Role of gut microbiota in the aetiology of obesity: proposed mechanisms and review of the literature

The aetiology of obesity has been attributed to several factors (environmental, dietary, lifestyle, host, and genetic factors); however none of these fully explain the increase in the prevalence of obesity worldwide. Gut microbiota located at the interface of host and environment in the gut are a new area of research being explored to explain the excess accumulation of energy in obese individuals and may be a potential target for therapeutic manipulation to reduce host energy storage. Several mechanisms have been suggested to explain the role of gut microbiota in the aetiology of obesity such as short chain fatty acid production, stimulation of hormones, chronic low-grade inflammation, lipoprotein and bile acid metabolism, and increased endocannabinoid receptor system tone. However, evidence from animal and human studies clearly indicates controversies in determining the cause or effect relationship between the gut microbiota and obesity. Metagenomics based studies indicate that functionality rather than the composition of gut microbiota may be important. Further mechanistic studies controlling for environmental and epigenetic factors are therefore required to help unravel obesity pathogenesis

Impact of phenylketonuria type meal on appetite, thermic effect of feeding and postprandial fat oxidation

Background: Dietary management of phenylketonuria (PKU) requires the replacement of natural protein-containing foods with special low protein foods. The effect of a PKU type diet on factors contributing to energy balance requires investigation. Objective: To investigate the impact of a PKU type meal on appetite ratings, gut appetite hormones, thermic effect of feeding (TEF) and fat oxidation. Methods: Twenty-three healthy adults (mean ± SD age: 24.3 ± 5.1 years; BMI: 22.4 ± 2.5 kg/m2) participated in a randomized, crossover design study. Each participant conducted two (PKU and Control) experimental trials which involved consumption of a PKU type meal and protein substitute drink or an isocaloric and weight matched ordinary meal and protein-enriched milk. Appetite, metabolic rate, fat oxidation measurements and blood collections were conducted for the duration of 300 min. On the completion of the measurements ad libitum buffet dinner was served. Results: Responses of appetite ratings, plasma concentrations of GLP-1 and PYY (P > 0.05, trial effect, two-way ANOVA) and energy intake during ad libitum buffet dinner (P > 0.05, paired t-test) were not significantly different between the two trials. The TEF (PKU, 10.2 ± 1.5%; Control, 13.2 ± 1.0%) and the total amount of fat oxidized (PKU, 18.90 ± 1.10 g; Control, 22.10 ± 1.10 g) were significantly (P < 0.05, paired t-tests) lower in the PKU than in the Control trial. The differences in TEF and fat oxidation were significant (P < 0.05, paired t-tests) for the post-meal period. Conclusions: Consumption of a meal composed of special low protein foods has no detrimental impact on appetite and appetite hormones but produces a lower TEF and postprandial fat oxidation than an ordinary meal. These metabolic alterations may contribute to the increased prevalence of obesity reported in patients with PKU on contemporary dietary management

Optimal distribution and utilization of donated human breast milk: a novel approach

Background: The nutritional content of donated expressed breast milk (DEBM) is variable. Using DEBM to provide for the energy requirements of neonates is challenging. Objective: The authors hypothesized that a system of DEBM energy content categorization and distribution would improve energy intake from DEBM. Methods: We compared infants’ actual cumulative energy intake with projected energy intake, had they been fed using our proposed system. Eighty-five milk samples were ranked by energy content. The bottom, middle, and top tertiles were classified as red, amber, and green energy content categories, respectively. Data on 378 feeding days from 20 babies who received this milk were analyzed. Total daily intake of DEBM was calculated in mL/kg/day and similarly ranked. Infants received red energy content milk, with DEBM intake in the bottom daily volume intake tertile; amber energy content milk, with intake in the middle daily volume intake tertile; and green energy content milk when intake reached the top daily volume intake tertile. Results: Actual median cumulative energy intake from DEBM was 1612 (range, 15-11 182) kcal. Using DEBM with the minimum energy content from the 3 DEBM energy content categories, median projected cumulative intake was 1670 (range 13-11 077) kcal, which was not statistically significant (P = .418). Statistical significance was achieved using DEBM with the median and maximum energy content from each energy content category, giving median projected cumulative intakes of 1859 kcal (P = .0006) and 2280 kcal (P = .0001), respectively. Conclusion: Cumulative energy intake from DEBM can be improved by categorizing and distributing milk according to energy content

An automated identification and analysis of ontological terms in gastrointestinal diseases and nutrition-related literature provides useful insights

With an unprecedented growth in the biomedical literature, keeping up to date with the new developments presents an immense challenge. Publications are often studied in isolation of the established literature, with interpretation being subjective and often introducing human bias. With ontology-driven annotation of biomedical data gaining popularity in recent years and online databases offering metatags with rich textual information, it is now possible to automatically text-mine ontological terms and complement the laborious task of manual management, interpretation, and analysis of the accumulated literature with downstream statistical analysis. In this paper, we have formulated an automated workflow through which we have identified ontological information, including nutrition-related terms in PubMed abstracts (from 1991 to 2016) for two main types of Inflammatory Bowel Diseases: Crohn’s Disease and Ulcerative Colitis; and two other gastrointestinal (GI) diseases, namely, Coeliac Disease and Irritable Bowel Syndrome. Our analysis reveals unique clustering patterns as well as spatial and temporal trends inherent to the considered GI diseases in terms of literature that has been accumulated so far. Although automated interpretation cannot replace human judgement, the developed workflow shows promising results and can be a useful tool in systematic literature reviews. The workflow is available at https://github.com/KociOrges/pytag

Dietitians’ perceptions and experience of blenderised feeds for paediatric tube-feeding

Objective: There is an emerging interest in the use of blenderised food for tube-feeding (BFTF). This survey explored paediatric dietitians' perceptions and experiences of BFTF use. Design: A web-based questionnaire was distributed to the Paediatric group of the British Dietetic Association. The survey captured dietitians' personal opinions and experience supporting children on BFTF, and the perceptions of carers. Results: Of the 77 respondents, 19 were aware of professional guidelines and 63 had never received training on BFTF. Thirty-four would not recommend BFTF and 11 would advise against its use; yet 43 would recommend it to supplement commercial feeds. Fifty-seven would change their perception about BFTF if there were evidence-based guidelines. Forty-four would feel confident to support a patient using BFTF. Forty-three had previous experience supporting a patient with BFTF. The main concerns perceived by dietitians, pertinent to the use of BFTF, were nutritional inadequacy (n=71), tube blockages (n=64) and increased infection risk (n=59) but these were significantly higher than those experienced by themselves in clinical practice (p<0.001 for all three). A reduction in reflux and vomiting and increased carer involvement were the main perceived and observed benefits by both dietitians and carers. Conclusions: The use of these feeds for tube-fed children is increasingly being seen as a viable choice. Dietitians experienced significantly fewer issues with the use of BFTF in clinical practice compared with their self-reported apprehensions in the survey. Well-controlled studies are now needed to objectively assess the benefits, risks, costs and practicality of BFTF

Dietary treatment of Crohn’s disease: perceptions of families with children treated by exclusive enteral nutrition, a questionnaire survey

Background: Diet is strongly associated with the aetiology of Crohn’s Disease (CD) and exclusive enteral nutrition (EEN) is the primary induction treatment in paediatric CD. This study explored opinions around the use of EEN and alternative novel, solid food-based diets (SFDs) expressed by paediatric patients with CD, previously treated with EEN and their parents. Methods: This anonymous questionnaire surveyed families of CD patients treated with EEN over 1 year. Two questionnaire forms were completed; one asking the patients’ opinions and another referring to their main carer. This questionnaire explored participants’ demographic characteristics; acceptability of a repeat EEN course to treat a future flare (EEN repeat); their opinion on how difficult EEN would be compared to an example SFD; and their intention to participate in a future clinical trial assessing the therapeutic efficacy of an SFD in CD. Results: Forty-one families of CD patients were approached with 29 sending replies (71%). Most of our participants were positive on completing another EEN course, however the majority would choose an SFD alternative (Patients: 66, Parents:72%). Both patients and their parents rated EEN to be more difficult to adhere to compared to an example SFD (p < 0.05), and their ratings were strongly correlated (EEN:r = 0.83, SFD:r = 0.75, p < 0.001). The majority of our respondents would agree to participate in a clinical trial assessing an SFD’s effectiveness (Patients:79, Parents:72%) for the management of active CD. Conclusions: While patients with CD and their families would accept an EEN repeat, the majority would prefer an SFD alternative. CD families surveyed are supportive of the development of solid food-based dietary treatments

The distinct features of microbial 'dysbiosis' of Crohn's disease do not occur to the same extent in their unaffected, genetically linked kindred

Background/Aims: Studying the gut microbiota in unaffected relatives of people with Crohn’s disease (CD) may advance our understanding of the role of bacteria in disease aetiology. Methods: Faecal microbiota composition (16S rRNA gene sequencing), genetic functional capacity (shotgun metagenomics) and faecal short chain fatty acids (SCFA) were compared in unaffected adult relatives of CD children (CDR, n = 17) and adult healthy controls, unrelated to CD patients (HUC, n = 14). The microbiota characteristics of 19 CD children were used as a benchmark of CD ‘dysbiosis’. Results: The CDR microbiota was less diverse (p = 0.044) than that of the HUC group. Local contribution of β-diversity analysis showed no difference in community structure between the CDR and HUC groups. Twenty one of 1,243 (1.8%) operational taxonomic units discriminated CDR from HUC. The metagenomic functional capacity (p = 0.207) and SCFA concentration or pattern were similar between CDR and HUC (p>0.05 for all SCFA). None of the KEGG metabolic pathways were different between these two groups. Both of these groups (HUC and CDR) had a higher microbiota α-diversity (CDR, p = 0.026 and HUC, p<0.001) with a community structure (β-diversity) distinct from that of children with CD. Conclusions: While some alterations were observed, a distinct microbial ‘dysbiosis’, characteristic of CD patients, was not observed in their unaffected, genetically linked kindred

Nutritional status, growth and disease management in children with single and dual diagnosis of type 1 diabetes mellitus and coeliac disease

Background: The consequences of subclinical coeliac disease (CD) in Type 1 diabetes mellitus (T1DM) remain unclear. We looked at growth, anthropometry and disease management in children with dual diagnosis (T1DM + CD) before and after CD diagnosis.<p></p> Methods: Anthropometry, glycated haemoglobin (HbA1c) and IgA tissue transglutaminase (tTg) were collected prior to, and following CD diagnosis in 23 children with T1DM + CD. This group was matched for demographics, T1DM duration, age at CD diagnosis and at T1DM onset with 23 CD and 44 T1DM controls.<p></p> Results: No differences in growth or anthropometry were found between children with T1DM + CD and controls at any time point. Children with T1DM + CD, had higher BMI z-score two years prior to, than at CD diagnosis (p <0.001). BMI z-score change one year prior to CD diagnosis was lower in the T1DM + CD than the T1DM group (p = 0.009). At two years, height velocity and change in BMI z-scores were similar in all groups. No differences were observed in HbA1c between the T1DM + CD and T1DM groups before or after CD diagnosis. More children with T1DM + CD had raised tTg levels one year after CD diagnosis than CD controls (CDx to CDx + 1 yr; T1DM + CD: 100% to 71%, p = 0.180 and CD: 100% to 45%, p < 0.001); by two years there was no difference.<p></p> Conclusions: No major nutrition or growth deficits were observed in children with T1DM + CD. CD diagnosis does not impact on T1DM glycaemic control. CD specific serology was comparable to children with single CD, but those with dual diagnosis may need more time to adjust to gluten free diet

An evaluation of enteral nutrition practices and nutritional provision in children during the entire length of stay in critical care

<b>Background</b> Provision of optimal nutrition in children in critical care is often challenging. This study evaluated exclusive enteral nutrition (EN) provision practices and explored predictors of energy intake and delay of EN advancement in critically ill children.<p></p> <b>Methods</b> Data on intake and EN practices were collected on a daily basis and compared against predefined targets and dietary reference values in a paediatric intensive care unit. Factors associated with intake and advancement of EN were explored.<p></p> <b>Results</b> Data were collected from 130 patients and 887 nutritional support days (NSDs). Delay to initiate EN was longer in patients from both the General Surgical and congenital heart defect (CHD) Surgical groups [Median (IQR); CHD Surgical group: 20.3 (16.4) vs General Surgical group: 11.4 (53.5) vs Medical group: 6.5 (10.9) hours; p <= 0.001]. Daily fasting time per patient was significantly longer in patients from the General Surgical and CHD Surgical groups than those from the Medical group [% of 24 h, Median (IQR); CHD Surgical group: 24.0 (29.2) vs General Surgical group: 41.7 (66.7) vs Medical group: 9.4 (21.9); p <= 0.001]. A lower proportion of fluids was delivered as EN per patient (45% vs 73%) or per NSD (56% vs 73%) in those from the CHD Surgical group compared with those with medical conditions. Protein and energy requirements were achieved in 38% and 33% of the NSDs. In a substantial proportion of NSDs, minimum micronutrient recommendations were not met particularly in those patients from the CHD Surgical group. A higher delivery of fluid requirements (p < 0.05) and a greater proportion of these delivered as EN (p < 0.001) were associated with median energy intake during stay and delay of EN advancement. Fasting (31%), fluid restriction (39%) for clinical reasons, procedures requiring feed cessation and establishing EN (22%) were the most common reasons why target energy requirements were not met.<p></p> <b>Conclusions</b> Provision of optimal EN support remains challenging and varies during hospitalisation and among patients. Delivery of EN should be prioritized over other "non-nutritional" fluids whenever this is possible.<p></p&gt

Nutritional aspects and gut microbiota in paediatric inflammatory bowel disease

As Crohn’s disease (CD) is a disease of the gastrointestinal tract, nutrition is very important and is implicated in several aspects of the disease, from aetiology, management, and the long-term health of the patient. Nutritional therapy with EEN is the mainstream approach in the management of active paediatric CD and has a dual effect, inducing clinical remission and providing nutritional support and rehabilitation. Although its efficacy is well established by human trials and clinical experience, the mode of action remains unknown. Initial speculations for a mechanism of action mediated through gut rest, and protein/energy reconstitution have not been established. On the other hand the strong evidence for the role of the indigenous microbiota and micronutrients in disease aetiology and mucosal injury, challenged the researcher to explore whether the action of EEN is mediated through changes in these parameters. This study aimed to assess aspects of the nutritional status of paediatric patients with inflammatory bowel disease (IBD), to appraise the use of nutritional remedies in the same population, and to explore putative mechanisms of action of EEN, the nutritional therapy, with the most robust evidence of clinically efficacy. The first of these studies was a questionnaire survey which assessed the use of special diets, nutritional supplements, herbals, and alternative medicine in a representative sample of paediatric patients with IBD. Use of these treatments was declared by two thirds of the patients with probiotic use and dairy free diet being the commonest forms used. Prevalence of anaemia and predictors of its progress at six and 12 months were assessed in a large retrospective case review study. Anaemia was as high as 73% of patients at diagnosis and haemoglobin concentration improvement at six and 12 post diagnosis was associated with the use of oral iron supplementation, improvement of nutritional status markers, growth, and systemic markers of disease activity. In a mechanistic study the validity of a bedside method, used to assess the body composition of children with CD, was compared against a reference method. The agreement of the two methods was low and the inter-individual bias between them was substantial. The aim of this thesis was to study the effect of EEN on gut microbiota diversity, bacterial metabolic activity, inflammatory response and nutritional status in paediatric patients with active CD. Newly diagnosed children with active CD, and patients with longstanding disease, on clinical relapse, who started treatment with EEN as part of their standard clinical management, were recruited. Four stool samples were collected while on treatment with EEN and one when the patient returned to their normal diet. Bacterial diversity was assessed with molecular microbiology techniques, and bacterial metabolites were measured in serial stool samples and correlated with faecal calprotectin levels, systemic inflammatory markers and clinical activity. A single stool sample was collected from their first-degree relatives and two serial samples from healthy children with no family history of IBD. Significant changes were observed for the metabolic activity of the commensal microbiota during the course of treatment. In particular, faecal butyrate significantly decreased by more than 100%, faecal pH moved into the alkaline range, and a five-fold increase was observed in total sulphide but only in those patients who achieved clinical remission, or in whom faecal calprotectin levels decreased at the end of treatment. No such changes were observed in children who did not achieve complete clinical remission or when the treatment failed. Gut bacterial diversity did not change significantly during treatment, but was significantly lower than in healthy children, who also presented a higher degree of similarity between the two serial samples. Interestingly the gut microbiota of the healthy first degree relatives of CD children had significantly lower bacterial diversity compared with the healthy children but no such difference was observed compared with their CD relatives. The majority of the healthy relatives had also significantly high levels of calprotectin suggesting intestinal inflammation but no clinical presentation of gastrointestinal disease. A secondary outcome of this study was to measure changes in the systemic and gut specific markers of disease activity during treatment. Although systemic markers of disease activity improved to normal levels in the majority of the patients, intestinal inflammation was still ongoing and only one of the 16 children had normal calprotectin levels at the end of EEN. Moreover, only in those patients who achieved clinically complete remission, did calprotectin levels decrease significantly at the end of treatment. From the same cohort of patients three blood samples were also collected before, at the end of treatment and on normal diet. Changes in the concentration of 19 different micronutrients were measured in the serum and some in erythrocytes and correlated with systemic markers of disease activity. Serial changes in anthropometry and body composition were assessed during EEN and correlated with disease activity markers. Body weight increased in all patients at the end of treatment but fat free mass significantly increased only in those patients who entered in clinical remission. Several micronutrients and mainly antioxidants were below the reference range for the majority of patients at the time of treatment initiation. Most of them improved by the end of treatment but the serum concentration of carotenoids further deteriorated with more than 90% of the patients presenting concentration lower than the lower sensitivity level of the assay. A strong association was found between systemic markers of disease activity and antioxidant vitamins, but not with intestinal inflammation. In conclusion, paediatric patients with IBD, and mainly those with CD present with suboptimal protein/energy status, anaemia, and low circulating levels for many antioxidants. Treatment with EEN corrected the majority of these markers of nutritional status but the carotenoid levels deteriorated. Although the improvement in the serum levels of some micronutrients can be an epiphenomenon of the acute phase response, it does not explain the depleted levels of carotenoids at the end of EEN. This may be attributed to the lack of carotenoids in the feeds used in conjunction with excessive utilisation during the active course of the disease. On the other hand, the unhealthy intestinal microenvironment observed, in only those patients who clinically improved at the end of treatment; do not support a prebiotic mode of EEN action, as was proposed by a recent Italian study. These changes may be a secondary phenomenon, associated with changes in gut motility, better absorption of butyrate with disease improvement, or changes in the availability of colonic bacterial substrates. Alternatively these changes may be associated with changes in the microbiota composition and production of so far unknown bacterial bioproducts which may have a causative association with the onset and propagation of intestinal inflammation in CD. These results may have significant implications in manufacturers of clinical nutrition products. Addition of carotenoids may improve the provision of antioxidant micronutrients and a dual nutritional therapy combining EEN with prebiotics, butyrate supplementation, or probiotics may increase the efficacy of the existing formulae. This should be addressed in future studies