Bile acid sequestrants (BAS) lower plasma low density lipoprotein levels and improve glycemic control. Colestimide, a BAS, has been claimed to reduce liver fat by computed tomography. Therefore, we examined the efficacy of colesevelam, a potent BAS, to decrease liver fat in patients with biopsy-proven nonalcoholic steatohepatitis (NASH). Liver fat was measured by a novel magnetic-resonance-imaging (MRI)-technique, the proton-density-fat-fraction (PDFF), as well as by conventional MR spectroscopy (MRS). Methods Fifty patients with biopsy-proven NASH were randomly assigned to either colesevelam 3.75 gram/day orally or placebo for 24 weeks. The primary outcome was change in liver fat as measured by MRI PDFF in co-localized regions of interest within each of the nine liver segments. Results Compared with placebo, colesevelam increased liver fat by MRI PDFF in all nine segments of the liver with a mean difference of 5.6% (p=0.002). We cross-validated the MRI-PDFF determined fat content with that assessed by co-localized MRS; the latter showed a mean difference of 4.9% (p=0.014) in liver fat between the colesevelam and the placebo-arms. MRI PDFF correlated strongly with MRS determined hepatic fat content (r2=0.96, P<0.0001). Liver biopsy assessment of steatosis, cellular injury and lobular inflammation did not detect any effect of treatment. Conclusion Colesevelam increases liver fat in patients with NASH as assessed by MRI as well as MRS without significant changes seen on histology. Thus, MRI and MRS may be better than histology to detect longitudinal changes in hepatic fat in NASH. Underlying mechanisms and whether the small MR detected increase in liver fat has clinical consequences is not known.

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To identify factors that regulate gut microbiota density and the impact of varied microbiota density on health, we assayed this fundamental ecosystem property in fecal samples across mammals, human disease, and therapeutic interventions. Physiologic features of the host (carrying capacity) and the fitness of the gut microbiota shape microbiota density. Therapeutic manipulation of microbiota density in mice altered host metabolic and immune homeostasis. In humans, gut microbiota density was reduced in Crohn’s disease, ulcerative colitis, and ileal pouch-anal anastomosis. The gut microbiota in recurrent Clostridium difficile infection had lower density and reduced fitness that were restored by fecal microbiota transplantation. Understanding the interplay between microbiota and disease in terms of microbiota density, host carrying capacity, and microbiota fitness provide new insights into microbiome structure and microbiome targeted therapeutics.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

Crohn's disease symptomaƟc remission Fecal calprotecƟn response CRP response Week 6 Outcomes Specific Carbohydrate Diet Mediterranean Diet Participants achieving outcome (%) See Covering the Cover synopsis on page 739; See editorial on page 798. BACKGROUND & AIMS: This study compared the effectiveness of the Specific Carbohydrate Diet (SCD) to the Mediterranean diet (MD) as treatment for Crohn's disease (CD) with mild to moderate symptoms. METHODS: Adult patients with CD and with mild-to-moderate symptoms were randomly assigned 1:1 to consume the MD or SCD for 12 weeks. For the first 6 weeks, participants received prepared meals and snacks according to their assigned diet. After 6 weeks, participants were instructed to follow the diet independently. The primary outcome was symptomatic remission at week 6. Key secondary outcomes at Gastroenterology 2021;161:837-852 CLINICAL ATweek 6 included fecal calprotectin (FC) response (FC <250 mg/g and reduction by >50% among those with baseline FC >250 mg/g) and C-reactive protein (CRP) response (highsensitivity CRP <5 mg/L and >50% reduction from baseline among those with high-sensitivity CRP >5 mg/L). RESULTS:The study randomized 194 patients, and 191 were included in the efficacy analyses. The percentage of participants who achieved symptomatic remission at week 6 was not superior with the SCD (SCD, 46.5%; MD, 43.5%; P ¼ .77). FC response was achieved in 8 of 23 participants (34.8%) with the SCD and in 4 of 13 participants (30.8%) with the MD (P ¼ .83). CRP response was achieved in 2 of 37 participants (5.4%) with the SCD and in 1 of 28 participants (3.6%) with the MD (P ¼ .68). CONCLUSIONS: The SCD was not superior to the MD to achieve symptomatic remission, FC response, and CRP response. CRP response was uncommon. Given these results, the greater ease of following the MD and other health benefits associated with the MD, the MD may be preferred to the SCD for most patients with CD with mild to moderate symptoms. ClinicalTrials.gov Identifier: NCT03058679