesion (p = 8.05E-6) were identified. CDH18 , a novel DEG identified in the present study is a pivotal gene involved in maintaining epithelial membrane organization and integrity. The functional significance of lower expression of CDH18 in pathogenesis of CD warranted to be investigated. CDH18 expression could be tested for its effectiveness in diagnostic, prognostic and therapeutic purposes. [ABSTRACT FROM AUTHOR]

Background: Malnutrition is usual in patients referred for endoscopic gastrostomy (PEG). Refeeding syndrome is rarely observed in PEG-fed patients, which could possibly be associated with reduced absorption induced by prolonged starvation. Objective: In patients submitted to PEG after a significant period of fasting, the present study aims to: 1. evaluate the histological/ultrastructural initial changes in the intestinal mucosa, potentially associated with reduced absorption, and 2. assess if these changes could reverse with enteral refeeding. Methods: The present study is an observational, prospective, controlled study. Adult patients with ingestion below 50% of daily needs for at least one month and/or diagnosis of malnutrition were enrolled. Duodenal biopsies were taken at baseline and after 3–6 months of PEG feeding, which then underwent histological/ultrastructural analysis. Random healthy individuals were used as controls. Results: A total of 30 patients (16 men/14 women) aged 67.1 ± 13.5 years were included. Malnutrition was found in 40% of patients. Approximately 14 patients completed follow-up during both periods (46.7%). At baseline: duodenal mucosal atrophy was evident in three patients (10%); the median villi length (MVL) was 0.4 mm (0.25–0.6 mm), with it being shorter than the controls, which was 0.6 mm (0.4–0.7 mm) (p = 0.006); ultrastructural changes included focal shortening, bending, and disruption of enterocyte microvilli, the presence of citoplasmatic autophagic vacuoles, dilation and vesiculation of the smooth endoplasmic reticulum, and the presence of dilated intercellular spaces with basement membrane detachment. After refeeding, most patients displayed normal histology (92.9%) and increase MVL (p < 0.001), ultrastructural changes disappeared, and enterocytes resumed a normal appearance, although retaining scarce, small, dense bodies in apical regions from the evolution of previous autophagy. Conclusions: Prolonged fasting induces histological and ultrastructural changes in the intestinal mucosa that may reflect impaired absorption in the early post-PEG period. These changes were reverted after refeeding with enteral nutrition. [ABSTRACT FROM AUTHOR]

Objective: The small intestinal bacterial overgrowth (SIBO) in acute pancreatitis correlates with the severity of the disease. However, corresponding studies on the microbial composition of the duodenal mucosa of patients are uncommon. Methods: Duodenal mucosal biopsies were collected by gastroscopy from 16 patients with mild acute pancreatitis (the Ap group) and 16 healthy individuals (the control group) and subjected to histological studies as well as bacterial 16S rRNA gene sequencing. Caerulein and l-arginine were used to induce mild acute pancreatitis (MAP) and severe acute pancreatitis (SAP) in mice, respectively, and their pancreas and duodenum were collected for histological studies. Results: H&E analysis displayed no significant pathological damage in the descending duodenum of patients with acute pancreatitis compared with that of the controls. Immunofluorescence and Real-time PCR revealed that the expressions of tight junction proteins (TJPs) in duodenal mucosa were decreased in acute pancreatitis. The results of the alpha diversity analysis revealed no significant difference between the two groups, while LEfSe and the random forest revealed a few differences, indicating that the descending duodenum mucosal microbiota changed slightly in patients with mild acute pancreatitis. We observed the pathological changes and the expression of TJPs in the duodenum in the three groups of mice and found that SAP mice had more severe pathological damage in the duodenum. Furthermore, the expression of TJPs in the duodenum was lower in the MAP and SAP groups of mice compared to control mice, but it was similar in both groups. Conclusion: Patients with mild acute pancreatitis had mild duodenal barrier dysfunction and slight changes in duodenal mucosal microbiota. [ABSTRACT FROM AUTHOR]

Background: Malnutrition is usual in patients referred for endoscopic gastrostomy (PEG). Refeeding syndrome is rarely observed in PEG-fed patients, which could possibly be associated with reduced absorption induced by prolonged starvation. Objective: In patients submitted to PEG after a significant period of fasting, the present study aims to: 1. evaluate the histological/ultrastructural initial changes in the intestinal mucosa, potentially associated with reduced absorption, and 2. assess if these changes could reverse with enteral refeeding. Methods: The present study is an observational, prospective, controlled study. Adult patients with ingestion below 50% of daily needs for at least one month and/or diagnosis of malnutrition were enrolled. Duodenal biopsies were taken at baseline and after 3–6 months of PEG feeding, which then underwent histological/ultrastructural analysis. Random healthy individuals were used as controls. Results: A total of 30 patients (16 men/14 women) aged 67.1 ± 13.5 years were included. Malnutrition was found in 40% of patients. Approximately 14 patients completed follow-up during both periods (46.7%). At baseline: duodenal mucosal atrophy was evident in three patients (10%); the median villi length (MVL) was 0.4 mm (0.25–0.6 mm), with it being shorter than the controls, which was 0.6 mm (0.4–0.7 mm) (p = 0.006); ultrastructural changes included focal shortening, bending, and disruption of enterocyte microvilli, the presence of citoplasmatic autophagic vacuoles, dilation and vesiculation of the smooth endoplasmic reticulum, and the presence of dilated intercellular spaces with basement membrane detachment. After refeeding, most patients displayed normal histology (92.9%) and increase MVL (p < 0.001), ultrastructural changes disappeared, and enterocytes resumed a normal appearance, although retaining scarce, small, dense bodies in apical regions from the evolution of previous autophagy. Conclusions: Prolonged fasting induces histological and ultrastructural changes in the intestinal mucosa that may reflect impaired absorption in the early post-PEG period. These changes were reverted after refeeding with enteral nutrition.

Background: Subepithelial microvascular pattern cannot be visualized on the surface of adenoma and carcinoma by magnifying endoscopy due to a white opaque substance (WOS), which consists of minute lipid droplets accumulated in the neoplastic epithelium. Aims: We aimed to investigate whether the WOS is visualized in the duodenum after exogenous fat loading (FL) administration in an open-label, randomized, controlled study. Methods: The patients scheduled to undergo endoscopic therapy for gastric epithelial neoplasms were enrolled in the study. They were randomly assigned to the FL or non-FL group. An initial (before FL administration) and follow-up (after two to three weeks) endoscopic examinations were conducted to observe the duodenal mucosa using magnifying narrow-band imaging. Each patient in the FL group consumed 250 ml of Ensure H® four hours before the follow-up examination. Two experienced endoscopists determined the grade of the WOS. FL test results were judged positive for patients who showed a higher grade at the follow-up examination than at the initial examination. The rate of positive test results was compared between the two groups. Results: Twenty patients (10 in the FL and 10 in the non-FL groups) were included. FL test results were positive for all 10 patients in the FL group, while they were negative for all 10 patients in the non-FL group (P < 0.001 by Fisher's exact test). Conclusions: Lipids loaded onto normal duodenal epithelium were absorbed, and the absorbed lipid droplets appeared as WOS on magnifying narrow-band imaging. [ABSTRACT FROM AUTHOR]

An unidentified cause of functional dyspepsia (FD) is closely associated with medication resistance. Acid suppression is a traditional and preferential method for the treatment of FD, but the efficacy of this treatment varies between epigastric pain syndrome (EPS) and postprandial syndrome (PDS): it is efficient in the former but not much in the latter. Transepithelial electrical resistance (TEER), a surrogate of mucosal barrier function, was measured under pH 3 and pH 5 acidic conditions using duodenal biopsy specimens obtained from the patients with EPS and PDS and asymptomatic healthy controls. The infiltration of inflammatory cells to the duodenal mucosa was accessed by immunohistochemical analysis. The duodenal mucosal TEER in EPS patients was decreased by exposure to the acidic solution compared to that of the controls and the PDS patients. The decrease in TEER of the EPS patients was observed even under pH 5 weak acidic condition and was correlated to degree of the epigastric pain. Moreover, the duodenal mucosa of EPS patients presented an increase in mast cells and plasma cells that expressed Ig-E. Duodenal mucosal vulnerability to acid is likely to develop EPS. [ABSTRACT FROM AUTHOR]

Obesity is a major universal health issue linked to a majority of illness. To evaluate the histological and biochemical changes occurred in the duodenal mucosa of high fat diet HFD and orlistat fed rats and to assess the possible protective role of N-acetyl cysteine NAC supplementation. Sixty male albino rats weighing 180–200 g were classified randomly into control group I and three experimental groups (HFD group II, HFD + orlistat group III, and HFD + orlistat + NAC group IV). All experimental groups received HFD alone/and treatment for 6 weeks. Group III received orlistat (32 mg/kg/day) before meals and group IV received the same regimen as group III in addition to NAC (230 mg/kg/day) after meals. After completion of the experiment, duodenal sections were processed for histological examination, oxidative stress parameters, and semiqualitative real time PCR for proinflammatory mediators TNFα and IL6 evaluation. Also, plasma lipid parameters were assessed and morphometric duodenal results were analyzed statistically. By histological examination of HFD and (HFD + orlistat) groups, we found severe to moderate duodenal structural disturbances, increased goblet cells, collagen fibers, and BAX and iNOS immunostaining. By Biochemical examination, both groups showed increased proinflammatory markers level (TNFα and IL6) with decreased all antioxidant parameters and increased MDA. Moreover, NAC treatment in group IV significantly reduced all structural changes, levels of proinflammatory mediators and increased all antioxidant parameter levels and decreased MDA. All findings elucidated that NAC could be accounted to be a useful drug for protection of duodenal mucosa of HFD and orlistat treated animals. [ABSTRACT FROM AUTHOR]

We studied the changes in the cellular composition of the duodenal's crypts induced by chronic action of Epichlorohydrin (ECH) and the efficiency of the treatment by Echinacea purpurea (EP) extract and thiotriazoline for possible correction of these changes. On the 15th, 30th and 60th days, rats subjected to ECH, EP and thiotriazoline were removed from the experiment. According to the standard histological technique, sections of duodenum were processed, stained with hematoxylin-eosin, acid fuchsine and picric acid. Chronic exposure to ECH on duodenum led to statistically significant changes in the cellular composition of the crypts, which persisted after the cessation of the action of the chemical. On the 15th day, there was a decrease in the total number of cells in one crypt of the duodenal mucous membrane (MM), the number of columnar epithelial cells, argyrophilic endocrinocytes and Paneth cells in one crypt of the duodenal MM compared with the corresponding indicators in rats of the control group. Administration of EP extract and thiotriazoline on the background of chronic action of ECH prevented the development of negative changes in crypt composition of the duodenal MM. [ABSTRACT FROM AUTHOR]

An unidentified cause of functional dyspepsia (FD) is closely associated with medication resistance. Acid suppression is a traditional and preferential method for the treatment of FD, but the efficacy of this treatment varies between epigastric pain syndrome (EPS) and postprandial syndrome (PDS): it is efficient in the former but not much in the latter. Transepithelial electrical resistance (TEER), a surrogate of mucosal barrier function, was measured under pH 3 and pH 5 acidic conditions using duodenal biopsy specimens obtained from the patients with EPS and PDS and asymptomatic healthy controls. The infiltration of inflammatory cells to the duodenal mucosa was accessed by immunohistochemical analysis. The duodenal mucosal TEER in EPS patients was decreased by exposure to the acidic solution compared to that of the controls and the PDS patients. The decrease in TEER of the EPS patients was observed even under pH 5 weak acidic condition and was correlated to degree of the epigastric pain. Moreover, the duodenal mucosa of EPS patients presented an increase in mast cells and plasma cells that expressed Ig-E. Duodenal mucosal vulnerability to acid is likely to develop EPS.

Background: Malnutrition is usual in patients referred for endoscopic gastrostomy (PEG). Refeeding syndrome is rarely observed in PEG-fed patients, which could possibly be associated with reduced absorption induced by prolonged starvation. Objective: In patients submitted to PEG after a significant period of fasting, the present study aims to: 1. evaluate the histological/ultrastructural initial changes in the intestinal mucosa, potentially associated with reduced absorption, and 2. assess if these changes could reverse with enteral refeeding. Methods: The present study is an observational, prospective, controlled study. Adult patients with ingestion below 50% of daily needs for at least one month and/or diagnosis of malnutrition were enrolled. Duodenal biopsies were taken at baseline and after 3-6 months of PEG feeding, which then underwent histological/ultrastructural analysis. Random healthy individuals were used as controls. Results: A total of 30 patients (16 men/14 women) aged 67.1 ± 13.5 years were included. Malnutrition was found in 40% of patients. Approximately 14 patients completed follow-up during both periods (46.7%). At baseline: duodenal mucosal atrophy was evident in three patients (10%); the median villi length (MVL) was 0.4 mm (0.25-0.6 mm), with it being shorter than the controls, which was 0.6 mm (0.4-0.7 mm) ( p = 0.006); ultrastructural changes included focal shortening, bending, and disruption of enterocyte microvilli, the presence of citoplasmatic autophagic vacuoles, dilation and vesiculation of the smooth endoplasmic reticulum, and the presence of dilated intercellular spaces with basement membrane detachment. After refeeding, most patients displayed normal histology (92.9%) and increase MVL ( p < 0.001), ultrastructural changes disappeared, and enterocytes resumed a normal appearance, although retaining scarce, small, dense bodies in apical regions from the evolution of previous autophagy. Conclusions: Prolonged fasting induces histological and ultrastructural changes in the intestinal mucosa that may reflect impaired absorption in the early post-PEG period. These changes were reverted after refeeding with enteral nutrition.

Objective: Functional dyspepsia (FD) is a complex disorder, with debilitating epigastric symptoms. Evidence suggests alterations in gastrointestinal (GI) motility, visceral hypersensitivity, permeability and low-level immune activation in the duodenum may play a role. However, we still have a relatively poor understanding of how these factors interact to precipitate the onset of FD symptoms which are frequently meal related. The duodenal microbiota, in combination with specific dietary substrates, may be important mediators in disease pathophysiology; however, these interlinked factors have not been thoroughly investigated in FD., Design: Eighty-six individuals (56 FD, 30 controls) undergoing endoscopy were consecutively recruited and underwent detailed clinical assessment, including upper GI symptoms, gastric emptying and dietary assessment. Duodenal biopsies were obtained aseptically, and the mucosa-associated microbiota (MAM) analysed via 16S rRNA gene amplicon sequencing., Results: The relative abundances of predominant members of the Firmicutes, Bacteroidota and Fusobacteriota phyla were linked to symptom burden in FD. Inverse relationships between the relative abundances of Streptococcus and Prevotella, and the relative abundance of Veillonella spp with gastric emptying time, were also observed. No significant differences in long-term nutrient intake or diet quality were found between FD and controls, and there appeared to be limited association between habitual diet and duodenal MAM profiles., Conclusion: This study suggests a link between the duodenal MAM, gastric emptying and FD symptoms, and this is largely independent of long-term dietary intake., Competing Interests: Competing interests: These authors disclose the following: NJT reports personal fees from Allakos, Aviro Health, from Antara Life Sciences, Arlyx, Bayer, Danone, Planet Innovation, Takeda, Viscera Labs, twoXAR, Viscera Labs, Dr Falk Pharma, Censa, Cadila Pharmaceuticals, Progenity Inc, Sanofi-aventis, Glutagen, ARENA Pharmaceuticals, IsoThrive, BluMaiden, HVN National Science Challenge, non-financial support from HVN National Science Challenge NZ, outside the submitted work; In addition, NJT has a patent Biomarkers of IBS licensed (#12735358.9 -1405/2710383 and (#12735358.9 -1405/2710384), a patent Licensing Questionnaires Talley Bowel Disease Questionnaire licensed to Mayo/Talley, a patent Nestec European Patent licensed, and a patent Singapore Provisional Patent NTU Ref: TD/129/17 “Microbiota Modulation Of BDNF Tissue Repair Pathway” issued and copyright Nepean Dyspepsia Index (NDI) 1998 and Editorial: Medical Journal of Australia (Editor in Chief), Up to Date (Section Editor), Precision and Future Medicine, Sungkyunkwan University School of Medicine, South Korea, Med (Journal of Cell Press). NJT participates on committees for: Australian Medical Council (AMC) Council Member (2016-2019), MBS Review Taskforce (2016-2020), NHMRC Principal Committee, Research Committee (2016-2021), Asia Pacific Association of Medical Journal Editors (APAME) (current), GESA Board Member (2017-2019). NJT Misc: Avant Foundation (judging of research grants) (2019). NJT community and patient advocacy groups: Advisory Board, IFFGD (International Foundation for Functional GI Disorders). NJT acknowledges funding from the National Health and Medical Research Council (NHMRC) for the Centre for Research Excellence in Digestive Health. NJT holds an NHMRC Investigator grant. SK reports Grant/Research Support: National Health and Medical Research Council (Ideas Grant and Centre for Research Excellence) Viscera Labs (Research contract), Microba Life Science (Research contract). Consultant/Advisory Boards: Gossamer Bio (Scientific Advisory Board), Anatara Lifescience (Scientific Advisory Board), Microba Life Science (Consultancy). SK, MM, GLB, and NJT are co-inventors of “Diagnostic marker for functional gastrointestinal disorders” Australian Provisional Patent Application 2021901692, submitted 07/06/2021, via the University of Newcastle and UniQuest (University of Queensland) with PCT application 07/06/2022 (PCT/AU2022/050556). MM has received research grants from Soho Flordis International (SFI) Australia Research, Bayer Steigerwald Arzneimittelwerk and Yakult-Nature Global Grant for Gut Health; speaker’s honoraria, and travel sponsorship from Janssen Australia; consultancy fees from Sanofi Australia and Danone-Nutricia Australia; speaker honoraria and travel sponsorship from Perfect Company (China), and travel sponsorship from Yakult Inc (Japan). MM also acknowledges funding from NHMRC Australia, Australian Research Council, Princess Alexandra Hospital Research Foundation, Medical Research Futures Fund of Australia, Helmsley Charitable Trust via the Australasian Gastrointestinal Research Foundation, and United States Department of Defense. MM serves on the science advisory board (non-remunerated) for GenieBiome, Hong Kong. GJH reports to be on the advisory boards Australian Biotherapeutics, Glutagen, Bayer and received research support from Bayer, Abbott, Pfizer, Janssen, Takeda, Allergan. He serves on the Boards of the West Moreton Hospital and Health Service, Queensland, UQ Healthcare, Brisbane and the Gastro-Liga, Germany. He has a patent for the Brisbane aseptic biopsy device and serves as Editor of the Gastro-Liga Newsletter., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Although gut dysbiosis is increasingly recognised as a pathophysiological component of metabolic syndrome (MetS), the role and mode of action of specific gut microbes in metabolic health remain elusive. Previously, we identified the commensal butyrogenic Anaerobutyricum soehngenii to be associated with improved insulin sensitivity in subjects with MetS. In this proof-of-concept study, we investigated the potential therapeutic effects of A. soehngenii L2-7 on systemic metabolic responses and duodenal transcriptome profiles in individuals with MetS., Design: In this randomised double-blind placebo-controlled cross-over study, 12 male subjects with MetS received duodenal infusions of A. soehngenii / placebo and underwent duodenal biopsies, mixed meal tests (6 hours postinfusion) and 24-hour continuous glucose monitoring., Results: A. soehngenii treatment provoked a markedly increased postprandial excursion of the insulinotropic hormone glucagon-like peptide 1 (GLP-1) and an elevation of plasma secondary bile acids, which were positively associated with GLP-1 levels. Moreover, A. soehngenii treatment robustly shaped the duodenal expression of 73 genes, with the highest fold induction in the expression of regenerating islet-protein 1B ( REG1B )-encoding gene. Strikingly, duodenal REG1B expression positively correlated with GLP-1 levels and negatively correlated with peripheral glucose variability, which was significantly diminished in the 24 hours following A. soehngenii intake. Mechanistically, Reg1B expression is induced upon sensing butyrate or bacterial peptidoglycan. Importantly, A. soehngenii duodenal administration was safe and well tolerated., Conclusions: A single dose of A. soehngenii improves peripheral glycaemic control within 24 hours; it specifically stimulates intestinal GLP-1 production and REG1B expression. Further studies are needed to delineate the specific pathways involved in REG1B induction and function in insulin sensitivity., Trial Registration Number: NTR-NL6630., Competing Interests: Competing interests: MN is in the scientific board of Kaleido Biosciences, Boston USA. WMDV is founder and in the board of A-mansia, Belgium. FB is in the scientific board of Metabogen AB, Sweden. MN and WMDV are founders and Scientific Advisory Board members of Caelus Pharmaceuticals, the Netherlands. SLH is a paid consultant for P&G and coinventor on pending and issued patents held by the Cleveland Clinic, and is eligible for receiving payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland HeartLab, Quest Diagnostics and P&G., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Hydrothermal duodenal mucosal resurfacing (DMR) is a safe, outpatient endoscopic procedure. REVITA-2, a double-blind, superiority randomised controlled trial, investigates safety and efficacy of DMR using the single catheter Revita system (Revita DMR (catheter and system)), on glycaemic control and liver fat content in type 2 diabetes (T2D)., Design: Eligible patients (haemoglobin A1c (HbA1c) 59-86 mmol/mol, body mass index≥24 and ≤40 kg/m 2 , fasting insulin >48.6 pmol/L, ≥1 oral antidiabetic medication) enrolled in Europe and Brazil. Primary endpoints were safety, change from baseline in HbA1c at 24 weeks, and liver MRI proton-density fat fraction (MRI-PDFF) at 12 weeks., Results: Overall mITT (DMR n=56; sham n=52), 24 weeks post DMR, median (IQR) HbA1c change was -10.4 (18.6) mmol/mol in DMR group versus -7.1 (16.4) mmol/mol in sham group (p=0.147). In patients with baseline liver MRI-PDFF >5% (DMR n=48; sham n=43), 12-week post-DMR liver-fat change was -5.4 (5.6)% in DMR group versus -2.9 (6.2)% in sham group (p=0.096). Results from prespecified interaction testing and clinical parameter assessment showed heterogeneity between European (DMR n=39; sham n=37) and Brazilian (DMR n=17; sham n=16) populations (p=0.063); therefore, results were stratified by region. In European mITT, 24 weeks post DMR, median (IQR) HbA1c change was -6.6 mmol/mol (17.5 mmol/mol) versus -3.3 mmol/mol (10.9 mmol/mol) post-sham (p=0.033); 12-week post-DMR liver-fat change was -5.4% (6.1%) versus -2.2% (4.3%) post-sham (p=0.035). Brazilian mITT results trended towards DMR benefit in HbA1c, but not liver fat, in context of a large sham effect. In overall PP, patients with high baseline fasting plasma glucose ((FPG)≥10 mmol/L) had significantly greater reductions in HbA1c post-DMR versus sham (p=0.002). Most adverse events were mild and transient., Conclusions: DMR is safe and exerts beneficial disease-modifying metabolic effects in T2D with or without non-alcoholic liver disease, particularly in patients with high FPG., Trial Registration Number: NCT02879383., Competing Interests: Competing interests: GM has received funding/grant support from Novo Nordisk, Fractyl Laboratories, Metacure, Keyron, and honorarium for consultancy from Johnson & Johnson, Novo Nordisk, and Fractyl Laboratories. JD has received research support from Fractyl Laboratories Inc for IRB-approved studies. DH has received honorarium for consultancy and/or speaker fees from Novo Nordisk, Sanofi, Astra Zeneca, Roche, Sunovion, and Fractyl Laboratories. EM has received honorarium for consultancy from Olympus do Brasil and Boston Scientific. CC has received funding/grant support from Novo Nordisk and honorarium for consultancy from Novo Nordisk and Eurofarma. DLB reports that he serves or has served on advisory boards for Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, PhaseBio, PLx Pharma and Regado Biosciences. He is or was a member of the board of directors for Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft. He is or was chair for the American Heart Association Quality Oversight Committee, and is or was on data monitoring committees for Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), and the Population Health Research Institute. He reports honoraria from the American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org; vice-chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (editor in chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (editor in chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor and associate editor), K2P (cochair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national coleader, funded by Bayer), Slack Publications (chief medical editor, Cardiology Today–Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), WebMD (CME steering committees). He reports other relationships with Clinical Cardiology (deputy editor), NCDR-ACTION Registry Steering Committee (chair), and VA CART Research and Publications Committee (chair). He reports research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, and The Medicines Company. He reports royalties from Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease). He is or was a site coinvestigator for Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), and Svelte. He is or was a trustee for the American College of Cardiology. He reports unfunded research for FlowCo, Merck, Novo Nordisk, and Takeda. HR, JCL-T, KW, and VB are full-time employees of Fractyl Laboratories and may hold Fractyl stock and/or stock options. GC has received research grant support from Boston Scientific and Apollo and is on the advisory board for Cook Medical, Olympus, and Ethicon. RH has received funding/grant support/honorarium for consultancy from Cook Endoscopy, Pentax Europe, Medtronic, C2 Therapeutics, and Fractyl Laboratories to support research infrastructure. EG has received consulting fees from Fractyl Laboratories Inc, Apollo Endosurgery, and Medtronic. MGN has received honorarium for consultancy from Fractyl Laboratories, GI Windows, GI Dynamics, Apollo, and for speaker bureaus for Ethicon, Medtronic, and Olympus. GPA has been a consultant and advisory board member for Agios Pharmaceuticals, Amryt Pharma, AstraZeneca, GlaxoSmithKline and Pfizer. AR has received grant support from Norgine, Fujifilm, Boston Scientific and ERBE, and served as a member of advisory boards for Medtronic, Boston Scientific, EndoStart, EndoKey, Alfasigma and FujiFilm. AJM has received honorarium for consultancy from Fractyl Laboratories and Cook Medical. ACGvB, BH, RB, AH, MDC and NSS have nothing to disclose. AJS has been a consultant for Conatus, Gilead, Elsevier, Echosens, Malinckrodt, Immuron, Intercept, Pfizer, Salix, Uptodate, Boehringer, Ingelhiem, Novartis, Nimbus, Nitto Denko, Hemoshear, Lilly, Novo Nordisk, Fractyl Laboratories, Allergan, Chemomab, Affimmune, Teva, Ardelyx, Terns, ENYO, Birdrock, Albireo, Sanofi, Jannsen, Takeda, Zydus, BASF, Amra, Perspectum, OWL, Poxel, Servier, Second Genome, General Electric, and 89Bio. He is a stock/shareholder at Exhalenz Stock, Akarna, Durect, Indalo and Tiziana. He has received grant/research support from Novartis, Merck, Galectin, Bristol Myers, Merck, Sequana, Boehringer Ingelheim, Echosense, Salix, Malinckrodt, Cumberland, and Gilead.JJGHMB has received research support from Fractyl Laboratories for IRB-based studies and has received a consultancy fee for a single advisory board meeting for Fractyl Laboratories in September 2019., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: MN is in the Scientific Advisory Board of Caelus Pharmaceuticals, The Netherlands, and Kaleido Biosciences, USA. None of these is directly relevant to the current paper. DH has received honoraria from Fractyl for participating in scientific advisory boards. There are no patents, products in development or marketed products to declare. The other authors declare no competing financial interests.