Zhao et al. 2018. Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes. Science.

This is a summary of our DalMUG journal club discussion of the above paper written by Akhilesh Dhanani.

Summary

Host diet associated nondigestible carbohydrates are often fermented by gut bacteria into beneficial short chain fatty acids (SCFA). Deficiency of SCFA has been linked to various human diseases including Type 2 diabetes mellitus (T2DM). Although previous dietary fiber interventions alleviated disease phenotypes, treatment responses were varied due to the confounding effect of the gut microbiome. Zhao et. al, used a large amount of diverse fiber in the treatment group to understand the dynamics of gut microbiome at strain level and its impact on glucose level in T2DM patients. The fiber rich diet significantly reduced glycated hemoglobin to adequate control level from day 28 onwards. Similar effects were also replicated in gnotobiotic mice fecal transplanted with T2DM patient feces of pre-and post-dietary intervention. Interestingly, co-abundance gene groups (CAGs) analysis of control and treatment group showed significant alteration of microbiome within 28 days of treatment time and a Procrustes analysis of biochemical variables and gut composition changes was found associated with better clinical outcomes. On further exploration of functional changes in the gut microbiome associated with SCFA production, both the groups had significant enrichment of genes associated with acetate formation. However, the treatment group also had significantly enriched butyrate pathway genes. Improved glucose homeostasis in treatment group was also supported by increased Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) which are known to stimulate insulin secretion. To study the strain level microbiome analysis, 154 high-quality draft genomes were assembled from CAGs for prevalent bacteria. Out of 141 SCFA producers studied, 15 were enriched in individuals on the high-fiber diet. These enriched SCFA producers belonged to diverse phyla: Firmicutes, Actinobacteria and Proteobacteria. Positive responders within the treatment group harbored both acetate and butyrate-associated genes, which explained the better treatment outcome, compared to only acetate-associated genes in the control group.

Points of Interest

• Interesting to know that high-fiber rich diet selectively promotes gut beneficial bacteria (in line with previous reports).
• Unlike most treatment positive outcomes associated with increased bacterial diversity and gene richness, this dietary intervention found significant reduction in gene richness within 28 days in both the groups.
• Binning individual genes into co-abundance gene groups (CAGs) was interesting as it improves the signal detection associated to bacterial community change in gut microbiome.
• High quality draft genomes were constructed from metagenomic reads.
• Use of high-fiber rich diet selectively induced starch and inulin degradation CAZy family and depleted pectin and mucin CAZy family.
• The relative abundance of Lachnospiraceae bacteria showed significant correlation with most clinical parameters in the treatment group.

Points of Confusion

• Germ free mice fecal transplant experiment was conducted with single donor from each group - would be interesting to use feces derived from different hosts.
• Is it normal to use healthy germ-free mice to study diabetic phenotype?
• In process of binning individual genes to small number of CAGs, a large number of sequences reads were omitted from the study. Would have been nice to have parallel analysis with all available genes without binning them.
• Control group wasn’t given formulated premix diet as compared to test group.
• Although acetate-producing Bifidobacterium pseudocatenulatum was most significantly promoted SCFA producer, it had limited correlation to metabolic outcome.
• It seemed like the control group received diet recommendations, but were not provided meals (like they were in the treatment group). If this is the case, a major confounding factor must be that a diet is harder to follow if the meals aren’t provided for you.