Fecal Microbiota Transplantation from Overweight or Obese Donors in Cachectic Patients with Advanced Gastroesophageal Cancer: A Randomized, Double-blind, Placebo-Controlled, Phase II Study.

PURPOSE: Cachexia is a multifactorial syndrome, associated with poor survival in patients with cancer, and is influenced by the gut microbiota. We investigated the effects of fecal microbiota transplantation (FMT) on cachexia and treatment response in patients with advanced gastroesophageal cancer. EXPERIMENTAL DESIGN: In a double-blind randomized placebo-controlled trial performed in the Amsterdam University Medical Center, we assigned 24 cachectic patients with metastatic HER2-negative gastroesophageal cancer to either allogenic FMT (healthy obese donor) or autologous FMT, prior to palliative chemotherapy (capecitabine and oxaliplatin). Primary objective was to assess the effect of allogenic FMT on satiety. Secondary outcomes were other features of cachexia, along with disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and toxicity. Finally, exploratory analyses were performed on the effect of FMT on gut microbiota composition (metagenomic sequencing) and metabolites (untargeted metabolomics). RESULTS: Allogenic FMT did not improve any of the cachexia outcomes. Patients in the allogenic group (n = 12) had a higher DCR at 12 weeks (P = 0.035) compared with the autologous group (n = 12), longer median OS of 365 versus 227 days [HR = 0.38; 95% confidence interval (CI), 0.14-1.05; P = 0.057] and PFS of 204 versus 93 days (HR = 0.50; 95% CI, 0.21-1.20; P = 0.092). Patients in the allogenic group showed a significant shift in fecal microbiota composition after FMT (P = 0.010) indicating proper engraftment of the donor microbiota. CONCLUSIONS: FMT from a healthy obese donor prior to first-line chemotherapy did not affect cachexia, but may have improved response and survival in patients with metastatic gastroesophageal cancer. These results provide a rational for larger FMT trials.

Donor Fecal Microbiota Transplantation Alters Gut Microbiota and Metabolites in Obese Individuals With Steatohepatitis.

The intestinal microbiota has been linked to the development and prevalence of steatohepatitis in humans. Interestingly, steatohepatitis is significantly lower in individuals taking a plant-based, low-animal-protein diet, which is thought to be mediated by gut microbiota. However, data on causality between these observations in humans is scarce. In this regard, fecal microbiota transplantation (FMT) using healthy donors is safe and is capable of changing microbial composition in human disease. We therefore performed a double-blind randomized controlled proof-of-principle study in which individuals with hepatic steatosis on ultrasound were randomized to two study arms: lean vegan donor (allogenic n = 10) or own (autologous n = 11) FMT. Both were performed three times at 8-week intervals. A liver biopsy was performed at baseline and after 24 weeks in every subject to determine histopathology (Nonalcoholic Steatohepatitis Clinical Research Network) classification and changes in hepatic gene expression based on RNA sequencing. Secondary outcome parameters were changes in intestinal microbiota composition and fasting plasma metabolomics. We observed a trend toward improved necro-inflammatory histology, and found significant changes in expression of hepatic genes involved in inflammation and lipid metabolism following allogenic FMT. Intestinal microbial community structure changed following allogenic FMT, which was associated with changes in plasma metabolites as well as markers of . Conclusion: Allogenic FMT using lean vegan donors in individuals with hepatic steatosis shows an effect on intestinal microbiota composition, which is associated with beneficial changes in plasma metabolites and markers of steatohepatitis.

Infusion of donor feces affects the gut-brain axis in humans with metabolic syndrome.

OBJECTIVE: Increasing evidence indicates that intestinal microbiota play a role in diverse metabolic processes via intestinal butyrate production. Human bariatric surgery data suggest that the gut-brain axis is also involved in this process, but the underlying mechanisms remain unknown. METHODS: We compared the effect of fecal microbiota transfer (FMT) from post-Roux-en-Y gastric bypass (RYGB) donors vs oral butyrate supplementation on (123I-FP-CIT-determined) brain dopamine transporter (DAT) and serotonin transporter (SERT) binding as well as stable isotope-determined insulin sensitivity at baseline and after 4 weeks in 24 male and female treatment-naïve metabolic syndrome subjects. Plasma metabolites and fecal microbiota were also determined at these time points. RESULTS: We observed an increase in brain DAT after donor FMT compared to oral butyrate that reduced this binding. However, no effect on body weight and insulin sensitivity was demonstrated after post-RYGB donor feces transfer in humans with metabolic syndrome. Increases in fecal levels of Bacteroides uniformis were significantly associated with an increase in DAT, whereas increases in Prevotella spp. showed an inverse association. Changes in the plasma metabolites glycine, betaine, methionine, and lysine (associated with the S-adenosylmethionine cycle) were also associated with altered striatal DAT expression. CONCLUSIONS: Although more and larger studies are needed, our data suggest a potential gut microbiota-driven modulation of brain dopamine and serotonin transporters in human subjects with obese metabolic syndrome. These data also suggest the presence of a gut-brain axis in humans that can be modulated. NTR REGISTRATION: 4488.

A salivary metabolite signature that reflects gingival host-microbe interactions: instability predicts gingivitis susceptibility.

Several proteins and peptides in saliva were shown to stimulate gingival wound repair, but the role of salivary metabolites in this process remains unexplored. In vitro gingival re-epithelialization kinetics were determined using unstimulated saliva samples from healthy individuals collected during an experimental gingivitis study. Elastic net regression with stability selection identified a specific metabolite signature in a training dataset that was associated with the observed re-epithelialization kinetics and enabled its prediction for all saliva samples obtained in the clinical study. This signature encompassed ten metabolites, including plasmalogens, diacylglycerol and amino acid derivatives, which reflect enhanced host-microbe interactions. This association is in agreement with the positive correlation of the metabolite signature with the individual's gingival bleeding index. Remarkably, intra-individual signature-variation over time was associated with elevated risk for gingivitis development. Unravelling how these metabolites stimulate wound repair could provide novel avenues towards therapeutic approaches in patients with impaired wound healing capacity.

Donor metabolic characteristics drive effects of faecal microbiota transplantation on recipient insulin sensitivity, energy expenditure and intestinal transit time.

OBJECTIVE: Bariatric surgery improves glucose metabolism. Recent data suggest that faecal microbiota transplantation (FMT) using faeces from postbariatric surgery diet-induced obese mice in germ-free mice improves glucose metabolism and intestinal homeostasis. We here investigated whether allogenic FMT using faeces from post-Roux-en-Y gastric bypass donors (RYGB-D) compared with using faeces from metabolic syndrome donors (METS-D) has short-term effects on glucose metabolism, intestinal transit time and adipose tissue inflammation in treatment-naïve, obese, insulin-resistant male subjects. DESIGN: Subjects with metabolic syndrome (n=22) received allogenic FMT either from RYGB-D or METS-D. Hepatic and peripheral insulin sensitivity as well as lipolysis were measured at baseline and 2 weeks after FMT by hyperinsulinaemic euglycaemic stable isotope (2H2-glucose and 2H5-glycerol) clamp. Secondary outcome parameters were changes in resting energy expenditure, intestinal transit time, faecal short-chain fatty acids (SCFA) and bile acids, and inflammatory markers in subcutaneous adipose tissue related to intestinal microbiota composition. Faecal SCFA, bile acids, glycaemic control and inflammatory parameters were also evaluated at 8 weeks. RESULTS: We observed a significant decrease in insulin sensitivity 2 weeks after allogenic METS-D FMT (median rate of glucose disappearance: from 40.6 to 34.0 µmol/kg/min; p<0.01). Moreover, a trend (p=0.052) towards faster intestinal transit time following RYGB-D FMT was seen. Finally, we observed changes in faecal bile acids (increased lithocholic, deoxycholic and (iso)lithocholic acid after METS-D FMT), inflammatory markers (decreased adipose tissue chemokine ligand 2 (CCL2) gene expression and plasma CCL2 after RYGB-D FMT) and changes in several intestinal microbiota taxa. CONCLUSION: Allogenic FMT using METS-D decreases insulin sensitivity in metabolic syndrome recipients when compared with using post-RYGB-D. Further research is needed to delineate the role of donor characteristics in FMT efficacy in human insulin-resistant subjects. TRIAL REGISTRATION NUMBER: NTR4327.

Does disease start in the mouth, the gut or both?

Oral bacteria colonize the gut more frequently than previously thought.

Interindividual variation, correlations, and sex-related differences in the salivary biochemistry of young healthy adults.

A cross-sectional observational study was conducted to evaluate interindividual biochemical variation in unstimulated whole saliva in a population of 268 systemically healthy young students, 18-30 yr of age, with no apparent caries lesions or periodontal disease. Salivary flow rate, protein content, pH, buffering capacity, mucins MUC5B and MUC7, albumin, secretory IgA, cystatin S, lactoferrin, chitinase, amylase, lysozyme, and proteases were measured using ELISAs and enzymatic activity assays. Significant differences were found between male and female subjects. Salivary pH, buffering capacity, protein content, MUC5B, secretory IgA, and chitinase activity were all lower in female subjects compared with male subjects, whereas MUC7 and lysozyme activity were higher in female subjects. There was no significant difference between sexes in salivary flow rate, albumin, cystatin S, amylase, and protease activity. Principal component analysis (PCA) and spectral clustering (SC) were used to assess intervariable relationships within the data set and to identify subgroups. Spectral clustering identified two clusters of participants, which were subsequently described. This study provides a comprehensive overview of the distribution and inter-relations of a set of important salivary biochemical variables in a systemically healthy young adult population, free of apparent caries lesions and periodontal disease. It highlights significant gender differences in salivary biochemistry.