Covering the Cover

Abstract

A prospective cohort study evaluated tissue transglutaminase antibodies tested at 2 time points nearly 9 years apart to examine the development of celiac disease. The natural history of adults with positive autoimmune markers for celiac disease without endoscopic determination of celiac disease is unknown. In this issue of Gastroenterology, Choung et al used a community cohort where residents were repeatedly tested for tissue transglutaminase antibodies to examine their natural history and the progression to celiac disease while consuming a gluten-containing diet. A total of 15,551 adults with tissue transglutaminase antibodies tested at 2 time points (median interval of 8.8 years) between 2006 and 2017 were included in the study. Of the 153 adults who initially tested positive for tissue transglutaminase antibodies, at the second time point 31 (20%) had a subsequent diagnosis of celiac disease, 81 (53%) remained positive but did not have a diagnosis of celiac disease, and 41 (27%) reverted to a negative test. Higher initial antibody titers, female sex, and a history of hypothyroidism and autoimmune disease were associated with an increased risk of subsequent diagnosis of celiac disease. Participants who reverted to negative at the second time point were older, had lower initial antibody titers, and a higher body mass index compared with other adults. Of the 15,398 adults whose initial antibody tests were negative, 49 (0.3%) developed positive results at the second time point and 6 were subsequently diagnosed as celiac disease. These results provide important observations about the progression to celiac disease among adults with positive celiac disease antibodies and suggest that systemic retesting in those with negative celiac serology may not be necessary. See page 151. A single-blind randomized trial explored the use of low-FODMAP diet in reducing gastrointestinal symptoms among patients with quiescent inflammatory bowel disease. Dietary fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) can induce gastrointestinal symptoms in patients with irritable bowel syndrome and inflammatory bowel disease. In this issue of Gastroenterology, Cox et al performed a single-blind trial of 52 patients with quiescent inflammatory bowel disease and persistent gut symptoms to examine whether low-FODMAP diet reduced gut symptoms. Patients were randomized to a low-FODMAP diet with dietary advice or control diet with sham dietary advice for 4 weeks. A higher proportion of patients reported relief of gut symptoms following a low-FODMAP diet (14/27 [52%]) than a control diet (4/25 [16%]; P = .007). In targeted analyses of stool samples collected at the end of study period, patients assigned to the low-FODMAP diet had lower abundance of Bifidobacteria and Faecalibacterium prausnitzii, both of which have beneficial immune-regulatory effects (Figure 1). However, overall microbiome diversity and markers of inflammation did not differ between the 2 groups. Although the observed alterations in certain nutritional intakes may have confounded the results, this study supported the efficacy of 4-week low-FODMAP diet in reducing gastrointestinal symptoms without affecting stool microbiome diversity. More research is needed before recommending low-FODMAP diet among this group of patients. See page 176. CEACAM5 mutations enhance colorectal cancer cell growth through disrupting TGFBR1 resulting in modulation of TGF-β signaling and alterations in the gut microbiome. Colorectal cancer (CRC) remains a significant health concern despite the implementation of effective screening strategies. Unfortunately, there is a perplexing increase in the incidence of CRC in younger patients, who often present at advanced stages. The hypermutator CRC subtype represents roughly 15% of all CRC and arises in the setting of defective mismatch repair programs. In this CRC subset, components of the transforming growth factor (TGF)-β signaling pathway are commonly mutated. During early tumorigenesis, TGF-β acts as a tumor suppressor, whereas during metastasis, the tumor-promoting TGF-β programs dominate; thus, the impact of TGF-β on cancer biology is context dependent. Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a member of the immunoglobulin superfamily that function as bacteria and virus sensors modulate gut immune responses, bacterial adherence. CEACAM5, in particular, is up-regulated in colonic adenomas and interferes with TGF-β signaling. Interestingly, TGF-β mutant mice do not develop adenomas or CRC under germ-free conditions, leading to the hypothesis that interactions between TGF-β signaling, CEACAM5, and the intestinal microbiota might promote tumorigenesis. In this issue of Gastroenterology, Gu et al use a TGF-β signaling deficient mouse model (Smad4+/- /Sptbn1+/-) to decipher the interplay between TGF-β, the microbiota, and microbial sensing machinery in the pathogenesis of CRC. Microbial community analysis in TGF-β–deficient mice revealed an increase in Fusobacterium nucleatum and Enterococcus faecalis species, both previously associated with CRC. Scrutinizing CRC TCGA datasets, they identified increased CEACAM family member expression and, in particular, CEACAM5 expression was associated with decreased survival. Also noted, was an inverse relationship between TGF-β and stemness signatures. Mining cBioportal, they identified mutations in the CEACAM5 B3 domain that were predicted to alter a known CEACAM5/TGFBR1 interaction. HCT-116 and SW480 cells engineered to model the CECAM5 mutations demonstrated enhanced proliferation, anchorage-independent growth, and inhibited TGF-β signaling. Collectively, these intriguing studies further refine our understanding of the complex role of TGF-β signaling in CRC and identify a nexus at the intersection of the microbiome composition, TGF-β activity, and defects in host–microbial sensing machinery in CRC biology. Whether the CEACUM5 TGF-β axis can be capitalized on as a therapeutic target will undoubtably be the goal of future investigations. See page 238. Development of systemic inflammatory and compensatory anti-inflammatory response syndrome in severe acute pancreatitis is promoted by infiltrating macrophages and Th2 class T cells. Therapeutic strategies directed at the inflammasome may attenuate disease severity. Severe acute pancreatitis (SAP) is a devastating disease with high morbidity, mortality, and use of health care resources, frequently requiring prolonged intensive care admission. The early phases of SAP are marked by pancreatic parenchymal tissue autodigestion, leading to progressive activation of local and systemic inflammatory responses that, if unabated, result in significant multi-organ damage. Macrophage infiltration and adoption of proinflammatory phenotypes result in cytokine production triggering systemic inflammatory response syndrome (SIRS). More recently, compensatory anti-inflammatory response syndrome (CARS) has been described and was considered to follow SIRS in attempts to attenuate excessive immune responses; however, this dampening of immunity may promote secondary infection of pancreatic necrosis. Thus, these two processes walk a delicate balance to limit end-organ damage during SAP. In this issue of Gastroenterology, Sendler et al use a combination of mouse models and clinical investigations to explore the contributions of adaptive immunity in the progression of both SIRS and CARS. Animal modeling demonstrated that SIRS and CARS develop concurrently, rather than sequentially, and are primarily driven by a combination of infiltrating macrophages and T cells. Macrophages promote both SIRS and T-cell–mediated immune attenuation. Macrophages were predominantly of the M1, proinflammatory phenotype defined by increased production of IL-1 cytokines and required NLRP3–inflammasome activation to induce SIRS and promote T-cell–driven CARS, in an IL-18–dependent fashion (Figure 2). Inflammasome inhibition using MCC950 reduced IL-1β and IL-18 release from bone marrow-derived macrophages and significantly attenuated disease severity. Last, serum cytokine profiles from patients with mild and severe pancreatitis were compared. SAP had increased IL-6 and IL-10, and consistent with observations made in the mouse models, Th1/Th17 cytokines were not increased; however, Th2 associated cytokines were elevated. Last, ASC and IL-18 levels positively correlated with disease severity indicative of inflammasome activation. In conclusion, macrophage inflammasome-matured cytokines drive SIRS and Th2 T-cell profiles resulting in concurrent CARS during SAP and sharply identifies the inflammasome as a potential therapeutic target in severe pancreatitis. See page 253; editorial on page 46. Mutated CEACAMs Disrupt Transforming Growth Factor Beta Signaling and Alter the Intestinal Microbiome to Promote Colorectal CarcinogenesisGastroenterologyVol. 158Issue 1PreviewWe studied interactions among proteins of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family, which interact with microbes, and transforming growth factor beta (TGFB) signaling pathway, which is often altered in colorectal cancer cells. We investigated mechanisms by which CEACAM proteins inhibit TGFB signaling and alter the intestinal microbiome to promote colorectal carcinogenesis. Full-Text PDF Effects of Low FODMAP Diet on Symptoms, Fecal Microbiome, and Markers of Inflammation in Patients With Quiescent Inflammatory Bowel Disease in a Randomized TrialGastroenterologyVol. 158Issue 1PreviewThere is limited evidence that a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) reduces gut symptoms in quiescent inflammatory bowel disease (IBD). We performed a randomized, controlled trial to investigate the effects of a low FODMAP diet on persistent gut symptoms, the intestinal microbiome, and circulating markers of inflammation in patients with quiescent IBD. Full-Text PDF Community-Based Study of Celiac Disease Autoimmunity Progression in AdultsGastroenterologyVol. 158Issue 1PreviewCeliac disease can develop at any age, but outcomes of adults with positive results from serologic tests for tissue transglutaminase antibodies (tTGA) without endoscopic determination of celiac disease (called celiac autoimmunity) have not been thoroughly evaluated. We investigated the proportion of adults with celiac autoimmunity at a community medical center and their progression to celiac disease. Full-Text PDF Know Thy Enemy—Understanding the Role of Inflammation in Severe Acute PancreatitisGastroenterologyVol. 158Issue 1PreviewAcute pancreatitis (AP), an inflammatory disease of the pancreas, is one of the most common gastrointestinal disease responsible for hospital admission, morbidity, and mortality.1 There is no specific therapy for these patients and even today treatment continues to be largely supportive. This lack of progress stems from gaps in our understanding of the pathogenesis of AP.2,3 Progression of pancreatitis can be broadly divided into 2 phases. An intra-acinar phase, where injury and inflammation is initiated in the acinar cells, and an extra-acinar phase, where the inflammation spills into local tissue and then progresses to a systemic level. Full-Text PDF NLRP3 Inflammasome Regulates Development of Systemic Inflammatory Response and Compensatory Anti-Inflammatory Response Syndromes in Mice With Acute PancreatitisGastroenterologyVol. 158Issue 1PreviewPancreatitis starts with primarily sterile local inflammation that induces systemic inflammatory response syndrome, followed by compensatory anti-inflammatory response syndrome (CARS). We investigated the mechanisms of these processes in mice and human serum. Full-Text PDF Open Access