He who controls Clostridia and Bacteroidia controls the gut microbiome: The concept of targeted probiotics to restore the balance of keystone taxa in irritable bowel syndrome.

This article describes the concept of probiotics for patients with irritable bowel syndrome to target functionally active bacteria predominantly belonging to the Clostridia and Bacteroidia, which play a key role in maintaining the balance of the gut microbiota.

Targeted Probiotics Against Bacterial-Fungal Biofilms: A New Concept Seems to Bring Us Closer to Microbiome-modulating Therapy for Inflammatory Bowel Disease.

This article describes the concept of microbiome-modulating therapy for inflammatory bowel diseases using targeted probiotics. A designed probiotic composition is discussed as an example, the targets for which are polymicrobial bacterial-fungal biofilms specific for Crohn's disease.

Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis.

BACKGROUND: Mirikizumab, a p19-directed antibody against interleukin-23, showed efficacy in the treatment of ulcerative colitis in a phase 2 trial. METHODS: We conducted two phase 3, randomized, double-blind, placebo-controlled trials of mirikizumab in adults with moderately to severely active ulcerative colitis. In the induction trial, patients were randomly assigned in a 3:1 ratio to receive mirikizumab (300 mg) or placebo, administered intravenously, every 4 weeks for 12 weeks. In the maintenance trial, patients with a response to mirikizumab induction therapy were randomly assigned in a 2:1 ratio to receive mirikizumab (200 mg) or placebo, administered subcutaneously, every 4 weeks for 40 weeks. The primary end points were clinical remission at week 12 in the induction trial and at week 40 (at 52 weeks overall) in the maintenance trial. Major secondary end points included clinical response, endoscopic remission, and improvement in bowel-movement urgency. Patients who did not have a response in the induction trial were allowed to receive open-label mirikizumab during the first 12 weeks of the maintenance trial as extended induction. Safety was also assessed. RESULTS: A total of 1281 patients underwent randomization in the induction trial, and 544 patients with a response to mirikizumab underwent randomization again in the maintenance trial. Significantly higher percentages of patients in the mirikizumab group than in the placebo group had clinical remission at week 12 of the induction trial (24.2% vs. 13.3%, P<0.001) and at week 40 of the maintenance trial (49.9% vs. 25.1%, P<0.001). The criteria for all the major secondary end points were met in both trials. Adverse events of nasopharyngitis and arthralgia were reported more frequently with mirikizumab than with placebo. Among the 1217 patients treated with mirikizumab during the controlled and uncontrolled periods (including the open-label extension and maintenance periods) in the two trials, 15 had an opportunistic infection (including 6 with herpes zoster infection) and 8 had cancer (including 3 with colorectal cancer). Among the patients who received placebo in the induction trial, 1 had herpes zoster infection and none had cancer. CONCLUSIONS: Mirikizumab was more effective than placebo in inducing and maintaining clinical remission in patients with moderately to severely active ulcerative colitis. Opportunistic infection or cancer occurred in a small number of patients treated with mirikizumab. (Funded by Eli Lilly; LUCENT-1 and LUCENT-2 ClinicalTrials.gov numbers, NCT03518086 and NCT03524092, respectively.).

Helicobacter pylori and Inflammatory Bowel Disease: An Unresolved Enigma.

The article describes the hypothesis that there may be a noncausal relationship between Helicobacter pylori infection and inflammatory bowel disease (IBD) that is related to the host mucin glycan fucosylation status in the gastrointestinal tract. The proposed hypothesis may explain why IBD is less prevalent in patients with H. pylori, and no increased risk of IBD is seen after H. pylori eradication therapy, as was shown in the study by Tanner et al.

Novel Budesonide Suppository and Standard Budesonide Rectal Foam Induce High Rates of Clinical Remission and Mucosal Healing in Active Ulcerative Proctitis: a Randomised, Controlled, Non-inferiority Trial.

BACKGROUND AND AIMS: Proctitis is the least extensive type of ulcerative colitis, for which rectal therapy is rarely studied and is underused. This study evaluated the efficacy, safety, and patient's preference of a novel formulation of budesonide suppository 4 mg, compared with a commercially available budesonide rectal foam 2 mg, for the treatment of mild to moderate ulcerative proctitis. METHODS: This was a randomised, double-blind, double-dummy, active-controlled trial. Patients were randomly assigned in a 1:1 ratio to receive either budesonide 4 mg suppository or budesonide 2 mg foam once daily for 8 weeks. The co-primary endpoints were changes from baseline to Week 8 in clinical symptoms, for which clinical remission was defined as having a modified Ulcerative Colitis-Disease Activity Index [UC-DAI] subscore for stool frequency of 0 or 1 and a subscore for rectal bleeding of 0, and mucosal healing, defined as having a modified UC-DAI subscore for mucosal appearance of 0 or 1. Using a more stringent criterion, we additionally analysed deepened mucosal healing, which was defined as a mucosal appearance subscore of 0. Patient's preference, physician's global assessment, and quality of life were also assessed and analysed. RESULTS: Overall, 286 and 291 patients were included in the 4 mg suppository and 2 mg foam groups, respectively. Budesonide 4 mg suppository met the prespecified criterion for non-inferiority to the 2 mg foam in both co-primary endpoints of clinical remission and mucosal healing. Secondary endpoints consistently supported the non-inferiority of the suppository. Trends in favour of the suppository were observed in the subgroup of mesalazine non-responders. More patients reported a preference for the suppository over rectal foam. CONCLUSIONS: In patients with ulcerative proctitis, budesonide 4 mg suppository was non-inferior to budesonide 2 mg foam in efficacy, and both were safe and well tolerated.

Bad "Good" Bile Acids and Gut Microbiota Dysbiosis in Inflammatory Bowel Disease: Mice and Humans Are Not the Same.

The effects of deoxycholic acid (DCA) on the intestinal microbiota, bile acid (BA) metabolism, and intestinal epithelium can be influenced by various factors. Depending on the specific conditions, DCA can be "bad" (proinflammatory) or "good" (anti-inflammatory). Mouse models of colitis show an increase in conjugated BAs and gut dysbiosis, including DCA-related dysbiosis, with a significant decrease in bile salt hydrolase (bsh) gene-containing taxa. Human patients with inflammatory bowel disease demonstrate, primarily, a decrease in bile acid-inducible (bai) gene-containing taxa and a deficiency in secondary BAs, suggesting their anti-inflammatory role.

Comparison between Diffusion-Weighted Sequences with Selective and Non-Selective Fat Suppression in the Evaluation of Crohn's Disease Activity: Are They Equally Useful?

Background: We compared the efficiency of two MRI diffusion weighted imaging (DWI) techniques: DWI with SPIR (DWISPIR) and DWI with STIR (DWISTIR), to estimate their eligibility for quantitative assessment of Crohn's disease activity in children and adults. Methods: In inflamed terminal ileum segments (n = 32 in adults, n = 46 in children), Magnetic Resonance Index of Activity (MaRIA) was calculated, ADC values of both DWI techniques were measured, and the corresponding Clermont scores calculated. ADC values of both DWI techniques were compared between both and within each patient group, assessing their mutual correlation. Correlations between MaRIA and the corresponding ADC values, and Clermont scores based on both DWI techniques were estimated. Results: No correlation between ADC of DWISPIR and DWISTIR was observed (rho = 0.27, p = 0.13 in adults, rho = 0.20, p = 0.17 in children). The correlation between MaRIA and Clermont scores was strong in both techniques-in SPIR, rho = 0.93; p < 0.0005 in adults, rho = 0.98, p < 0.0005 in children, and, in STIR, rho = 0.89; p < 0.0005 in adults, rho = 0.95, p < 0.0005 in children. The correlation between ADC and MaRIA was moderate negative for DWISTIR (rho = 0.93, p < 0.0005 in adults, rho = 0.95, p < 0.0005 in children), but, in DWISTIR, no correlation between ADC and MaRIA score was observed in adults (rho = -0.001, p = 0.99), whereas children presented low negative correlation (rho = -0.374, p = 0.01). Conclusions: DWISTIR is not suitable for quantitative assessment of Crohn's disease activity both in children and adult patients.

The Influence of Bowel Preparation on ADC Measurements: Comparison between Conventional DWI and DWIBS Sequences.

Background and objectives: The aim of the study was to assess whether there were differences between apparent diffusion coefficient (ADC) values of diffusion-weighted imaging (DWI) and diffusion-weighted imaging with background body signal suppression (DWIBS) sequences in non-prepared and prepared bowels before and after preparation with an enteric hyperosmolar agent, to assess whether ADC measurements have the potential to avoid bowel preparation and whether ADC-DWIBS has advantages over ADC-DWI. Materials and Methods: 106 adult patients without evidence of inflammatory bowel disease (IBD) underwent magnetic resonance (MR) enterography before and after bowel preparation. ADC-DWI and ADC-DWIBS values were measured in the intestinal and colonic walls demonstrating high signal intensity (SI) at DWI tracking images of b = 800 s/mm2 before and after preparation. Results: There were significant difference (p < 0.0001) in both ADC-DWI and ADC-DWIBS results between non-prepared and prepared jejunum for DWI being 1.09 × 10-3 mm2/s and 1.76 × 10-3 mm2/s, respectively, and for DWIBS being 0.91 × 10-3 mm2/s and 1.75 × 10-3 mm2/s, respectively. Both ADC-DWI and DWIBS also showed significant difference between non-prepared and prepared colon (p < 0.0001), with DWI values 1.41 × 10-3 mm2/s and 2.13 × 10-3 mm2/s, and DWIBS-1.01 × 10-3 mm2/s and 2.04 × 10-3 mm2/s, respectively. No significant difference between ADC-DWI and ADC-DWIBS was found in prepared jejunum (p = 0.84) and prepared colon (p = 0.58), whereas a significant difference was found in non-prepared jejunum and non-prepared colon (p = 0.0001 in both samples). Conclusions: ADC between DWI and DWIBS does not differ in prepared bowel walls but demonstrates a difference in non-prepared bowel. ADC in non-prepared bowel is lower than in prepared bowel and possible overlap with the ADC range of IBD is possible in non-prepared bowel. ADC-DWIBS has no advantage over ADC-DWI in regard to IBD assessment.

Once versus three times daily dosing of oral budesonide for active Crohn's disease: a double-blind, double-dummy, randomised trial.

BACKGROUND: Oral budesonide 9 mg/day represents first-line treatment of mild-to-moderately active ileocolonic Crohn's disease. However, there is no precise recommendation for budesonide dosing due to lack of comparative data. A once-daily (OD) 9 mg dose may improve adherence and thereby efficacy. METHODS: An eight-week, double-blind, double-dummy randomised trial compared budesonide 9 mg OD versus 3mg three-times daily (TID) in patients with mild-to-moderately active ileocolonic Crohn's disease. Primary endpoint was clinical remission defined as CDAI <150 at week 8 (last observation carried forward). RESULTS: The final intent-to-treat population comprised 471 patients (238 [9 mg OD], 233 [3 mg TID]). The confirmatory population for the primary endpoint analysis was the interim per protocol population (n=377; 188 [9 mg OD], 189 [3mg TID]), in which the primary endpoint was statistically non-inferior with budesonide 9 mg OD versus 3 mg TID. Clinical remission was achieved in 71.3% versus 75.1%, a difference of -3.9% (95% CI [-14.6%; 6.4%]; p=0.020 for non-inferiority). The mean (SD) time to remission was 21.9 (13.8) days versus 21.4 (14.6) days with budesonide 9 mg OD versus 3 mg TID, respectively. In a subpopulation of 122 patients with baseline SES-CD ulcer score ≥1, complete mucosal healing occurred in 32.8% (21/64) on 9 mg OD and 41.4% (24/58) on 3mg TID; deep remission (mucosal healing and clinical remission) was observed in 26.6% (17/64) and 32.8% (19/58) of patients, respectively. Treatment-emergent suspected adverse drug reactions were reported in 4.6% of 9 mg OD and 4.7% of 3 mg TID patients. CONCLUSIONS: Budesonide at the recommended dose of 9 mg/day can be administered OD without impaired efficacy and safety compared to 3mg TID dosing in mild-to-moderately active Crohn's disease.

Current opinion on the management of iron deficiency anaemia in gastrointestinal diseases.

Iron deficiency is the most common cause of anaemia in the world. Despite frequently weak and masked clinical presentation of iron deficiency anaemia (IDA), this disease is very serious with complications leading to early mortality. In the developed countries IDA is predominantly diagnosed as the complication of another disease or as the result of major bleeding events. Diagnosis of IDA should be based on laboratory findings i.e. haemoglobin, mean corpuscular hemoglobin concentration and ferritin. Latter is the most sensitive marker for iron deficiency. Anaemia of chronic disease should be taken into an account as a potential differential diagnosis or coexisting state. For women in fertility age with IDA, gynaecological disorders should be ruled out first. Males and postmenopausal women with IDA should undergo upper, lower and in certain cases capsule endoscopy and/or enteroscopy to find a plausible cause of IDA. The ultimate goal of therapy is to find out and treat the primary cause of IDA. Iron body stores should be restored using either oral or parenteral iron preparations. The use of parenteral iron preparations in patients with gastrointestinal pathologies is often clinically substantiated for the treatment of IDA. Red blood cell transfusion should be administered in emergency cases only.

Effect of infliximab induction therapy on secondary systemic amyloidosis associated with Crohn's disease: case report and review of the literature.

Secondary systemic (AA) amyloidosis is reported as a serious complication that occurs in long-standing Crohn's disease (CD), with an incidence of 0.3-10.9%. Various therapeutic approaches using medicines and elemental diet have been recommended, but still there are no established standards of treatment for secondary systemic amyloidosis in CD. Only a few studies have shown the role of TNFα ihibitors in the treatment of AA amyloidosis over a long term period. We report the case of a 24-year-old male with CD complicated by AA amyloidosis with renal and gastrointestinal tract involvement treated with infliximab as induction therapy. Intestinal AA amyloidosis progression occurred at the same time with the development of CD as an early complication, whereas duration of CD prior to the diagnosis of renal AA amyloidosis was 6 years. Infliximab therapy (3 infusions) caused a significant decrease of serum amyloid A protein (by 97.9%), C-reactive protein (by 70%), improvement of disease activity index, and CD caused clinical symptoms. At the same time gradual progression of the renal damage (reduction of renal function) was not affected by the treatment. Direct efficacy of infliximab infusions on serum amyloid protein level may support the hypothesis of TNFα induced reduction on the progression of AA amyloidosis described in previous study reports. Targeted histological analysis of tissue biopsy is crucial to clarify the presence of AA amyloidosis in CD induced multiorgan damage cases.