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Kwashiorkor, an enigmatic form of severe acute malnutrition, is the consequence of inadequate nutrient intake plus additional environmental insults. To investigate the role of the gut microbiome, we studied 317 Malawian twin pairs during the first 3 years of life. During this time, half of the twin pairs remained well nourished, whereas 43% became discordant, and 7% manifested concordance for acute malnutrition. Both children in twin pairs discordant for kwashiorkor were treated with a peanut-based, ready-to-use therapeutic food (RUTF). Time-series metagenomic studies revealed that RUTF produced a transient maturation of metabolic functions in kwashiorkor gut microbiomes that regressed when administration of RUTF was stopped. Previously frozen fecal communities from several discordant pairs were each transplanted into gnotobiotic mice. The combination of Malawian diet and kwashiorkor microbiome produced marked weight loss in recipient mice, accompanied by perturbations in amino acid, carbohydrate, and intermediary metabolism that were only transiently ameliorated with RUTF. These findings implicate the gut microbiome as a causal factor in kwashiorkor.

Faecal or biopsy samples are frequently used to analyse the gut microbiota, but issues remain with the provision and collection of such samples. Rectal swabs are widely-utilised in clinical practice and previous data demonstrate their potential role in microbiota analyses; however, studies to date have been heterogenous, and there are a particular lack of data concerning the utility of swabs for the analysis of the microbiota’s functionality and metabolome. We compared paired stool and rectal swab samples from healthy individuals to investigate whether rectal swabs are a reliable proxy for faecal sampling. There were no significant differences in key alpha and beta diversity measures between swab and faecal samples, and inter-subject variability was preserved. Additionally, no significant differences were demonstrated in abundance of major annotated phyla. Inferred gut functionality using Tax4Fun2 showed excellent correlation between the two sampling techniques (Pearson’s coefficient r = 0.9217, P  < 0.0001). Proton nuclear magnetic resonance ( 1 H NMR) spectroscopy enabled the detection of 20 metabolites, with overall excellent correlation identified between rectal swab and faecal samples for levels all metabolites collectively, although more variable degrees of association between swab and stool for levels of individual metabolites. These data support the utility of rectal swabs in both compositional and functional analyses of the gut microbiota.

Colorectal cancer is driven by genetic and epigenetic changes in cells to confer phenotypes that promote metastatic transformation and development. Tumour necrosis factor-alpha (TNF-α), a pro-inflammatory mediator, regulates cellular communication within the tumour microenvironment and is associated with the progression of the metastatic phenotype. Oncogenic miR-21 has been shown to be overexpressed in most solid tumours, including colorectal cancer, and is known to target proteins involved in metastatic transformation. In this study, we investigated the relationship between TNF-α and miR-21 regulation in colorectal cancer epithelial cells (SW480 and HCT116). We observed that TNF-α, at concentrations reported to be present in serum and tumour tissue from colorectal cancer patients, upregulated miR-21 expression in both cell lines. TNF-α treatment also promoted cell migration, downregulation of the expression of E-cadherin, a marker of epithelial to mesenchymal transition, and anti-apoptotic BCL-2 (a validated target for miR-21). Knockdown of miR-21 had the opposite effect on each of these TNF-a induced phenotypic changes. Additionally, in the SW480 cell line, although TNF-α treatment selectively induced expression of a marker of metastatic progression VEGF-A, it failed to affect MMP2 expression or invasion activity. Our data indicate that exposing colorectal cancer epithelial cells to TNF-α, at concentrations occurring in the serum and tumour microenvironment of colorectal cancer patients, upregulated miR-21 expression and promoted the metastatic phenotype.

Background Fecal abundances of Enterobacteriaceae and Enterococcaceae are elevated in patients following Roux-en-Y gastric bypass (RYGB) surgery. Concurrently, fecal concentrations of tyramine, derived from gut bacterial metabolism of tyrosine and/or food, increased post-RYGB. Furthermore, emerging evidence suggests that RYGB is associated with increased colorectal cancer (CRC) risk. However, the causal link between RYGB-associated microbial metabolites and CRC risk remains unclear. Hence, this study investigated the tyrosine metabolism of Enterobacteriaceae and Enterococcaceae strains isolated from patients post-RYGB and explored the causal effects of tyramine on the CRC risk and tumorigenesis using both human colonic cancer cell line (HCT 116) and wild-type and Apc Min/ + mice. Results We isolated 31 bacterial isolates belonging to Enterobacteriaceae and Enterococcaceae families from the feces of patients with RYGB surgery. By culturing the isolates in tyrosine-supplemented medium, we found that Citrobacter produced phenol as a main product of tyrosine, whereas Enterobacter and Klebsiella produced 4-hydroxyphenylacetate, Escherichia produced 4-hydroxyphenyllactate and 4-hydroxyphenylpyruvate, and Enterococcus and two Klebsiella isolates produced tyramine. These observations suggested the gut bacterial contribution to increased fecal concentrations of tyramine post-RYGB. We subsequently evaluated the impact of tyramine on CRC risk and development. Tyramine induced necrosis and promoted cell proliferation and DNA damage of HCT 116 cells. Daily oral administration of tyramine for 49 days to wild-type mice resulted in visible adenomas in 5 out of 12 mice, accompanied by significantly enhanced DNA damage (γH2AX +) and an increased trend of cell proliferation (Ki67 +) in the ileum, along with an upregulated expression of the cell division cycle gene ( Cdc34b ) in the colon. To evaluate the impact of tyramine on intestinal tumor growth, we treated Apc Min/ + mice with the same doses of tyramine and duration. These mice showed larger colonic tumor size and increased intestinal cell proliferation and inflammation (e.g., increased mRNA expression of IL-17A and higher number of Ly6G + neutrophils) compared to water-treated Apc Min/ + control mice. Conclusions Our results collectively suggested that RYGB-associated fecal bacteria could contribute to tyramine production and tyramine increased CRC risk by increasing DNA damage, cell proliferation, and pro-inflammatory responses of the gut. Monitoring and modulating tyramine concentrations in high-risk individuals could aid CRC prognosis and management. ASN3gMreFwZW2XcEbgQvGB Video Abstract

Background Bariatric surgery, used to achieve effective weight loss in individuals with severe obesity, modifies the gut microbiota and systemic metabolism in both humans and animal models. The aim of the current study was to understand better the metabolic functions of the altered gut microbiome by conducting deep phenotyping of bariatric surgery patients and bacterial culturing to investigate causality of the metabolic observations. Methods Three bariatric cohorts ( n = 84, n = 14 and n = 9) with patients who had undergone Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG) or laparoscopic gastric banding (LGB), respectively, were enrolled. Metabolic and 16S rRNA bacterial profiles were compared between pre- and post-surgery. Faeces from RYGB patients and bacterial isolates were cultured to experimentally associate the observed metabolic changes in biofluids with the altered gut microbiome. Results Compared to SG and LGB, RYGB induced the greatest weight loss and most profound metabolic and bacterial changes. RYGB patients showed increased aromatic amino acids-based host-bacterial co-metabolism, resulting in increased urinary excretion of 4-hydroxyphenylacetate, phenylacetylglutamine, 4-cresyl sulphate and indoxyl sulphate, and increased faecal excretion of tyramine and phenylacetate. Bacterial degradation of choline was increased as evidenced by altered urinary trimethylamine- N -oxide and dimethylamine excretion and faecal concentrations of dimethylamine. RYGB patients’ bacteria had a greater capacity to produce tyramine from tyrosine, phenylalanine to phenylacetate and tryptophan to indole and tryptamine, compared to the microbiota from non-surgery, normal weight individuals. 3-Hydroxydicarboxylic acid metabolism and urinary excretion of primary bile acids, serum BCAAs and dimethyl sulfone were also perturbed following bariatric surgery. Conclusion Altered bacterial composition and metabolism contribute to metabolic observations in biofluids of patients following RYGB surgery. The impact of these changes on the functional clinical outcomes requires further investigation. 1v6mePHgvKoyyAii3YMczB Video abstract

IntroductionRecently published studies support the beneficial effects of consuming fibre-rich legumes, such as cooked dry beans, to improve metabolic health and reduce cancer risk. In participants with overweight/obesity and a history of colorectal polyps, the Fibre-rich Foods to Treat Obesity and Prevent Colon Cancer randomised clinical trial will test whether a high-fibre diet featuring legumes will simultaneously facilitate weight reduction and suppress colonic mucosal biomarkers of colorectal cancer (CRC).Methods/designThis study is designed to characterise changes in (1) body weight; (2) biomarkers of insulin resistance and systemic inflammation; (3) compositional and functional profiles of the faecal microbiome and metabolome; (4) mucosal biomarkers of CRC risk and (5) gut transit. Approximately 60 overweight or obese adults with a history of noncancerous adenomatous polyps within the previous 3 years will be recruited and randomised to one of two weight-loss diets. Following a 1-week run-in, participants in the intervention arm will receive preportioned high-fibre legume-rich entrées for two meals/day in months 1–3 and one meal/day in months 4–6. In the control arm, entrées will replace legumes with lean protein sources (eg, chicken). Both groups will receive in-person and written guidance to include nutritionally balanced sides with energy intake to lose 1–2 pounds per week.Ethics and disseminationThe National Institutes of Health fund this ongoing 5-year study through a National Cancer Institute grant (5R01CA245063) awarded to Emory University with a subaward to the University of Pittsburgh. The study protocol was approved by the Emory Institutional Review Board (IRB approval number: 00000563).Trial registration number NCT04780477.

We have performed a metabolite quantitative trait locus (mQTL) study of the (1)H nuclear magnetic resonance spectroscopy ((1)H NMR) metabolome in humans, building on recent targeted knowledge of genetic drivers of metabolic regulation. Urine and plasma samples were collected from two cohorts of individuals of European descent, with one cohort comprised of female twins donating samples longitudinally. Sample metabolite concentrations were quantified by (1)H NMR and tested for association with genome-wide single-nucleotide polymorphisms (SNPs). Four metabolites' concentrations exhibited significant, replicable association with SNP variation (8.6×10(-11)

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