Long-term impact of the low-FODMAP diet on gastrointestinal symptoms, dietary intake, patient acceptability, and healthcare utilization in irritable bowel syndrome

Background: The low-FODMAP diet is a frequently used treatment for irritable bowel syndrome (IBS). Most research has focused on short-term FODMAP restriction; however, guidelines recommend that high-FODMAP foods are reintroduced to individual tolerance. This study aimed to assess the long-term effectiveness of the low-FODMAP diet following FODMAP reintroduction in IBS patients. Methods: Patients with IBS were prospectively recruited to a questionnaire study following completion of dietitian-led low-FODMAP education. At baseline and following FODMAP restriction (short term) only, gastrointestinal symptoms were measured as part of routine clinical care. Following FODMAP reintroduction, (long term), symptoms, dietary intake, acceptability, food-related quality of life (QOL), and healthcare utilization were assessed. Data were reported for patients who continued long-term FODMAP restriction (adapted FODMAP) and/or returned to a habitual diet (habitual). Key Results: Of 103 patients, satisfactory relief of symptoms was reported in 12% at baseline, 61% at short-term follow-up, and 57% at long-term follow-up. At long-term follow-up, 84 (82%) patients continued an ‘adapted FODMAP’ diet (total FODMAP intake mean 20.6, SD 14.9\ua0g/d) compared with 19 (18%) of patients following a ‘habitual’ diet (29.4, SD 22.9\ua0g/d, P=.039). Nutritional adequacy was not compromised for either group. The ‘adapted FODMAP’ group reported the diet cost significantly more than the ‘habitual’ group (

TIGAR is abundant in large pyramidal neurons in deep cortical layers (V–VI) of STG from the human brain.

<p>(A–C) Immunostaining for TIGAR visualized by peroxidase substrate DAB (brown staining) and counterstained with hematoxylin to visualize nuclei (blue). (D) Single staining with TIGAR; insert -negative control (secondary antibody staining). Strong staining of TIGAR was prevalent in cytoplasm and sometimes shows nuclear or perinuclear localization in large neurons as indicated by arrows (D).</p

Assessment of enriched subcellular fractions isolated from postmortem human frontal cortex by electron microscopy.

<p>100 mg of total unfractionated sample (T, 1650x magnification), endoplasmic reticulum (P4, 11,000x), light membranes and cytosol (S3, 4,400x), mitochondria (P2, 11,000x), and nuclei (P1, 1650x) were processed for electron microscopy. The ER and L/C fractions do not have intact Mit, Nuc, or postsynaptic density (PSD)-like structures. The Mit and Nuc fractions have PSD-like structures (black arrows).</p

Cycle Checkpoint Abnormalities during Dementia: A Plausible Association with the Loss of Protection against Oxidative Stress in Alzheimer’s Disease

<div><p>Background</p><p>Increasing evidence suggests an association between neuronal cell cycle (CCL) events and the processes that underlie neurodegeneration in Alzheimer’s disease (AD). Elevated levels of oxidative stress markers and mitochondrial dysfunction are also among early events in AD. Recent studies have reported the role of CCL checkpoint proteins and tumor suppressors, such as ATM and p53 in the control of glycolysis and oxidative metabolism in cancer, but their involvement in AD remains uncertain.</p><p>Methods and Findings</p><p>In this postmortem study, we measured gene expression levels of eight CCL checkpoint proteins in the superior temporal cortex (STC) of persons with varying severities of AD dementia and compare them to those of cognitively normal controls. To assess whether the CCL changes associated with cognitive impairment in AD are specific to dementia, gene expression of the same proteins was also measured in STC of persons with schizophrenia (SZ), which is also characterized by mitochondrial dysfunction. The expression of CCL-checkpoint and DNA damage response genes: MDM4, ATM and ATR was strongly upregulated and associated with progression of dementia (cognitive dementia rating, CDR), appearing as early as questionable or mild dementia (CDRs 0.5–1). In addition to gene expression changes, the downstream target of ATM-p53 signaling - TIGAR, a p53-inducible protein, the activation of which can regulate energy metabolism and protect against oxidative stress was progressively decreased as severity of dementia evolved, but it was unaffected in subjects with SZ. In contrast to AD, different CCL checkpoint proteins, which include p53, CHEK1 and BRCA1 were significantly downregulated in SZ.</p><p>Conclusions</p><p>These results support the activation of an ATM signaling and DNA damage response network during the progression of AD dementia, while the progressive decrease in the levels of TIGAR suggests loss of protection initiated by ATM-p53 signaling against intensifying oxidative stress in AD.</p></div

Western blot analysis of AMPA Receptor subunit expression in enriched endoplasmic reticulum fraction (A – GluR1, B – GluR2, C – GluR3, D – GluR4) normalized to relative expression in total homogenate.

<p>Representative blots of ER fraction. Error bars represent standard deviation. GluR1: F(1,30) = 0.57558, p = 0.45. GluR2: F(1,30) = 0.00725, p = 0.93. GluR3: F(1,30) = 0.28370, p = 0.59. GluR4: F(1,32) = 0.15205, p = 0.69.</p

Pooled Subject Demographics.

<p>Abbreviations: Male (M). Female (F). Postmortem Interval (PMI). Data are presented as mean ± SD.</p

Neurochemical characterization of subcellular fractions isolated from postmortem human frontal cortex.

<p>Fractions enriched for endoplasmic reticulum (P4), cytosol and ‘light’ membranes (S3), mitochondria (P2), and nuclei (P1) were assayed by Western blot for compartment-specific markers: Calnexin (ER), histone3 (Nuc), glucose regulated 75 kDa protein (Grp75, Mito), early endosome antigen 1 (EEA1, endosomes), postsynaptic density 95 (PSD95, PSD), and α1,2 mannosidase (α1,2-Man, Golgi). The PSD segregated with the other ‘heavy’ membranes in the Mit and Nuc fractions. As expected, AMPA receptor subunit 2 (GluR2) was detected in the ER and fractions containing the PSD.</p

The mitotic cell cycle checkpoint gene network generated by the MetaCore and overlaid with the color coded gene expression changes during dementia.

<p>(red – upregulation; blue – downregulation; combination red/blue – differential effect at various stages of dementia). Highlighted is ATM/ATR regulation of G1/S transition pathways. The tumor protein p53 is a hub gene in this network.</p

Most relevant common and unique gene networks in the STG (BA22) derived from MetaCore analysis by comparing groups of cognitively impaired individuals with cognitively intact controls (CDR = 0).

<p>a Size = number of selected nodes (genes);</p><p>b Pathways = number of MetaCore pathways recognized within network and.</p><p>c G-score = ranks gene networks and based on the enrichment of expressed genes within the network, which is additionally modified with the saturation of the canonical pathways.</p><p>Cell cycle related networks highlighted in bold font.</p

Western blot (A) and protein expression levels of TIGAR (B) in STG (BA22) in dementia (CDRs >0.5) and schizophrenia.

<p>TIGAR expression values were normalized to GAPDH. **-p≤0.01; ***-p≤0.001.</p