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Randomised clinical trial: linaclotide vs placebo-a study of bi-directional gut and brain axis.

ABSTRACT: BACKGROUND:Linaclotide, a guanylate cyclase C agonist relieves irritable bowel syndrome with predominant constipation (IBS-C) symptoms, but how it improves pain in humans is unknown. AIMS:To investigate the effects of linaclotide and placebo on the afferent and efferent gut-brain-gut signalling in IBS-C patients, in a randomised clinical trial. METHODS:Patients with IBS-C (Rome III) and rectal hypersensitivity were randomised (2:1) to receive linaclotide (290 µg) or placebo for 10 weeks and undergo bi-directional gut and brain axis assessment using anorectal electrical stimulations and transcranial/transspinal-anorectal magnetic stimulations. Rectal sensations were examined by balloon distention. Assessments included abdominal pain, bowel symptoms and quality of life (QOL) scores. Primary outcomes were latencies of recto-cortical and cortico-rectal evoked potentials. RESULTS:Thirty-nine patients participated; 26 received linaclotide and 13 received placebo. Rectal cortical evoked potentials latencies (milliseconds) were significantly prolonged with linaclotide compared to baseline (P1:? 19 ± 6, P < 0.005; N1:? 20 ± 7, P < 0.02) but not with placebo (P1:? 3 ± 5; N1:? 4.7 ± 5,P = 0.3) or between groups. The efferent cortico-anorectal and spino-anorectal latencies were unchanged. The maximum tolerable rectal volume (cc) increased significantly with linaclotide compared to baseline (P < 0.001) and placebo (? 29 ± 10 vs 4 ± 20, (P < 0.03). Abdominal pain decreased (P < 0.001) with linaclotide but not between groups. Complete spontaneous bowel movement frequency increased (P < 0.001), and IBS-QOL scores improved (P = 0.01) with linaclotide compared to baseline and placebo. There was no difference in overall responders between linaclotide and placebo (54% vs 23%, P = 0.13). CONCLUSIONS:Linaclotide prolongs afferent gut-brain signalling from baseline but both afferent and efferent signalling were unaffected compared to placebo. Linaclotide significantly improves rectal hypersensitivity, IBS-C symptoms and QOL compared to placebo. These mechanisms may explain the effects of linaclotide on pain relief in IBS-C patients. ClinicalTrials.Gov: Registered at Clinical trials.gov no NCT02078323.

SUBMITTER: Rao SSC

PROVIDER: S-EPMC7384154 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Randomised clinical trial: linaclotide vs placebo-a study of bi-directional gut and brain axis.

Rao Satish S C SSC Xiang Xuelian X Yan Yun Y Rattanakovit Kulthep K Patcharatrakul Tanisa T Parr Rachael R Ayyala Deepak D Sharma Amol A

Alimentary pharmacology & therapeutics 20200513 12

<h4>Background</h4>Linaclotide, a guanylate cyclase C agonist relieves irritable bowel syndrome with predominant constipation (IBS-C) symptoms, but how it improves pain in humans is unknown.<h4>Aims</h4>To investigate the effects of linaclotide and placebo on the afferent and efferent gut-brain-gut signalling in IBS-C patients, in a randomised clinical trial.<h4>Methods</h4>Patients with IBS-C (Rome III) and rectal hypersensitivity were randomised (2:1) to receive linaclotide (290 µg) or placebo ...[more]

PMID: 32406112

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Project description:BackgroundIt is well established that traumatic brain injury (TBI) causes acute and chronic alterations in systemic immune function and that systemic immune changes contribute to posttraumatic neuroinflammation and neurodegeneration. However, how TBI affects bone marrow (BM) hematopoietic stem/progenitor cells chronically and to what extent such changes may negatively impact innate immunity and neurological function has not been examined.MethodsTo further understand the role of BM cell derivatives on TBI outcome, we generated BM chimeric mice by transplanting BM from chronically injured or sham (i.e., 90 days post-surgery) congenic donor mice into otherwise healthy, age-matched, irradiated CD45.2 C57BL/6 (WT) hosts. Immune changes were evaluated by flow cytometry, multiplex ELISA, and NanoString technology. Moderate-to-severe TBI was induced by controlled cortical impact injury and neurological function was measured using a battery of behavioral tests.ResultsTBI induced chronic alterations in the transcriptome of BM lineage-c-Kit+Sca1+ (LSK+) cells in C57BL/6 mice, including modified epigenetic and senescence pathways. After 8 weeks of reconstitution, peripheral myeloid cells from TBI→WT mice showed significantly higher oxidative stress levels and reduced phagocytic activity. At eight months after reconstitution, TBI→WT chimeric mice were leukopenic, with continued alterations in phagocytosis and oxidative stress responses, as well as persistent neurological deficits. Gene expression analysis revealed BM-driven changes in neuroinflammation and neuropathology after 8 weeks and 8 months of reconstitution, respectively. Chimeric mice subjected to TBI at 8 weeks and 8 months post-reconstitution showed that longer reconstitution periods (i.e., time post-injury) were associated with increased microgliosis and leukocyte infiltration. Pre-treatment with a senolytic agent, ABT-263, significantly improved behavioral performance of aged C57BL/6 mice at baseline, although it did not attenuate neuroinflammation in the acutely injured brain.ConclusionsTBI causes chronic activation and progressive dysfunction of the BM stem/progenitor cell pool, which drives long-term deficits in hematopoiesis, innate immunity, and neurological function, as well as altered sensitivity to subsequent brain injury.

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Randomised clinical trial: linaclotide vs placebo-a study of bi-directional gut and brain axis.

Publications

Randomised clinical trial: linaclotide vs placebo-a study of bi-directional gut and brain axis.

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