Carbohydrate-restricted diets in diabetes and the irritable bowel syndrome. Effects on symptoms, inflammation and microbiota.

This doctoral thesis explores the effects of carbohydrate(CHO)-restricted diets on symptoms and disease-related variables in type 2 diabetes mellitus (T2DM) and the irritable bowel syndrome (IBS). Aims were to examine the effects of (I) the moderately-low CHO Okinawan-based Nordic diet on anthropometry and metabolism and microbiota-related, inflammatory, and cognitive parameters in T2DM, and (II) the low-CHO starch- and sucrose reduced diet on gastrointestinal (GI) symptoms, dietary intakes, inflammatory parameters, microbiota and microribonucleic acid (miRNA) expression in IBS. (I) A prospective 12-week Okinawan-based Nordic dietary intervention with 30 T2DM patients was performed. Questionnaires and fecal and blood samples were collected and analyzed before and after the study. Fecal samples were analyzed for Enterobacteriaceae abundance by polymerase chain reaction (PCR) assay and alpha diversity by terminal restriction fragment length polymerization (T-RFLP). From blood, metabolic parameters were measured according to clinical routine by the Clinical Chemistry department, short-chain fatty acid concentrations were measured by gas-liquid chromatography, circulating cytokine concentrations by immunoassay and neurofilament levels by an in-house assay. (II) A randomized clinical trial with a 4-week starch- and sucrose-reduced diet (SSRD) was performed in 105 IBS patients. Questionnaires, 4-day food diaries and fecal and blood samples were collected before and at the end the study. GI symptoms were measured from questionnaires, i.e., the irritable bowel syndrome symptom severity score (IBS-SSS), the visual analog scale for IBS (VAS-IBS) and the Rome IV questionnaires. Dietary intakes were calculated by the dietician using the AIVO diet computer program. From plasma, C-reactive protein (CRP) was analyzed by the Clinical Chemistry department, cytokine concentrations by multiplex immunoassay and miRNA by RNA sequencing. Microbiota (taxonomy at phylum, genus and ASV level, alpha- and beta diversity) was analyzed from fecal samples by 16S ribosomal RNA (rRNA) gene sequencing. Results from study I showed that T2DM participants experienced significant weight loss (mean decrease of 6.2 kg), decreased waist circumference and body-mass index (BMI) after the intervention (p < 0.001 for all). Cortisol, fasting glucose, insulin, glycated hemoglobin (HbA1c) and lipid parameters decreased significantly (p < 0.001 for all). Microbiota-related parameters, i.e., Enterobacteriaceae abundance, microbial diversity measures and SCFA concentrations, were largely unaltered after the 12-week trial. There was an overall trend towards decreased proinflammatory parameters, significant for interleukin 18 (IL-18) (median value [IQR] at baseline [pg/mL]: 226 [173-280] and 12 weeks: 189 [136-242], p = 0.001). In study II, there was a 74% responder rate (RR=ΔTotal IBS-SSS≥-50 points) to the SSRD among IBS patients in the intervention group (RR = 24% for controls), with primarily decreased abdominal pain and bloating. The intakes of starch, sucrose, disaccharides and CHO decreased in the intervention group (p <0.001 for all). At 4 weeks, fat and protein energy percentages (E%) were significantly higher in the intervention compared to the control group. Sugar- and starch reductions correlated weakly-moderately with the improved GI symptom scores. CRP and cytokines levels were mainly unaltered in both groups. Microbiota analyses showed increased Proteobacteria (p=0.0036), decreased Bacteroidetes (p<0.001), as well as changes in gut microbiota composition (β-diversity: p<0.001) but not alpha diversity. There were 20 genus-level changes in the intervention group, compared to 2 in the control group. MiRNA was unaffected by the SSRD intervention. Conclusion: CHO-restricted diets improve key disease aspects with improved anthropometry and metabolism in T2DM and markedly reduced GI symptoms in IBS. Systemic inflammation was reduced and microbiota unaltered with the moderately-low CHO Okinawan-based Nordic diet in T2DM, whereas systemic inflammation was unaltered and gut microbiota composition significantly impacted with the low-CHO starch- and sucrose-reduced diet in IBS

A carbohydrate-restricted diet for patients with irritable bowel syndrome lowers serum C-peptide, insulin, and leptin without any correlation with symptom reduction

Alterations in gut endocrine cells and hormone levels have been measured in patients with irritable bowel syndrome (IBS). The hypothesis of the present study was that hormone levels would change after 4 weeks of a starch- and sucrose-reduced diet (SSRD) intervention corresponding to decreased carbohydrate intake and symptoms. Among 105 IBS patients from primary and tertiary healthcare, 80 were randomized to SSRD, while 25 followed their ordinary diet. Food diaries, Rome IV, and IBS-symptom severity score (IBS-SSS) questionnaires were completed, and blood samples were collected at baseline and after the intervention. Serum C-peptide, gastric inhibitory peptide, glucagon, glucagon-like peptide-1, insulin, leptin, luteinizing hormone, polypeptide YY, and glucose were measured, along with the prevalence of autoantibodies against gonadotropin-releasing hormone; its precursor, progonadoliberin-2, and receptor; and tenascin C. Carbohydrate intake was lower in the intervention group than in controls at week 4 (median: 88 [66-128] g vs 182 [89-224] g; P < .001). The change in carbohydrate intake, adjusted for weight, was associated with a decrease in C-peptide (β: 14.43; 95% confidence interval [CI]: 4.12-24.75) and insulin (β: 0.18; 95% CI: 0.04-0.32) levels. Glucose levels remained unchanged. The IBS-SSS scores were lower in the intervention group but not in controls (P < .001), without any association with changes in hormone concentrations. There was no difference in autoantibody prevalence between patients and healthy controls. In conclusion, the hypothesis that reduced carbohydrate intake corresponded to altered hormonal levels in IBS was accepted; however, there was no relationship between hormonal concentrations and symptoms

A starch‐ and sucrose‐reduced dietary intervention in irritable bowel syndrome patients produced a shift in gut microbiota composition along with changes in phylum, genus, and amplicon sequence variant abundances, without affecting the micro‐RNA levels

Background/AimA randomized clinical trial with a starch- and sucrose-reduced diet (SSRD) in irritable bowel syndrome (IBS) patients has shown clear improvement of participants' symptoms. The present study aimed to explore the effects of the SSRD on the gut microbiota and circulating micro-RNA in relation to nutrient intake and gastrointestinal symptoms.MethodsIBS patients were randomized to a 4-week SSRD intervention (n = 80) or control group (n = 25); habitual diet). At baseline and 4 weeks, blood and fecal samples, 4 day-dietary records, and symptom questionnaires were collected, that is, Rome IV questionnaires, IBS-symptom severity score (IBS-SSS) and visual analog scale for IBS (VAS-IBS). Micro-RNA was analyzed in blood and microbiota in faeces by 16S rRNA from regions V1–V2.ResultsThe alpha diversity was unaffected, whereas beta diversity was decreased (p < 0.001) along with increased abundance of Proteobacteria (p = 0.0036) and decreased abundance of Bacteroidetes phyla (p < 0.001) in the intervention group at 4 weeks. Few changes were noted in the controls. The shift in beta diversity and phyla abundance correlated with decreased intakes of carbohydrates, disaccharides, and starch and increased fat and protein intakes. Proteobacteria abundance also correlated positively (R2 = 0.07, p = 0.0016), and Bacteroidetes negatively (R2 = 0.07, p = 0.0017), with reduced total IBS-SSS. Specific genera, for example, Eubacterium eligens, Lachnospiraceae UCG-001, Victivallis, and Lachnospira increased significantly in the intervention group (p < 0.001 for all), whereas Marvinbryantia, DTU089 (Ruminoccocaceae family), Enterorhabdus, and Olsenella decreased, together with changes in amplicon sequence variant (ASV) levels. Modest changes of genus and ASV abundance were observed in the control group. No changes were observed in micro-RNA expression in either group.ConclusionThe SSRD induced a shift in beta diversity along with several bacteria at different levels, associated with changes in nutrient intakes and reduced gastrointestinal symptoms. No corresponding changes were observed in the control group. Neither the nutrient intake nor the microbiota changes affected micro-RNA expression.The study was registered at ClinicalTrials.gov data base (NCT03306381)

Irregular dietary habits with a high intake of cereals and sweets are associated with more severe gastrointestinal symptoms in IBS patients.

Dietary advice constitutes one of the first choices of treatment for irritable bowel syndrome (IBS). We have recognized an increased prevalence of sucrase-isomaltase (SI) gene variants in IBS patients, possibly rendering starch- and sucrose-intolerance. The aims were to examine participants’ dietary habits at baseline, to correlate habits with gastrointestinal (GI) symptoms and blood levels of minerals and vitamins, and to examine the effect of a starch- and sucrose-reduced diet (SSRD) on GI symptoms. In the study 105 IBS patients (82 women, 46.06 ± 13.11 years), irritable bowel syndrome-symptom severity scale (IBS-SSS)>175, were randomized to SSRD for 2 weeks or continued ordinary eating habits. Blood samples, visual analog scale for irritable bowel syndrome (VAS-IBS), IBS-SSS, and 4-day food diaries were collected at baseline and after 2 weeks. Patients with irregular dietary habits exhibited higher IBS-SSS than patients with regular habits (p = 0.029). Women already on a diet had lower ferritin levels than others (p = 0.029). The intervention led to 66.3% of patients being responders, with differences in the change of IBS-SSS (p < 0.001), abdominal pain (p = 0.001), diarrhea (p = 0.002), bloating and flatulence (p = 0.005), psychological well-being (p = 0.048), and intestinal symptoms’ influence on daily life (p < 0.001), compared to controls. Decreased intake of cereals and sweets/soft drinks correlated with decreased scores

Assessment of a 4-Week Starch- and Sucrose-Reduced Diet and Its Effects on Gastrointestinal Symptoms and Inflammatory Parameters among Patients with Irritable Bowel Syndrome

Dietary advice constitutes a treatment strategy for irritable bowel syndrome (IBS). We aimed to examine the effect of a starch- and sucrose-reduced diet (SSRD) on gastrointestinal symptoms in IBS patients, in relation to dietary intake and systemic inflammatory parameters. IBS patients (n = 105) were randomized to a 4-week SSRD intervention (n = 80) receiving written and verbal dietary advice focused on starch and sucrose reduction and increased intake of protein, fat and dairy, or control group (n = 25; habitual diet). At baseline and 4 weeks, blood was sampled, and participants filled out IBS-SSS, VAS-IBS, and Rome IV questionnaires and dietary registrations. C-reactive protein and cytokines TNF-α, IFN-γ, IL-6, IL-8, IL-10, and IL-18 were analyzed from plasma. At 4 weeks, the intervention group displayed lower total IBS-SSS, 'abdominal pain', 'bloating/flatulence' and 'intestinal symptoms´ influence on daily life' scores (p ≤ 0.001 for all) compared to controls, and a 74%, responder rate (RR = ΔTotal IBS-SSS ≥ -50; RRcontrols = 24%). Median values of sucrose (5.4 vs. 20 g), disaccharides (16 vs. 28 g), starch (22 vs. 82 g) and carbohydrates (88 vs. 182 g) were lower for the intervention group compared to controls (p ≤ 0.002 for all), and energy percentages (E%) of protein (21 vs. 17 E%, p = 0.006) and fat (47 vs. 38 E%, p = 0.002) were higher. Sugar-, starch- and carbohydrate-reductions correlated weakly-moderately with total IBS-SSS decrease for all participants. Inflammatory parameters were unaffected. IBS patients display high compliance to the SSRD, with improved gastrointestinal symptoms but unaltered inflammatory parameters. In conclusion, the SSRD constitutes a promising dietary treatment for IBS, but needs to be further researched and compared to established dietary treatments before it could be used in a clinical setting

Metabolic profiling of plasma in patients with irritable bowel syndrome after a 4-week starch- and sucrose-reduced diet

A 4-week dietary intervention with a starch- and sucrose-restricted diet (SSRD) was conducted in patients with irritable bowel syndrome (IBS) to examine the metabolic profile in relation to nutrient intake and gastrointestinal symptoms. IBS patients were randomized to SSRD intervention (n = 69) or control continuing with their ordinary food habits (n = 22). Food intake was registered and the questionnaires IBS-symptoms severity scale (IBS-SSS) and visual analog scale for IBS (VAS-IBS) were completed. Metabolomics untargeted analysis was performed by gas chromatography mass spectrometry (GC-MS) and liquid chromatography mass spectrometry (LC-MS) in positive and negative ionization modes. SSRD led to marked changes in circulating metabolite concentrations at the group level, most prominent for reduced starch intake and increased polyunsaturated fat, with small changes in the control group. On an individual level, the correlations were weak. The marked reduction in gastrointestinal symptoms did not correlate with the metabolic changes. SSRD was observed by clear metabolic effects mainly related to linoleic acid metabolism, fatty acid biosynthesis, and beta-oxidation

Anthropometric and metabolic improvements in human type 2 diabetes after introduction of an Okinawan-based Nordic diet are not associated with changes in microbial diversity or SCFA concentrations

The Okinawan-based Nordic (O-BN) diet improves anthropometry and metabolism in type 2 diabetes mellitus (T2DM) patients. The aim of this study was to study mechanisms behind improvements by examining Enterobacteriaceae abundance, microbial diversity, and concentrations of short-chain fatty acids (SCFAs). A secondary aim was exploring if metformin treatment affects microbiota or SCFAs. Thirty T2DM patients received the O-BN diet for 12 weeks. Faecal and blood samples were collected at baseline, 12 and 28 weeks. Although patients experienced weight loss and improved metabolic parameters, there were no significant changes in Enterobacteriaceae abundance or microbial diversity. Patients on metformin displayed higher Enterobacteriaceae abundance throughout the study (p = .008, p = .038, and p = .001, respectively). Isovaleric acid was decreased after 12 weeks (p = .018). Butyric acid was decreased at follow-up (p = .007). Improved anthropometry and metabolism in T2DM after introduction of the O-BN diet is not associated with changes in Enterobacteriaceae abundance, microbial diversity or SCFA concentrations