Search

The human ileum contains a high density of enteroendocrine L-cells, which release the appetite-suppressing hormones glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) in response to food intake. Recent evidence highlighted the potential role of food structures in PYY release, but the link between food structures, ileal metabolites, and appetite hormone release remains unclear owing to limited access to intact human ileum. In a randomized crossover trial (ISRCTN11327221; isrctn.com), we investigated the role of human ileum in GLP-1 and PYY release by giving healthy volunteers diets differing in fiber and food structure: high-fiber (intact or disrupted food structures) or low-fiber disrupted food structures. We used nasoenteric tubes to sample chyme from the intact distal ileum lumina of humans in the fasted state and every 60 min for 480 min postprandially. We demonstrate the highly dynamic, wide-ranging molecular environment of the ileum over time, with a substantial decrease in ileum bacterial numbers and bacterial metabolites after food intake. We also show that high-fiber diets, independent of food structure, increased PYY release compared with a low-fiber diet during 0 to 240 min postprandially. High-fiber diets also increased ileal stachyose, and a disrupted high-fiber diet increased certain ileal amino acids. Treatment of human ileal organoids with ileal fluids or an amino acid and stachyose mixture stimulated PYY expression in a similar profile to blood PYY concentrations, confirming the role of ileal metabolites in PYY release. Our study demonstrates the diet-induced changes over time in the metabolite environment of intact human ileum, which play a role in PYY release. Editor's summary: The digestion of different foods as they travel the length of the gastrointestinal tract is highly orchestrated, and the true complexity of this process is just beginning to be understood. Dagbasi et al. studied how fiber content and food structure affect nutrient metabolism and release of appetite-controlling peptides such as PYY in the human ileum. They found that high dietary fiber consumption, regardless of the extent of food processing, promoted ileal PYY (but not GLP-1) release in healthy volunteers. This PYY release was promoted by ileal metabolites, showing how what we eat may signal to the intestine to feed back on whole-body physiology. —Catherine Charneski [ABSTRACT FROM AUTHOR]

Objectives: Peptide tyrosine tyrosine (PYY) exists as two species, PYY1‐36 and PYY3‐36, with distinct effects on insulin secretion and appetite regulation. The detailed effects of bariatric surgery on PYY1‐36 and PYY3‐36 secretion are not known as previous studies have used nonspecific immunoassays to measure total PYY. Our objective was to characterize the effect of sleeve gastrectomy (SG) and Roux‐en‐Y gastric bypass (RYGB) on fasting and postprandial PYY1‐36 and PYY3‐36 secretion using a newly developed liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) assay. Design and Subjects: Observational study in 10 healthy nonobese volunteers and 30 participants with obesity who underwent RYGB (n = 24) or SG (n = 6) at the Imperial Weight Centre [NCT01945840]. Participants were studied using a standardized mixed meal test (MMT) before and 1 year after surgery. The outcome measures were PYY1‐36 and PYY3‐36 concentrations. Results: Presurgery, the fasting and postprandial levels of PYY1‐36 and PYY3‐36 were low, with minimal responses to the MMT, and these did not differ from healthy nonobese volunteers. The postprandial secretion of both PYY1‐36 and PYY3‐36 at 1 year was amplified after RYGB, but not SG, with the response being significantly higher in RYGB compared with SG. Conclusions: There appears to be no difference in PYY secretion between nonobese and obese volunteers at baseline. At 1 year after surgery, RYGB, but not SG, is associated with increased postprandial secretion of PYY1‐36 and PYY3‐36, which may account for long‐term differences in efficacy and adverse effects between the two types of surgery. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer is one of the most common cancers in the world, and despite improvements in treatment, it remains a significant health burden. B7-H3 is a member of the B7 immune checkpoint family of membrane proteins and shows increased expression in lung cancers; however, the functional consequences of this to cancer cell signalling remain unclear. Here, we show that B7-H3 forms a complex with the metabolic enzyme IMPDH2, and this protects cancer cells from oxidative stress and resulting apoptosis triggered by chemotherapy. The removal of B7-H3 from cancer cells in 2D results in sensitisation to chemotherapeutic stress and reduces cell viability in an IMPDH2-dependent manner. However, the loss of B7-H3 in 3D spheroid models results in enhanced IMPDH2-dependent spheroid growth, likely due to the weakening of cell–cell adhesion. These findings demonstrate that B7-H3 functionally contributes to metabolic signalling in lung cancer cells in the absence of immune cell interactions. Lung cancer is one of the most common cancers worldwide, and despite improvements in treatment regimens, patient prognosis remains poor. Lung adenocarcinomas develop from the lung epithelia and understanding how specific genetic and environmental factors lead to oncogenic transformation in these cells is of great importance to define the pathways that contribute to tumorigenesis. The recent rise in the use of immunotherapy to treat different cancers has prompted the exploration of immune modulators in tumour cells that may provide new targets to manipulate this process. Of these, the B7 family of cell surface receptors, which includes PD-1, is of particular interest due to its role in modulating immune cell responses within the tumour microenvironment. B7-H3 (CD276) is one family member that is upregulated in many cancer types and suggested to contribute to tumour–immune interactions. However, the function and ligand(s) for this receptor in normal lung epithelia and the mechanisms through which the overexpression of B7-H3 regulate cancer progression in the absence of immune cell interactions remain unclear. Here, we present evidence that B7-H3 is associated with one of the key rate-limiting metabolic enzymes IMPDH2, and the localisation of this complex is altered in human lung cancer cells that express high levels of B7-H3. Mechanistically, the IMPDH2:B7-H3 complex provides a protective role in cancer cells to escape oxidative stress triggered by chemotherapy, thus leading to cell survival. We further demonstrate that the loss of B7-H3 in cancer cells has no effect on growth or migration in 2D but promotes the expansion of 3D spheroids in an IMPDH2-dependent manner. These findings provide new insights into the B7-H3 function in the metabolic homeostasis of normal and transformed lung cancer cells, and whilst this molecule remains an interesting target for immunotherapy, these findings caution against the use of anti-B7-H3 therapies in certain clinical settings. [ABSTRACT FROM AUTHOR]

Background: We conducted a single-arm interventional study, to explore mucosal changes associated with clinical remission under oral vancomycin (OV) treatment, in primary sclerosing cholangitis associated inflammatory bowel disease (PSC-IBD); NCT05376228., Method: Fifteen patients with PSC and active colitis (median faecal calprotectin 459µg/g; median total Mayo score 5) were treated with OV (125mg QID) for 4 weeks and followed-up for a further 4 weeks of treatment withdrawal (8 weeks, end-of-study). Colonic biopsies were obtained at baseline and week 4. Clinical assessments, and serum and stool samples (metagenomics, metatranscriptomics and metabolomics) were collected at weeks 0, 2, 4 and 8. The primary efficacy outcome measure was induction of clinical remission., Results: OV resulted in clinical remission in 12/15 patients and significant reductions in faecal calprotectin. OV was associated with reduced abundances of Lachnospiraceae, genera Blautia and Bacteroides; and enrichment of Enterobacteriaceae, and genera Veillonella, Akkermansia and Escherichia. OV treatment was associated with downregulation of multiple metatranscriptomic pathways (including short chain fatty acid [SCFA] metabolism and bile acid [BA] biotransformation), along with host genes and multiple pathways involved in inflammatory responses and antimicrobial defence; and an upregulation of genes associated with extracellular matrix repair. OV use resulted in loss of specific faecal SCFAs and secondary BAs, including lithocholic acid derivatives. Colitis activity relapsed following OV withdrawal, with host mucosal and microbial changes trending towards baseline., Conclusion: Four weeks of OV induces remission in PSC-IBD activity, associated with a reduction in gut bacterial diversity and compositional changes relating to BA and SCFA homeostasis., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Objectives: Peptide tyrosine tyrosine (PYY) exists as two species, PYY 1-36 and PYY 3-36 , with distinct effects on insulin secretion and appetite regulation. The detailed effects of bariatric surgery on PYY 1-36 and PYY 3-36 secretion are not known as previous studies have used nonspecific immunoassays to measure total PYY. Our objective was to characterize the effect of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on fasting and postprandial PYY 1-36 and PYY 3-36 secretion using a newly developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay., Design and Subjects: Observational study in 10 healthy nonobese volunteers and 30 participants with obesity who underwent RYGB (n = 24) or SG (n = 6) at the Imperial Weight Centre [NCT01945840]. Participants were studied using a standardized mixed meal test (MMT) before and 1 year after surgery. The outcome measures were PYY 1-36 and PYY 3-36 concentrations., Results: Presurgery, the fasting and postprandial levels of PYY 1-36 and PYY 3-36 were low, with minimal responses to the MMT, and these did not differ from healthy nonobese volunteers. The postprandial secretion of both PYY 1-36 and PYY 3-36 at 1 year was amplified after RYGB, but not SG, with the response being significantly higher in RYGB compared with SG., Conclusions: There appears to be no difference in PYY secretion between nonobese and obese volunteers at baseline. At 1 year after surgery, RYGB, but not SG, is associated with increased postprandial secretion of PYY 1-36 and PYY 3-36 , which may account for long-term differences in efficacy and adverse effects between the two types of surgery., (© 2022 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)