Effect of Instruction on Preventing Delayed Bleeding after Colorectal Polypectomy and Endoscopic Mucosal Resection.

BACKGROUND: The frequency of delayed bleeding after colorectal polypectomy has been reported as 0.6-2.8%. With the increasing performance of polypectomy under continuous use of antithrombotic agents, care is required regarding delayed post-polypectomy bleeding (DPPB). Better instruction to educate endoscopists is therefore needed. We aimed to evaluate the effect of instruction and factors associated with delayed bleeding after endoscopic colorectal polyp resection. METHODS: This single-center, retrospective study was performed to assess instruction in checking complete hemostasis and risk factors for onset of DPPB. The incidence of delayed bleeding, comorbidities, and medications were evaluated from medical records. Characteristics of historical control patients and patients after instruction were compared. RESULTS: A total of 3318 polyps in 1002 patients were evaluated. The control group comprised 1479 polyps in 458 patients and the after-instruction group comprised 1839 polyps in 544 patients. DPPB occurred in 1.1% of polyps in control, and 0.4% in after-instruction. Instruction significantly decreased delayed bleeding, particularly in cases with antithrombotic agents. Hot polypectomy, clip placement, and use of antithrombotic agents were significant independent risk factors for DPPB even after instruction. CONCLUSION: The rate of delayed bleeding significantly decreased after instruction to check for complete hemostasis. Even after instruction, delayed bleeding can still occur in cases with antithrombotic agents or hot polypectomy.

Chenodeoxycholic Acid Releases Proinflammatory Cytokines from Small Intestinal Epithelial Cells Through the Farnesoid X Receptor.

BACKGROUND/AIMS: Bile acids have recently been associated with the pathogenesis of irritable bowel syndrome (IBS). We therefore evaluated the expression of bile acid receptors in the intestinal mucosa of IBS patients as well as the effects of bile acids on small intestinal epithelial cells. METHODS: Intestinal biopsy specimens were obtained from 15 IBS patients and 15 healthy controls. The effects of bile acid stimulation on trans-epithelial electrical resistance (TEER) and permeability in differentiated Caco-2 cells were measured. Proinflammatory cytokines were measured by enzyme-linked immunosorbent assay. mRNA levels of bile acid receptors, including farnesoid X receptor (FXR), and cytokines were determined by real-time reverse transcription-PCR. Caco-2 cells were pre-incubated with the FXR antagonist guggulsterone. RESULTS: FXR mRNA expression at the terminal ileum was increased in IBS patients. Chenodeoxycholic acid (CDCA) significantly decreased TEER, increased permeability, and increased interleukin-8 (IL-8) release from Caco-2 cells. Pre-incubation with guggulsterone blocked CDCA-mediated IL-8 release; however, the decrease in TEER was not reversed. CDCA-induced IL-6 and IL-8 mRNA levels were blocked by guggulsterone. CDCA increased IL-6, tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor release, whereas guggulsterone significantly blocked IL-6 and TNF-α release. CONCLUSIONS: FXR expression was elevated at the terminal ileum in IBS patients. CDCA increased proinflammatory cytokines, while guggulsterone blocked these increases.

Objective image analysis of non-magnifying image-enhanced endoscopy for diagnosis of small depressed early gastric cancers.

Background Gastric cancers (GC) after H. pylori eradication are difficult to diagnose even by magnifying narrow-band imaging (NBI) or blue laser imaging (BLI) endoscopy. Little is known with regard to non-magnifying (NM)-NBI/BLI for early GC so we examined the efficacy of NM-NBI/BLI for early GC diagnosis. Methods We retrospectively analyzed the images of 29 small (≤ 1 cm) intramucosal GC that had been treated with endoscopic submucosal dissection and 137 benign depressed lesions (BDLs). The brightness and shape of the GCs and BDLs by NM-NBI/BLI were assessed with ImageJ software. Results The NBI/BLI-index, which indicates the brightness of NBI/BLI for visualization, was significantly higher in GC than BDLs in both the H. pylori -infected ( P  = 0.009) and -eradicated group ( P  < 0.0001), indicating that GC exhibited brighter colors than the normal surrounding mucosa. The C-index, which refers to the circularity of the lesion, was also significantly higher in GC than BDLs in both H. pylori -infected ( P  = 0.006) and -eradicated cases ( P  = 0.004). Based on receiver-operating characteristic curve analysis, cutoff values for the NBI/BLI- and C-indices for GC were 1.04 and 0.58 in the H. pylori -infected cases, and 0.98 and 0.64 in the H. pylori -eradicated cases. With the reference value of the NBI/BLI-index set at ≥ 0.69 with the C-index at ≥ 0.21 in the H. pylori -infected and the NBI/BLI-index at ≥ 0.80 with the C-index at ≥ 0.32 in the H. pylori -eradicated cases, both the sensitivity and negative predictive value for early GC were 100 %. A high NBI/BLI-index tended to be associated with a wide length of the intervening part histologically in the H. pylori -eradicated cases ( P  = 0.09). Conclusions The small depressed-type early GC had brighter color and rounder shape compared to BDLs in both H. pylori -infected and -eradicated cases. The NBI/BLI- and C-indices calculated by the image analysis may facilitate identification of small depressed-type GC.

Sex differences in associations among metabolic syndrome, obesity, related biomarkers, and colorectal adenomatous polyp risk in a Japanese population.

To investigate sex differences in the associations among metabolic syndrome, obesity, adipose tissue-related biomarkers, and colorectal adenomatous polyps, a cross-sectional, multicenter study was conducted on 489 consecutive individuals who underwent their first colonoscopy at 3 hospitals. Plasma concentrations of adiponectin and leptin, as well as homeostatic model assessment of insulin resistance were also evaluated. The presence and number of adenomatous polyps, including advanced adenoma, were higher in men than in women. Metabolic syndrome was a risk factor for adenomatous polyps in both sexes. Large waist circumference was an independent risk factor for adenomatous polyps in men, and high BMI and large waist circumference were risk factors for adenomatous polyps in women. Interestingly, low BMI was associated with large adenomatous polyps (≥10 mm) and advanced adenoma, and waist-hip ratio was involved in proximal adenomatous polyp development only in women. In contrast, the highest quartile of leptin concentration had a 3.67-fold increased adenomatous polyp risk compared with the lowest quartile only in men. These results indicate that regarding colorectal pathogenesis, sex differences were identified in obesity but not in metabolic syndrome. Visceral obesity and a high serum leptin level may be risk factors for colorectal adenomatous polyp development in Japanese men.

Long-term effects of H. pylori eradication on epigenetic alterations related to gastric carcinogenesis.

The risk of gastric cancer (GC) remains in precancerous conditions, including atrophic mucosa and intestinal mucosa (IM), even after H. pylori treatment. To define the molecular changes following H. pylori eradication, molecular alterations in the gastric mucosa with and without GC were evaluated in a long-term follow-up study. A total of 232 biopsy specimens from 78 consecutive patients, including atrophic gastritis patients with follow-up ≥3 y after successful H. pylori eradication (AG group), patients who developed early GC after successful eradication (≥3 y) (GC group), and patients with H. pylori-positive atrophic gastritis (Hp group), were analyzed. H. pylori eradication was associated with significant reductions of methylation of several genes/loci in atrophic mucosa (non-IM), but not in IM. In contrast, the incidence of CpG island methylator phenotype (CIMP) in IM was significantly higher in the GC group than in the AG group. miR-124a-3 methylation and miR-34c methylation were more frequently identified in IM, with very few in non-IM mucosa among the three groups. H. pylori eradication can reverse methylation only in non-IM mucosa. CIMP in IM may have potential as a surrogate maker of GC development, and methylation of miR-124a-3 and miR-34c is a molecular event in IM that may not be associated with GC development.

[Diagnosis of duplication of the sigmoid colon prior to surgery:a case study].

A 16-year-old woman identified with colonic distention using chest X-rays visited our hospital. Although abdominal computed tomography (CT), colonoscopy, and barium enema study indicated suspected duplication of the sigmoid colon, the exact portion of communication between the normal colon and the duplicated colon could not be determined. The patient was released, but followed up due to the lack of symptoms. After 7 months, she was urgently re-hospitalized due to the complaint of abdominal pain. Her abdominal CT revealed the wall thickness and distention of the duplication as well as voluminous stool containing barium. After the improvement of her symptoms and on the basis of the inflammatory findings, laparoscopic surgery was performed on the patient. Finally, the lesion was diagnosed as tubular- and continuous-type colonic duplication. Duplication of the colon is a relatively rare occurrence in adulthood. Herein, we report a case of duplication of the sigmoid colon diagnosed prior to surgery in an adult.

Effects of long-term aspirin use on molecular alterations in precancerous gastric mucosa in patients with and without gastric cancer.

The risk of gastric cancer (GC) remains even after H. pylori eradication; thus, other combination treatments, such as chemopreventive drugs, are needed. We evaluated the effects of aspirin on genetic/epigenetic alterations in precancerous conditions, i.e., atrophic mucosa (AM) and intestinal metaplasia (IM), in patients with chronic gastritis who had taken aspirin for more than 3 years. A total of 221 biopsy specimens from 74 patients, including atrophic gastritis (AG) cases without aspirin use (control), AG cases with aspirin use (AG group), and GC cases with aspirin use (GC group), were analyzed. Aspirin use was associated with a significant reduction of CDH1 methylation in AM (OR: 0.15, 95% CI: 0.06-0.41, p = 0.0002), but was less effective in reversing the methylation that occurred in IM. Frequent hypermethylation including that of CDH1 in AM increased in the GC group compared to the AG group, and CDH1 methylation was an independent predictive marker of GC (OR: 8.50, 95% CI: 2.64-25.33, p = 0.0003). In patients with long-term aspirin use, the changes of molecular events in AM but not IM may be an important factor in the reduction of cancer incidence. In addition, methylation of the CDH1 gene in AM may be a surrogate of GC.

Genetic instability, CpG island methylator phenotype, and proliferative activity are distinct differences between diminutive and small tubular adenoma of the colorectum.

It is recommended that small (6-10 mm) lesions be treated with endoscopic resection (ER), whereas diminutive (≤5 mm) lesions are not currently an indication for ER according to the Japanese guidelines. The aim of this study was to evaluate the molecular alterations, and therefore treatment indications, in diminutive versus small tubular adenoma (TA). We prospectively analyzed genetic instability, including microsatellite instability and loss of heterozygosity, methylation status, KRAS/BRAF mutations, and Ki-67 staining in 96 TAs without a villous component. Although no microsatellite instability was identified in either diminutive or small TAs, genetic instability was seen in small TAs (9.1%) but not diminutive TAs (P = .04). In addition, the low-level CpG island methylator phenotype (CIMP-L) was more frequently observed in small TAs (31.8%) than in diminutive TAs (P = .01). Thus, genetic instability and CIMP-L were associated with small TAs, and only CIMP-L was an independent predictive marker for small TAs (odds ratio, 3.29; P = .03). Intriguingly, the Ki-67 proliferative index tended to be higher in small TAs than in diminutive TAs (P = .06) and higher in TAs with CIMP-L than in those without CIMP (P = .08). KRAS mutations were seen in codon 12 in 5.2% of TAs, but no BRAF gene mutations were found. As the molecular events and proliferative activity for the progression may increase from diminutive to small TAs, small TAs should be treated with ER, whereas a "predict, resect, and discard" strategy may be acceptable in most diminutive lesions except flat and depressed-type lesions, in keeping with the current strategy in the West.

What types of early gastric cancer are indicated for endoscopic ultrasonography staging of invasion depth?

AIM: To clarify the diagnostic efficacy and limitations of endoscopic ultrasonography (EUS) and the characteristics of early gastric cancers (EGCs) that are indications for EUS-based assessment of cancer invasion depth. METHODS: We retrospectively investigated the cases of 153 EGC patients who underwent conventional endoscopy (CE) and EUS (20 MHz) before treatment. RESULTS: We found that 13.7% were "inconclusive" cases with low-quality EUS images, including all nine of the cases with protruded (0-I)-type EGCs. There was no significant difference in the diagnostic accuracy between CE and EUS. Two significant independent risk factors for misdiagnosis by EUS were identified-ulcer scarring [UL(+); odds ratio (OR) = 4.49, P = 0.003] and non-indication criteria for endoscopic resection (ER) (OR = 3.02, P = 0.03). In the subgroup analysis, 23.1% of the differentiated-type cancers exhibiting SM massive invasion (SM2) invasion (submucosal invasion ≥ 500 µm) by CE were correctly diagnosed by EUS, and 23.1% of the undifferentiated-type EGCs meeting the expanded-indication criteria for ER were correctly diagnosed by EUS. CONCLUSION: There is no need to perform EUS for UL(+) EGCs or 0-I-type EGCs, but EUS may enhance the pretreatment staging of differentiated-type EGCs with SM2 invasion without UL or undifferentiated-type EGCs revealed by CE as meeting the expanded-indication criteria for ER.

Localization of specialized intestinal metaplasia and the molecular alterations in Barrett esophagus in a Japanese population: an analysis of biopsy samples based on the "Seattle" biopsy protocol.

It remains unclear why Barrett esophagus (BE)-associated adenocarcinoma (EAC) frequently occurs in the 0 to 3 o'clock area of the BE. The aims of this study were to clarify the localization of specialized intestinal metaplasia (SIM) as a precancerous lesion and of molecular alterations among different locations using 4-quadrant biopsies based on the "Seattle" protocol. We prospectively evaluated microsatellite instability; methylation status at the APC, CDKN2A, hMLH1, RUNX3, and MGMT genes; the immunoreactivity of the monoclonal antibody Das-1 for the colonic phenotype; and Ki-67 staining in 10 early EACs and 128 biopsy samples from 32 BE patients. Among the molecular changes, only APC gene hypermethylation was an independent predictive marker of EAC (odds ratio, 24.4; P = .01). SIM was more frequently identified in the 0 to 3 o'clock quadrant than in the 6 to 9 o'clock quadrant (P = .08). The Ki-67 index was higher in SIM than in the columnar-lined epithelium (CLE) without goblet cells (P < .0001) and in both SIM and CLE with Das-1 reactivity than in those without (P = .04 and P = .06, respectively). Furthermore, the index was relatively higher in the 0 to 3 o'clock quadrant than in the 6 to 9 o'clock quadrant in cases with Das-1 reactivity. RUNX3 methylation was more frequently found in SIM than in CLE (P = .04), whereas the incidence of the other biomarkers did not show a significant difference between the 0 to 3 o'clock and 6 to 9 o'clock areas, nor between SIM and CLE. SIM with Das-1 reactivity, but not molecular alterations, in the 0 to 3 o'clock quadrant may have higher proliferative activity compared to the other areas of the BE.

Efficacy of Intrathecal MTX/Ara-C Combined with Systemic Chemotherapy in a Gastric Cancer Patient with Meningeal Carcinomatosis.

A 35-year-old man was diagnosed to have gastric cancer by endoscopic and histological examinations. Staging laparoscopy detected peritoneal metastasis. Systemic chemotherapy was started, but the patient complained of severe headache. Subsequently, a lumbar puncture demonstrated adenocarcinoma cells in the spinal fluid, suggesting the occurrence of meningeal carcinomatosis (MC) from gastric cancer. MC occurs only rarely in patients with gastric cancer, but the prognosis is invariably poor. However, this patient nevertheless survived for 12 months after receiving intrathecal MTX/Ara-C together with systemic chemotherapy. Therefore, the early detection of meningeal irritation sign and intrathecal chemotherapy might greatly improve the prognosis of gastric cancer patients with MC.

Histological diagnosis of gastric submucosal tumors: A pilot study of endoscopic ultrasonography-guided fine-needle aspiration biopsy vs mucosal cutting biopsy.

AIM: To compare the usefulness of endoscopic ultrasonography-guided fine-needle aspiration biopsy (EUS-FNAB) without cytology and mucosal cutting biopsy (MCB) in the histological diagnosis of gastric submucosal tumor (SMT). METHODS: We prospectively compared the diagnostic yield, feasibility, and safety of EUS-FNAB and those of MCB based on endoscopic submucosal dissection. The cases of 20 consecutive patients with gastric SMT ≥ 1 cm in diameter. who underwent both EUS-FNAB and MCB were investigated. RESULTS: The histological diagnoses were gastrointestinal stromal tumors (n = 7), leiomyoma (n = 6), schwannoma (n = 2), aberrant pancreas (n = 2), and one case each of glomus tumor, metastatic hepatocellular carcinoma, and no-diagnosis. The tumors' mean size was 23.6 mm. Histological diagnosis was made in 65.0% of the EUS-FNABs and 60.0% of the MCBs, a nonsignificant difference. There were no significant differences in the diagnostic yield concerning the tumor location or tumor size between the two methods. However, diagnostic specimens were significantly more frequently obtained in lesions with intraluminal growth than in those with extraluminal growth by the MCB method (P = 0.01). All four SMTs with extraluminal growth were diagnosed only by EUS-FNAB (P = 0.03). No complications were found in either method. CONCLUSION: MCB may be chosen as an alternative diagnostic modality in tumors showing the intraluminal growth pattern regardless of tumor size, whereas EUS-FNAB should be performed for SMTs with extraluminal growth.

Diagnosis of small intramucosal signet ring cell carcinoma of the stomach by non-magnifying narrow-band imaging: A pilot study.

AIM: To examine the efficacy of non-magnifying narrow-band imaging (NM-NBI) imaging for small signet ring cell carcinoma (SRC). METHODS: We retrospectively analyzed 14 consecutive small intramucosal SRCs that had been treated with endoscopic submucosal dissection (ESD) and 14 randomly selected whitish gastric ulcer scars (control). The strength and shape of the SRCs and whitish scars by NM-NBI and white-light imaging (WLI) were assessed with Image J (NIH, Bethesda). RESULTS: NM-NBI findings of SRC showed a clearly isolated whitish area amid the brown color of the surrounding normal mucosa. The NBI index, which indicates the potency of NBI for visualizing SRC, was significantly higher than the WLI index (P = 0.001), indicating SRC was more clearly identified by NM-NBI. Although the NBI index was not significantly different between SRCs and controls, the circle (C)-index, as an index of circularity of tumor shape, was significantly higher in SRCs (P = 0.001). According to the receiver-operating characteristic analysis, the resulting cut-off value of the circularity index (C-index) for SRC was 0.60 (85.7% sensitivity, 85.7% specificity). Thus a lesion with a C-index ≥ 0.6 was significantly more likely to be an SRC than a gastric ulcer scar (OR = 36.0; 95%CI: 4.33-299.09; P = 0.0009). CONCLUSION: Small isolated whitish round area by NM-NBI endoscopy is a useful finding of SRCs which is the indication for ESD.

Asymptomatic Free Air Caused by Mallory-Weiss Tears during Endoscopy.

An 80-year-old woman was referred to our hospital for the treatment of advanced gastric cancer which extended from the antrum to the bulbus of the duodenum. Although the patient did not struggle or retch during endoscopy, multiple mucosal lacerations were observed in the proximal stomach by Mallory-Weiss tears. No evidence of perforation was identified at the sites. The day after endoscopy, computed tomography revealed free air close to the gastric cardia, but the patient did not complain of any symptoms; she was able to consume a normal diet and did not require any treatment.

Marked efficacy of adalimumab for secondary gastrointestinal amyloidosis accompanied with ankylosing spondylitis.

A 39-year-old man with seronegative rheumatoid arthritis which was refractory to methotrexate and prednisolone therapy complained of epigastralgia, melena and diarrhea. Diffuse mucosal damage was observed on endoscopic examination, and histological findings of the gastric and colonal mucosa showed AA type amyloidosis. He was diagnosed with ankylosing spondylitis (AS) on the basis of the clinical feature such as the limitation in range of motion of lumber spine, and sacroiliitis on MR imaging. Although digestive symptom ameliorated by fasting and antibiotic therapy, laboratory findings continued to reveal an elevation of serum C-reactive protein (CRP) value and arthritis worsened. However, after the initiation of the treatment with adalimumab (ADA), not only his manifestation but also serum levels of CRP became normalized promptly. As far as we could evaluated, follow-up colonoscopic examination showed normal mucosal findings and histologic examination proved that amyloid protein disappeared. Secondary gastrointestinal amyloidosis is ralely associated with AS. Therefore standard therapy is not established. This case might indicate an efficacy of ADA for secondary gastrointestinal amyloidosis accompanied with AS.

Evaluation of discomfort during colonoscopy with conventional and ultrathin colonoscopes in ulcerative colitis patients.

BACKGROUND AND AIM: In patients with ulcerative colitis (UC), colonoscopy is an essential procedure for evaluating mucosal damage, and treatment outcomes. A new flexible ultrathin colonoscope (PCF-PQ260) has been developed to readily pass through tortuous and narrow lesions of the colon and cause minimum patient discomfort. The objective of the present study was to evaluate the comfort and performance of this new type of scope in UC patients who underwent colonoscopy for estimation of mucosal inflammation, basically without sedation. METHODS: In a prospective, single-center setting, among 107 UC patients who were to undergo colonoscopy, 84 eligible cases were randomly assigned to the new ultrathin flexible colonoscope, PCF-PQ260 (n = 42) or to a conventional colonoscope, PCF-Q260A (n = 42). Main outcome measure was patient pain level determined by visual analogue scale (VAS) with 0 = none, and 100 = extremely painful. Other outcomes were cecal intubation time, rate of complete intubation (to reach the cecum) and rate of procedural complications. RESULTS: VAS score was significantly lower in the new-scope group as compared with the conventional-scope group: mean ± SD, median (range): 19.3 ± 16.9, 14 (0-62) vs 32.0 ± 21.6, 31.8 (0-100, P = 0.005). However, cecal intubation rate (97.6%) and time (4 min) were similar in the two groups. There was no procedure-related serious complication in either group. CONCLUSION: The findings indicated that the flexible ultrathin colonoscope PCF-PQ260 has significantly better tolerability in UC patients compared to a conventional colonoscope.

Prospective postsurgical capsule endoscopy in patients with Crohn's disease.

AIM: To clarify the usefulness of postsurgical capsule endoscopy (CE) in the diagnosis of recurrent small bowel lesions of Crohn's disease (CD). METHODS: This prospective study included 19 patients who underwent ileocolectomy or partial ileal resection for CD. CE was performed 2-3 wk after surgery to check for the presence/absence and severity of lesions remaining in the small bowel, and for any recurrence at the anastomosed area. CE was repeated 6-8 mo after surgery and the findings were compared with those obtained shortly after surgery. The Lewis score (LS) was used to evaluate any inflammatory changes of the small bowel. RESULTS: One patient was excluded from analysis because of insufficient endoscopy data at the initial CE. The total LS shortly after surgery was 428.3 on average (median, 174; range, 8-4264), and was ≥ 135 (active stage) in 78% (14 of 18) of the patients. When the remaining unresected small bowel was divided into 3 equal portions according to the transition time (proximal, middle, and distal tertiles), the mean LS was 286.6, 83.0, and 146.7, respectively, without any significant difference. Ulcerous lesions in the anastomosed area were observed in 83% of all patients. In 38% of the 13 patients who could undergo CE again after 6-8 mo, the total LS was higher by ≥ 100 than that recorded shortly after surgery, thus indicating a diagnosis of endoscopic progressive recurrence. CONCLUSION: Our pilot study suggests that CE can be used to objectively evaluate the postoperative recurrence of small bowel lesions after surgery for CD.

Immunoregulatory effects of adsorptive granulocyte and monocyte apheresis in patients with drug refractory Crohn's disease.

In Japan, adsorptive granulocyte/monocyte apheresis (GMA) is an approved treatment option in patients with active Crohn's disease (CD). However, there is inadequate knowledge regarding the mechanism(s) of therapeutic effects of this non-pharmacologic treatment strategy. Further, recently we have been interested in the regulatory T-cell (Treg) profile which has an essential immunoregulatory function. Thirteen CD patients were treated with a single GMA session. The mean CD activity index (CDAI) and duration of CD were 218.5 and 9.8 years, respectively. Eight healthy volunteers participated as a control group. From CD patients, whole blood was taken immediately before and after the GMA session directly from the GMA column inflow and outflow lines. Broad spectrum serum key cytokines and chemokines were measured by suspension-array and ELISA. At baseline, almost all assayed inflammatory cytokines were significantly elevated in CD patients. Treg-associated cytokines including IL-10 (P < 0.02) and transforming growth factor (TGF)-ß1 (P < 0.03), were higher in the GMA column outflow vs. inflow. In contrast, the Th1/Th2 balance, defined as IFN-γ/IL-10 was lower during hemofiltration (P = 0.05), potentially due to an elevated IL-10 (P < 0.02) because an elevation of pro-inflammatory IFN-γ (Th1) was not observed at the GMA column outflow. A single GMA session had a significant impact on the Treg profile. Treg-related cytokines like IL-10 and TGF-ß1 in the blood returning to the patients from the GMA column outflow were elevated, while pro-inflammatory cytokines like IFN-γ were not. This action of GMA is potentially very interesting in patients with immune disorders, like CD patients.