Magnesium Depletion Score (MDS) Predicts Risk of Systemic Inflammation and Cardiovascular Mortality among US Adults.

BACKGROUND: Kidney reabsorption of magnesium (Mg) is essential for homeostasis. OBJECTIVES: We developed and validated models with the kidney reabsorption-related magnesium depletion score (MDS) to predict states of magnesium deficiency and disease outcomes. METHODS: MDS was validated in predicting body magnesium status among 77 adults (aged 62 ± 8 y, 51% men) at high risk of magnesium deficiency in the Personalized Prevention of Colorectal Cancer Trial (PPCCT) (registered at clinicaltrials.gov as NCT01105169) using the magnesium tolerance test (MTT). We then validated MDS for risk stratification and for associations with inflammation and mortality among >10,000 US adults (weighted: aged 48 ± 0.3 y, 47% men) in the NHANES, a nationally representative study. A proportional hazards regression model was used for associations between magnesium intake and the MDS with risks of total and cardiovascular disease (CVD) mortality. RESULTS: In the PPCCT, the area under the receiver operating characteristic (ROC) curve (AUC) for magnesium deficiency was 0.63 (95% CI: 0.50, 0.76) for the model incorporating the MDS with sex and age compared with 0.53 (95% CI: 0.40, 0.67) for the model with serum magnesium alone. In the NHANES, mean serum C-reactive protein significantly increased with increasing MDS (P-trend < 0.01) after adjusting for age and sex and other covariates, primarily among individuals with magnesium intake less than the Estimated Average Requirement (EAR; P-trend < 0.05). Further, we found that low magnesium intake was longitudinally associated with increased risks of total and CVD mortality only among those with magnesium deficiency predicted by MDS. MDS was associated with increased risks of total and CVD mortality in a dose-response manner only among those with magnesium intake less than the EAR. CONCLUSIONS: The MDS serves as a promising measure in identifying individuals with magnesium deficiency who may benefit from increased intake of magnesium to reduce risks of systemic inflammation and CVD mortality. This lays a foundation for precision-based nutritional interventions.

Calcium: magnesium intake ratio and colorectal carcinogenesis, results from the prostate, lung, colorectal, and ovarian cancer screening trial.

BACKGROUND: We aimed to evaluate the associations between calcium and various stages of colorectal carcinogenesis and whether these associations are modified by the calcium to magnesium (Ca:Mg) ratio. METHODS: We tested our hypotheses in the prostate lung, colorectal and ovarian cancer screening trial. RESULTS: Calcium intake did not show a dose-response association with incident adenoma of any size/stage (P-trend = 0.17), but followed an inverse trend when restricted to synchronous/advanced adenoma cases (P-trend = 0.05). This inverse trend was mainly in participants with Ca:Mg ratios between 1.7 and 2.5 (P-trend = 0.05). No significant associations were observed for metachronous adenoma. Calcium intake was inversely associated with CRC (P-trend = 0.03); the association was primarily present for distal CRC (P-trend = 0.01). The inverse association between calcium and distal CRC was further modified by the Ca:Mg ratio (P-interaction < 0.01); significant dose-response associations were found only in participants with a Ca:Mg ratio between 1.7 and 2.5 (P-trend = 0.04). No associations for calcium were found in the Ca:Mg ratio above 2.5 or below 1.7. CONCLUSION: Higher calcium intake may be related to reduced risks of incident advanced and/or synchronous adenoma and incident distal CRC among subjects with Ca:Mg intake ratios between 1.7 and 2.5.

Factors Associated With Response to Teduglutide in Patients With Short-Bowel Syndrome and Intestinal Failure.

BACKGROUND & AIMS: Clinical studies showed teduglutide to increase urine production and reduce need for parenteral support volume in patients with short bowel syndrome (SBS) with intestinal failure, increasing intestinal wet weight absorption and reducing diarrhea. However, the effects of teduglutide on parenteral support vary among patients. We performed a post hoc analysis of a phase III placebo-controlled study to identify characteristics of patients in whom teduglutide has the largest effects on parenteral support volume response. METHODS: We collected data from 85 patients with SBS with intestinal failure, according to the European Society for Clinical Nutrition and Metabolism classification system, who received teduglutide or placebo between November 25, 2008, and January 4, 2011, at 27 sites in 10 countries. Changes in parenteral support volume were evaluated according to baseline parenteral support volume, bowel anatomy (group 1, jejunostomy/ileostomy; group 2, ≥50% colon-in-continuity without stoma; and group 3, other colon anatomies), and disease features (with inflammatory bowel disease, mesenteric vascular diseases, or other conditions). Correlation analyses were conducted using simple linear regression models, with unadjusted r2 values reported. Two-sided t tests were used for comparisons between treatment groups. RESULTS: We correlated parenteral support volume reduction with teduglutide treatment and baseline parenteral support volume (y = -0.3870x + 90.0279, r2 = 0.61; P < .0001). The effects of teduglutide on absolute parenteral support volume were significantly greater in group 1 patients (reduction of 919 ± 644 mL/d), not only compared with patients given placebo (reduction of 340 ± 436 mL/d; P = .0112) but also compared with teduglutide-treated patients in group 2 (reduction of 355 ± 306 mL/d; P = .0066). Teduglutide had an intermediate effect on patients in group 3. A minority of patients with SBS and inflammatory bowel diseases had colon-in-continuity (10.5% [n = 2/19]), whereas most patients with SBS and vascular or other diseases had colon-in-continuity (84.4% [n = 27/32] and 67.6% [n = 23/34], respectively). CONCLUSIONS: In a post hoc analysis of data from a phase III study of the effects of teduglutide on patients with SBS, we associated reduced parenteral support volume with baseline parenteral support volume, bowel anatomy, and SBS features. These findings may inform initial parenteral support volume adjustments and management of these severely disabled patients. ClinicalTrials.gov no: NCT00798967; ClinicalTrialsRegister.eu no: 2008-006193-15.

Teduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure.

BACKGROUND & AIMS: Teduglutide, a glucagon-like peptide 2 analogue, might restore intestinal structural and functional integrity by promoting growth of the mucosa and reducing gastric emptying and secretion. These factors could increase fluid and nutrient absorption in patients with short bowel syndrome with intestinal failure (SBS-IF). We performed a prospective study to determine whether teduglutide reduces parenteral support in patients with SBS-IF. METHODS: We performed a 24-week study of patients with SBS-IF who were given subcutaneous teduglutide (0.05 mg/kg/d; n = 43) or placebo (n = 43) once daily. Parenteral support was reduced if 48-hour urine volumes exceeded baseline values by ≥ 10%. The primary efficacy end point was number of responders (patients with >20% reduction in parenteral support volume from baseline at weeks 20 and 24). RESULTS: There were significantly more responders in the teduglutide group (27/43 [63%]) than the placebo group (13/43 [30%]; P = .002). At week 24, the mean reduction in parenteral support volume in the teduglutide group was 4.4 ± 3.8 L/wk (baseline 12.9 ± 7.8 L/wk) compared with 2.3 ± 2.7 L/wk (baseline 13.2 ± 7.4 L/wk) in the placebo group (P < .001). The percentage of patients with a 1-day or more reduction in the weekly need for parenteral support was greater in the teduglutide group (21/39 [54%]) than in the placebo group (9/39 [23%]; P = .005). Teduglutide increased plasma concentrations of citrulline, a biomarker of mucosal mass. The distribution of treatment-emergent adverse events that led to study discontinuation was similar between patients given teduglutide (n = 2) and placebo (n = 3). CONCLUSIONS: Twenty-four weeks of teduglutide treatment was generally well tolerated in patients with SBS-IF. Treatment with teduglutide reduced volumes and numbers of days of parenteral support for patients with SBS-IF; ClinicalTrials.gov Number, NCT00798967.

Magnesium, vitamin D status and mortality: results from US National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 and NHANES III.

BACKGROUND: Magnesium plays an essential role in the synthesis and metabolism of vitamin D and magnesium supplementation substantially reversed the resistance to vitamin D treatment in patients with magnesium-dependent vitamin-D-resistant rickets. We hypothesized that dietary magnesium alone, particularly its interaction with vitamin D intake, contributes to serum 25-hydroxyvitamin D (25(OH)D) levels, and the associations between serum 25(OH)D and risk of mortality may be modified by magnesium intake level. METHODS: We tested these novel hypotheses utilizing data from the National Health and Nutrition Examination Survey (NHANES) 2001 to 2006, a population-based cross-sectional study, and the NHANES III cohort, a population-based cohort study. Serum 25(OH)D was used to define vitamin D status. Mortality outcomes in the NHANES III cohort were determined by using probabilistic linkage with the National Death Index (NDI). RESULTS: High intake of total, dietary or supplemental magnesium was independently associated with significantly reduced risks of vitamin D deficiency and insufficiency respectively. Intake of magnesium significantly interacted with intake of vitamin D in relation to risk of both vitamin D deficiency and insufficiency. Additionally, the inverse association between total magnesium intake and vitamin D insufficiency primarily appeared among populations at high risk of vitamin D insufficiency. Furthermore, the associations of serum 25(OH)D with mortality, particularly due to cardiovascular disease (CVD) and colorectal cancer, were modified by magnesium intake, and the inverse associations were primarily present among those with magnesium intake above the median. CONCLUSIONS: Our preliminary findings indicate it is possible that magnesium intake alone or its interaction with vitamin D intake may contribute to vitamin D status. The associations between serum 25(OH)D and risk of mortality may be modified by the intake level of magnesium. Future studies, including cohort studies and clinical trials, are necessary to confirm the findings.

Characteristics of chronic intestinal failure in the USA based on analysis of claims data.

BACKGROUND: This study investigated the prevalence, characteristics, and management of patients with chronic intestinal failure (CIF) in the United States in 2012-2020, based on parenteral support (PS) prescription claims and healthcare utilization. METHODS: Patients with CIF were identified from the Integrated DataVerse® claims database if they had at least two PS prescriptions within 6 months and a relevant diagnosis. Analysis included prevalence and characteristics of patients with CIF, their travel distance to receive PS prescriptions, and the distribution of PS providers and their prescribing history. RESULTS: Up to 24,048 patients with CIF were identified, equivalent to 75 patients per million. CIF affected people of all ages, being more prevalent in women than in men. Many providers signed PS orders for small patient groups over short time periods, whereas few providers signed PS orders for large patient groups long term, indicating a lack of centralization. The distribution of PS providers suggested a disparity in healthcare coverage in rural vs urban areas, leading to patients traveling considerable distances to receive PS prescriptions. This may be exacerbated by a decline of providers with expertise in CIF and nutrition. CONCLUSIONS: Healthcare disparities for patients with CIF have likely been obscured by the lack of CIF-specific diagnostic and procedure codes, obliging providers to code for their patients under other codes. Effective policy changes, including centralized care, revision of reimbursement models, and expansion of nutrition-focused education in addition to the newly introduced International Classification of Diseases codes, are needed to provide the best care for patients.

Ca:Mg ratio, medium-chain fatty acids, and the gut microbiome.

BACKGROUND & AIMS: Ketogenic medium-chain fatty acids (MCFAs) with profound health benefits are commonly found in dairy products, palm kernel oil and coconut oil. We hypothesize that magnesium (Mg) supplementation leads to enhanced gut microbial production of MCFAs and, in turn, increased circulating MCFAs levels. METHODS: We tested this hypothesis in the Personalized Prevention of Colorectal Cancer Trial (PPCCT) (NCT01105169), a double-blind 2 × 2 factorial randomized controlled trial enrolling 240 participants. Six 24-h dietary recalls were performed for all participants at the baseline and during the intervention period. Based on the baseline 24-h dietary recalls, the Mg treatment used a personalized dose of Mg supplementation that would reduce the calcium (Ca): Mg intake ratio to around 2.3. We measured plasma MCFAs, sugars, ketone bodies and tricarboxylic acid cycle (TCA cycle) metabolites using the Metabolon's global Precision Metabolomics™ LC-MS platform. Whole-genome shotgun metagenomics (WGS) sequencing was performed to assess microbiota in stool samples, rectal swabs, and rectal biopsies. RESULTS: Personalized Mg treatment (mean dose 205.58 mg/day with a range from 77.25 to 389.55 mg/day) significantly increased the plasma levels of C7:0, C8:0, and combined C7:0 and C8:0 by 18.45%, 25.28%, and 24.20%, respectively, compared to 14.15%, 10.12%, and 12.62% decreases in the placebo arm. The effects remain significant after adjusting for age, sex, race and baseline level (P = 0.0126, P = 0.0162, and P = 0.0031, respectively) and FDR correction at 0.05 (q = 0.0324 for both C7:0 and C8:0). Mg treatment significantly reduced the plasma level of sucrose compared to the placebo arm (P = 0.0036 for multivariable-adjusted and P = 0.0216 for additional FDR correction model) whereas alterations in daily intakes of sucrose, fructose, glucose, maltose and C8:0 from baseline to the end of trial did not differ between two arms. Mediation analysis showed that combined C7:0 and C8:0 partially mediated the effects of Mg treatment on total and individual ketone bodies (P for indirect effect = 0.0045, 0.0043, and 0.03, respectively). The changes in plasma levels of C7:0 and C8:0 were significantly and positively correlated with the alterations in stool microbiome α diversity (r = 0.51, p = 0.0023 and r = 0.34, p = 0.0497, respectively) as well as in stool abundance for the signatures of MCFAs-related microbiota with acyl-ACP thioesterase gene producing C7:0 (r = 0.46, p = 0.0067) and C8:0 (r = 0.49, p = 0.003), respectively, following Mg treatment. CONCLUSIONS: Optimizing Ca:Mg intake ratios to around 2.3 through 12-week personalized Mg supplementation leads to increased circulating levels of MCFAs (i.e. C7:0 and C8:0), which is attributed to enhanced production from gut microbial fermentation and, maybe, sucrose consumption.

Predictors and timing of response to teduglutide in patients with short bowel syndrome dependent on parenteral support.

BACKGROUND AND AIMS: This study aimed to identify predictors and estimate time to teduglutide response among adult patients with short bowel syndrome with intestinal failure (SBS-IF) dependent on parenteral support (PS). METHODS: Post-hoc analysis was performed on individual patient data from teduglutide-treated patients in the phase III teduglutide trial STEPS and the STEPS-2 extension. Response was defined as ≥20% PS volume reduction from baseline for two consecutive visits. Early responders experienced the reduction at 20 and 24 weeks during STEPS while late responders experienced the reduction during STEPS-2. Timing and predictors for response were assessed among the treated population using Cox proportional hazard model. Time to response was compared in aetiological subgroups using Kaplan-Meier analysis. Patient characteristics and time to response were compared between early vs. late responders. RESULTS: A total of 34 patients were included in this analysis; overall median time to response was 4.3 months. The presence of stoma predicted a positive response to teduglutide (hazard ratio [HR]: 5.6; 95% confidence interval [CI]: 1.4-21.9; p = 0.013). Vascular disease (vs. inflammatory bowel disease [IBD]) as cause of major intestinal resection (HR: 0.2; 95% CI: 0.0-0.8; p = 0.015), presence of ileocecal valve (HR: 0.1; 95% CI: 0.0-0.8; p = 0.047), and female sex (HR: 0.3; 95% CI: 0.1-1.0; p = 0.026) are negatively associated with response. In subgroup analyses, patients with IBD (vs. vascular disease), with (vs. without) a stoma, and without (vs. with) colon-in-continuity had a shorter time to response (all p < 0.05). The mean times to response were 3.6 (standard deviation (SD): 1.1) months for early responders (n = 27) and 10.0 (SD: 6.1) months for late responders (n = 7). Fewer early responders had colon-in-continuity (51.9%) and ileocecal valve (0.0%) compared to late responders (100% and 28.6%, respectively; both p < 0.05). Early responders had a lower mean percentage of colon remaining compared to late responders (24.6% vs. 57.1%, respectively; p = 0.016). CONCLUSIONS: Time to response to teduglutide depends on bowel anatomy and SBS-IF aetiology. IBD, presence of a stoma, and absence of ileocecal valve were associated with earlier response to teduglutide. These findings may enhance management of patients with SBS-IF; however, due to sample size limitations, additional studies are needed to confirm these findings.

Magnesium Treatment on Methylation Changes of Transmembrane Serine Protease 2 (TMPRSS2).

BACKGROUND: The viral entry of SARS-CoV-2 requires host-expressed TMPRSS2 to facilitate the viral spike (S) protein priming. OBJECTIVES: To test the hypothesis that Mg treatment leads to DNA methylation changes in TMPRSS2 . METHODS: This study is nested within the Personalized Prevention of Colorectal Cancer Trial (PPCCT), a double-blind 2×2 factorial randomized controlled trial, which enrolled 250 participants from Vanderbilt University Medical Center. Target doses for both Mg and placebo arms were personalized. RESULTS: We found that 12-week of personalized Mg treatment significantly increased 5-mC methylation at cg16371860 (TSS1500, promoter) by 7.2% compared to placebo arm (decreased by 0.1%) in those aged < 65 years old. The difference remained statistically significant after adjusting for age, sex and baseline methylation as well as FDR correction (FDR-adjusted P =0.014). Additionally, Mg treatment significantly reduced 5-hmC level at cg26337277 (close proximity to TSS200 and 5'UTR, promoter) by 2.3% compared to increases by 7.1% in the placebo arm after adjusting for covariates in those aged < 65 years old ( P =0.003). The effect remained significant at FDR of 0.10 (adjusted P value=0.088). CONCLUSION: Among individuals aged younger than 65 years with the Ca:Mg intake ratios equal to or over 2.6, reducing Ca:Mg ratios to around 2.3 increased 5-mC modifications (i.e. cg16371860) and reduced 5-hmC modifications (i.e. cg26337277) in the TMPRSS2 gene. These findings, if confirmed, provide another mechanism for the role of Mg intervention for the prevention of COVID-19 and treatment of early and mild disease by modifying the phenotype of the TMPRSS2 genotype.

Magnesium treatment on methylation changes of transmembrane serine protease 2 (TMPRSS2).

OBJECTIVES: The viral entry of SARS-CoV-2 requires host-expressed TMPRSS2 to facilitate the viral spike protein priming. This study aims to test the hypothesis that magnesium (Mg) treatment leads to DNA methylation changes in TMPRSS2. METHODS: This study is nested within the Personalized Prevention of Colorectal Cancer Trial, a double-blind 2 × 2 factorial randomized controlled trial, which enrolled 250 participants from Vanderbilt University Medical Center. RESULTS: We found that 12 wk of personalized Mg treatment significantly increased 5-methylcytosine methylation at cg16371860 (TSS1500, promoter) by 7.2% compared to the placebo arm (decreased by 0.1%) in those ages < 65 y. The difference remained statistically significant after adjusting for age, sex, and baseline methylation as well as correction for false discovery rate (adjusted P = 0.014). Additionally, Mg treatment significantly reduced 5-hydroxymethylcytosine levels at cg26337277 (close proximity to TSS200 and the 5' untranslated region, promoter) by 2.3% compared to an increase of 7.1% in the placebo arm after adjusting for covariates in those ages < 65 y (P = 0.003). The effect remained significant at a false discovery rate of 0.10 (adjusted P = 0.088). CONCLUSIONS: Among individuals ages < 65 y with calcium-to-magnesium intake ratios equal to or over 2.6, reducing the ratio to around 2.3 increased 5-methylcytosine modifications (i.e., cg16371860) and reduced 5-hydroxymethylcytosine modifications (i.e., cg26337277) in the TMPRSS2 gene. These findings, if confirmed, provide another mechanism for the role of Mg intervention in the prevention of COVID-19 and treatment of early and mild disease by modifying the phenotype of the TMPRSS2 genotype.

Blunted PTH response to vitamin D insufficiency/deficiency and colorectal neoplasia risk.

BACKGROUND & AIMS: In contrast to many observational studies, large-scale randomized trials do not support the protective role of vitamin D for the prevention of colorectal neoplasia. However, in previous studies, individuals with blunted parathyroid hormone (PTH) response to vitamin D insufficiency/deficiency (BPRVID), were not differentiated from those with high PTH response to vitamin D insufficiency/deficiency (HPRVID). Individuals with BPRVID are responsive to magnesium treatment, particularly treatment of magnesium plus vitamin D while those with HPRVID are responsive to vitamin D treatment. We prospectively compared these two distinct groups (i.e. BPRVID and HPRVID) for risk of incident adenoma, metachronous adenoma, and incident colorectal cancer (CRC) METHODS: Three nested case-control studies in the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial. RESULTS: We found optimal 25(OH)D levels were associated with a significantly reduced risk of CRC, primarily among women. The associations between 25(OH)D and CRC risk significantly differed by PTH levels, particularly among women. Compared to individuals with optimal levels for both 25(OH)D and PTH, all others were at an elevated risk of incident CRC, primarily in women. We found those with BPRVID had 2.56-fold significantly increased risk of CRC compared to 1.65-fold non-significantly increased risk for those with HPRVID. Among women, we observed those with BPRVID had 4.79-6.25-fold significantly increased risks of incident CRC and adenoma whereas those with HPRVID had 3.65-fold significantly increased risk of CRC. CONCLUSIONS: Individuals with BPRVID are at higher risks of incident adenoma and CRC compared to those with HPRVID, particularly among women.

On the robustness of inference of association with the gut microbiota in stool, rectal swab and mucosal tissue samples.

The gut microbiota plays an important role in human health and disease. Stool, rectal swab and rectal mucosal tissue samples have been used in individual studies to survey the microbial community but the consequences of using these different sample types are not completely understood. In this study, we report differences in stool, rectal swab and rectal mucosal tissue microbial communities with shotgun metagenome sequencing of 1397 stool, swab and mucosal tissue samples from 240 participants. The taxonomic composition of stool and swab samples was distinct, but less different to each other than mucosal tissue samples. Functional profile differences between stool and swab samples are smaller, but mucosal tissue samples remained distinct from the other two types. When the taxonomic and functional profiles were used for inference in association with host phenotypes of age, sex, body mass index (BMI), antibiotics or non-steroidal anti-inflammatory drugs (NSAIDs) use, hypothesis testing using either stool or rectal swab gave broadly significantly correlated results, but inference performed on mucosal tissue samples gave results that were generally less consistent with either stool or swab. Our study represents an important resource for determination of how inference can change for taxa and pathways depending on the choice of where to sample within the human gut.

Enteral Autonomy and Days Off Parenteral Support With Teduglutide Treatment for Short Bowel Syndrome in the STEPS Trials.

BACKGROUND: Teduglutide response, in terms of parenteral support (PS) volume reduction, is associated with specific disease characteristics among adults with short bowel syndrome-associated intestinal failure (SBS-IF). Whether these associations apply to PS weaning with teduglutide is unknown. METHODS: Adults with SBS-IF treated with teduglutide in the phase III STEPS study and open-label extensions STEPS-2 and STEPS-3 were included in the analysis. Patients required PS ≥ 3 times weekly for ≥ 12 months at enrollment. The study population was stratified 3 times to create 3 distinct analysis populations based on bowel anatomy, etiology, and baseline PS volume. Outcomes included characteristics of patients who achieved PS independence and total and percentage of patients who had ≥ 1, ≥ 2, and ≥ 3 d/wk off PS at the end of STEPS, STEPS-2, and STEPS-3. RESULTS: Eight of 39 patients who received teduglutide in STEPS obtained PS independence during the STEPS study series. Patients required > 6 months of teduglutide treatment before enteral autonomy was achieved, regardless of underlying disease characteristics. Patients who attained PS independence and greater numbers of days per week off PS tended to have lower baseline PS volumes and noninflammatory bowel disease (non-IBD) etiology. Patients with ≥ 50% colon-in-continuity showed a trend for achieving greater numbers of days per week off PS. CONCLUSION: Although this analysis was limited by low patient numbers, results suggest that SBS-IF characteristics of lower baseline PS volume and non-IBD etiology were associated with PS reduction benefits with teduglutide in terms of days off per week and enteral autonomy.

Citrulline correlations in short bowel syndrome-intestinal failure by patient stratification: Analysis of 24 weeks of teduglutide treatment from a randomized controlled study.

BACKGROUND & AIMS: Disease-associated factors influence parenteral support (PS) reduction in response to teduglutide in patients with intestinal failure associated-short bowel syndrome (SBS-IF). We sought to determine correlative relationships between plasma citrulline levels, small bowel length, and PS volume. METHODS: A post hoc analysis of plasma citrulline levels from patients in the STEPS 24-week study of teduglutide in patients with SBS-IF. Plasma citrulline was assessed in all patients; patients were stratified 3 times into subgroups based on bowel anatomy, cause of SBS-IF, and baseline PS volumes. Correlation analyses used simple linear regression models. Statistical comparisons between study groups were conducted using 2-sided t tests for 2 independent mean differences. RESULTS: Baseline plasma citrulline correlated with remnant small bowel length (r = 0.355, P = 0.002), but not with baseline PS volume (r = -0.167, P = 0.14), in the overall population. There was a robust correlation between the baseline and Week 24 citrulline (r = 0.705, P < 0.0001), and an inverse correlation between change from baseline in citrulline and PS volume from baseline to Week 24 (r = -0.359, P = 0.001). In all subgroups, patients treated with teduglutide showed numerically greater increases in plasma citrulline at Week 24 compared with placebo. CONCLUSION: Baseline plasma citrulline showed significant correlations with small bowel length in patients with ≥50% colon remaining/no stoma/colon-in-continuity, and patients with SBS-IF causes other than IBD/vascular disease. Citrulline levels may correlate with PS changes in response to teduglutide and more research may reveal a relationship between citrulline levels within the heterogeneous population of patients with SBS-IF. ClinicalTrials.gov NCT00798967, ClinicalTrialsRegister.eu 2008-006193-15.

Colon polyps in patients with short bowel syndrome before and after teduglutide: Post hoc analysis of the STEPS study series.

BACKGROUND & AIMS: Teduglutide promotes intestinal growth and is approved for the treatment of short bowel syndrome and intestinal failure (SBS-IF). Based on the pharmacologic activity and preclinical findings, teduglutide can potentially induce proliferative colonic mucosal changes. The aim of this study is to report the occurrence of colorectal polyps in adult patients with SBS-IF who received teduglutide in clinical studies conducted to date. METHODS: A post hoc analysis of the completed Study of Teduglutide Effectiveness in Parenteral Nutrition-Dependent Short Bowel Syndrome Subjects (STEPS) clinical study series (NCT00798967, EudraCT 2008-006193-15; NCT00930644, EudraCT 2009-011679-65; NCT01560403) evaluated electronic case report form data for baseline colonoscopies (performed before treatment) and for surveillance or end-of-study (performed after treatment with teduglutide 0.05 mg/kg/day for 24 and 36 months) post-exposure procedures. RESULTS: In the STEPS studies, 73 patients treated with teduglutide had a baseline colonoscopy. No post-exposure colonoscopy was scheduled in STEPS. In STEPS-2/3, 50 of 65 patients with remnant colon (77%) underwent a protocol-mandated post-exposure colonoscopy. Colon polyps were reported at baseline in 12% (9/73) of patients and post-exposure in 18% (9/50) of patients. Two had polyps both at baseline and post-exposure. On histology, available for 7 patients, 5 had adenomas (1 serrated, 4 tubular) and none had malignancy or high-grade dysplasia. CONCLUSION: These data support recommendations for colonoscopic screening before teduglutide therapy and subsequent on-therapy colonoscopic surveillance for patients with SBS-IF. Further studies are required to assess the risk of polyp formation in patients with SBS-IF and the most appropriate colon polyp surveillance strategies.

Teduglutide for the treatment of adults with intestinal failure associated with short bowel syndrome: pooled safety data from four clinical trials.

BACKGROUND: In multiple clinical studies, teduglutide reduced parenteral support (PS) with a consistent safety profile in adults with short bowel syndrome-associated intestinal failure (SBS-IF). The objective of this study was to assess adverse events (AEs) from a pooled data set. METHODS: Safety data from four prospective clinical trials of teduglutide in patients with SBS-IF were assimilated. AEs were evaluated in patient groups based on treatment received in each study and in populations stratified to create distinct subgroups based on aetiology, bowel anatomy and baseline PS volume requirements. RESULTS: Safety data are reported for up to 2.5 years, totalling 222 person-years exposure to teduglutide. In most patients, AEs were reported as mild or moderate in severity in all patient groups and occurred at comparable rates between patients who received teduglutide or placebo. Several common gastrointestinal AEs, including abdominal pain, nausea and abdominal distension, were reported more frequently earlier in the course of treatment, with their frequency declining over time. Fewer gastrointestinal AEs were reported in patients with vascular causes of SBS-IF and patients with most of their colon-in-continuity than in other patient subgroups. Across the patient stratification subgroups, the predominant treatment-emergent AEs for which patients receiving teduglutide had a significantly increased relative risk were abdominal distension and gastrointestinal stoma complication compared with patients receiving placebo. CONCLUSIONS: Teduglutide had a safety profile consistent with prior adult data and no new safety concerns were identified. The most frequently reported AEs were gastrointestinal in origin, consistent with the underlying disease condition and intestinotrophic actions of teduglutide. CLINICAL TRIAL REGISTRY INFORMATION: NCT00081458/EudraCT, 2004-000438-35; NCT00798967/EudraCT, 2008-006193-15; NCT00172185/EudraCT, 2004-000439-27; NCT00930644/EudraCT, 2009-011679-65.

Ca:Mg Ratio, APOE Cytosine Modifications, and Cognitive Function: Results from a Randomized Trial.

BACKGROUND: Deterioration of ionized calcium (Ca2+) handling in neurons could lead to neurodegenerative disease. Magnesium (Mg) antagonizes Ca during many physiologic activities, including energy metabolism and catalyzation of demethylation from 5-methylcytosine(5-mC) to 5-hydroxymethylcytosine(5-hmC). OBJECTIVE: To test the hypothesis that actively reducing the Ca:Mg intake ratio in the diet through Mg supplementation improves cognitive function, and to test whether this effect is partially mediated by modified cytosines in Apolipoprotein E (APOE). METHODS: This study is nested within the Personalized Prevention of Colorectal Cancer Trial (PPCCT), a double-blind 2×2 factorial randomized controlled trial, which enrolled 250 participants from Vanderbilt University Medical Center. Target doses for both Mg and placebo arms were personalized. RESULTS: Among those aged > 65 years old who consumed a high Ca:Mg ratio diet, we found that reducing the Ca:Mg ratio to around 2.3 by personalized Mg supplementation significantly improved cognitive function by 9.1% (p = 0.03). We also found that reducing the Ca:Mg ratio significantly reduced 5-mC at the cg13496662 and cg06750524 sites only among those aged > 65 years old (p values = 0.02 and 0.03, respectively). Furthermore, the beneficial effect of reducing the Ca:Mg ratio on cognitive function in those aged over 65 years was partially mediated by reductions in 5-mC levels (i.e., cg13496662 and cg06750524) in APOE (p for indirect effect = 0.05). CONCLUSION: Our findings suggest that, among those age 65 and over with a high dietary Ca:Mg ratio, optimal Mg status may improve cognitive function partially through modifications in APOE methylation. These findings, if confirmed, have significant implications for the prevention of cognitive aging and Alzheimer's disease.Clinical Trial Registry number and website: #100106 https://clinicaltrials.gov/ct2/show/NCT03265483.

Is there a role for bowel rest in nutrition management of Crohn's disease?

In 1988, Greenberg and colleagues published a large randomized controlled trial to address whether bowel rest could lead to improved disease activity in patients with active Crohn's disease. The results of this study provide substantial evidence that bowel rest is not necessary to achieve remission in patients with active Crohn's disease receiving nutrition support. Before this study, great controversy existed about the use of nutrition support and bowel rest in the treatment of active Crohn's disease because of a limited number of conflicting studies providing evidence for and against its application. The results of the publication by Greenberg et al are fundamental because they helped to settle this important argument. Furthermore, this pivotal paper changed the clinical guidelines for the use of nutrition support in the management of active Crohn's disease. Since the publication of this pivotal article, many developments in the field of nutrition and in the treatment of Crohn's disease have helped validate and further its results. Subsequent studies and debate center on the use of enteral nutrition as primary treatment in patients with active Crohn's disease. Data regarding the efficacy, composition, and overall role of adult enteral nutrition in the management of Crohn's disease are presented. This article revisits the Greenberg paper and discusses some of these innovations in nutrition.

Nutritional Consideration in Celiac Disease and Nonceliac Gluten Sensitivity.

Celiac disease is an autoimmune disorder due to the inflammatory response to gluten in genetically predisposed individuals. It causes an enteropathy associated with several nutritional complications. Strict compliance to a gluten-free diet (GFD) is the current primary therapy. Nonceliac gluten sensitivity (NCGS) is a condition in which gluten ingestion leads to systemic symptoms but is not associated with small bowel atrophy or abnormal celiac serologies. A GFD heals celiac disease enteropathy and improves symptoms in NCGS. However, a long-term GFD can be associated with nutritional deficiencies and requires monitoring and guidance.

Parenteral Nutrition: Indications, Access, and Complications.

Parenteral nutrition (PN) is a life-sustaining therapy in patients with intestinal failure who are unable to tolerate enteral feedings. Patient selection should be based on a thorough assessment to identify those at high nutrition risk based on both disease severity and nutritional status. This article reviews both the acute and chronic indications for PN as well as special formulation consideration in specific disease states, vascular access, and complications of both short-term and long-term PN.