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Gut microbiome: debugging the obesity and cancer link
Overview
Carrie R. Daniel-MacDougall, PhD, MPHDepartment of Epidemiology Division of Cancer Prevention and Population Sciences
Biological mechanisms linking adiposity and cancer risk
Adapted from Ho et al. Cancer Res 2012
Cancer
Secretion of leptinHepatic insulin sensitivity and lipid synthesisModulate intestinal environment and appetite signaling
Energy balance regulation
Diet, energy balance, and gut microbiomeDiet
The composition of bacteria living within the gut can be linked to functional metabolic pathways in the host
Figure of healthy gut (fecal) microbiome: NIH-HMP Consortium, Nature 2012
SCFA (Propionate, acetate, butyrate) act as signaling molecules on G-protein coupled receptors expressed in colon and adipocytes
Secretion of leptin; hepatic insulin sensitivity and lipid synthesis; modulate intestinal environment and appetite signaling
Prebiotic fibers (e.g., legumes) resist digestion until they reach the colon; undergo bacterial fermentation
Microbial energy harvest from the diet; fat storage by host; energy loss in fecesMicrobial
production of SCFA
Endocrine
Regulation of EB
Obesity or weight-loss
Diet may directly and indirectly modulate association between energy balance (EB) and cancer
Satiety
Insulin signaling
Diet, gut microbiome, obesity, and cancer
Gut microbiome
Obesity
Cancer
Energy balance
Inflammation
Insulin Resistance
Relevant exposures (e.g., diet, medications)
Nadim Ajami, PhD, Baylor College of Medicine– Alkek Center for Metagenomics and Microbiome Research
(Director: Joe Petrosino, PhD), Department of Molecular Virology and Microbiology
– Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity (Everard 2013)
Manasi Shah, MS, MD Anderson & UT-SPH– Decreased dietary fiber intake and structural alteration of gut
microbiota in patients with advanced colorectal adenoma (Chen 2013)
Nadim J. Ajami, Ph.D.Alkek Center for Metagenomics and Microbiome Research
Department of Molecular Virology and MicrobiologyBaylor College of Medicine
Houston, TX
Key concepts
Akkermansia muciniphila• Gram-negative anaerobe• Degrades mucin• Resides in the mucus layer of the intestinal epithelium• Abundant in nutrient-rich environments• Represents 3-5% of the microbial community in healthy subjects• Abundance inversely correlates with body weight, severity of appendicitis,
and T1D
Obesity and Type 2 Diabetes• Altered gut microbiota• Inflammation• Gut barrier disruption
• Increased gut permeability -> endotoxemia & metabolic inflammation
ObjectiveTo define the physiological role of Akkermansia muciniphila in obesity.
HypothesisA. Muciniphila controls gut barrier function
Experimental designAdministration of live or heat-killed A. muciniphila to mice fed a high-fat diet.
• Gut barrier• Glucose homeostasis• Adipose tissue metabolism
Findings
Akkermansia muciniphila treatment reverses high-fat diet-induced metabolic disorders, including fat-mass gain, metabolic endotoxemia, adipose tissue
inflammation, and insulin resistance.
Abundance of A. muciniphila is decreased in obese and diabetic mice
Prebiotic: Oligofructose 0.3gr/mouse/day
Prebiotic treatment restores A. muciniphila to basal levels and reverses metabolic endotoxemia
High fat (HF) diet increases macrophage infiltration and fat mass
Treatment with A. muciniphila does not induce changes in the gut microbiota
MITChipV1/V6 16S rRNA gene
A. Muciniphila counteracts metabolic endotoxemia, diet induced obesity, adipose tissue macrophage infiltration, improves glucose
homeostasis, and adipose tissue metabolism
A. Muciniphila colonization restores gut barrier function and increases intestinal endocannabinoids in diet-induced obese mice
Intestinal acylglycerols previously demonstrated to reduce metabolic endotoxemia and systemic inflammation gut barrier function
46% thinner mucus layer in HF-fed mice
A. Muciniphila treatment counteracts this decrease
Heat-killed A. muciniphila does not counteract metabolic endotoxemia, diet induced obesity, oral glucose intolerance, gut
barrier dysfunction or poor adipose tissue metabolism
EndotoxemiaFat massPlasma GlucoseMarkers of adipocyte differentiation
Viable A. muciniphila is required
Conclusions and future directions
• A. muciniphila:– Restores the mucus layer of the intestine– Restores gut barrier function and thereby contributes to
normalize metabolic endotoxemia and adipose tissue metabolism
– Improves glucose tolerance and decreases endogenous hepatic glucose production
Development of a treatment that uses A. muciniphila for the prevention or treatment of obesity and its associated metabolic disorders?
Thank you for your attention
Nadim J. Ajami, Ph.D.Alkek Center for Metagenomics and Microbiome Research
Gut microbiome: debugging the obesity and cancer link
Manasi Shah, MSDepartment of Epidemiology
Division of Cancer Prevention and Population Sciences
The Gut Microbiome
Gut Microbiome
Surrogate marker of diet and
environmental history?
Emerging technology
Multiple sequencing
procedures being developed (WGS)
Modifiable!
Structural and functional
constitution related to diet,
obesity and inflammation
Background
Diet may influence colon cancer risk via the microbiota and its metabolites
Dietary habits may influence early events in the colon carcinogenic process Fiber Short Chain Fatty Acids (SCFA) in colon lower risk of CRC
Colon cancer risk influenced by the balance between microbial production of health-promoting metabolites, such as butyrate; and potentially carcinogenic metabolites, such as secondary bile acids
Gut Microbiome and Colon Cancer- The Balancing Act
Fig: Jobin, Inflamm Bowel Dis 2011
Gut Microbiome and Colorectal Neoplasia
Four high resolution maps of colonic dysbiosis have been independently reported:
CRC tissue as compared to adjacent non-malignant mucosa: Potential pathogenic bacteria in CRC tissue Coriobacteridae, Roseburia, Fusobacterium and Faecalibacterium (Marchesi, PLoS 2011)
Fusobacterium sequences were enriched in carcinomas while the Bacteroidetes and Firmicutes phyla were depleted (Kostic, Genome Res 2012)
Overabundance of Fusobacterium sequences in tumor vs matched control tissue ( Castellarin, Genome Res 2012)
Significantly lower level of Lachnospiraceace, Ruminococcaceae and Lactobacillaceae in cancerous tissues compared to normal intestinal lumen. Relative abundance of Bacteroidaceae, Streptococcacea, Fusobacteriaceae was also higher in the cancerous tissue (Chen, PLoS One 2012)
Cross Sectional Study Flow:
Subjects and Methods Consecutive patients who had undergone colonoscopy in 5 medical
centers in China, ≥ 50 yrs of age NO previous history of colorectal adenoma or carcinoma or IBD, normal
bowel movement Pathological confirmation of advanced colorectal adenoma (A-CRA) Patients with no obvious abnormalities allotted in the healthy control
(HC) group Data on demographics, colonoscopy results, lifestyle factors and dietary
intake were collected via interview-administered questionnaires Fresh stool samples were collected from all the participants. Fecal SCFA content analyzed by gas chromatography Analysis of 16s rRNA sequences done by 454 pyrosequencing of fecal
samples
Results
Multivariate logistic analysis identified four statistically significant factors associated with advanced colorectal adenoma (A-CRA)
Significantly lower yields of fecal SCFAs were found in the A-CRA group (n = 47) than in the HC group (n = 47).
Separation between the microbiota genus in the HC (n = 47) and A-CRA (n = 47) groups was significant
PC analysis plots based on the unweighted UniFrac. p = 0.001, t test of permutation
Differences in butyrate and butyrate-producing bacteria:
Summary and Discussion
Main Findings: Structural imbalance in the fecal gut microbiota and difference in SCFA
concentrations was defined in the A-CRA, as compared to HC Butyrate and other SCFA’s associated with reduced risk of CRC: 3
genera of butyrate-producing bacteria (Clostridium, Roseburia, and Eubacterium) were lower in the A-CRA group than in the HC group
Significant higher levels of opportunistic pathogens: Enterococcus and Streptococcus in A-CRA
Implications: Microbial community may play an important role in pathogenesis of
the progression from A-CRA to CRC via dietary SCFA products Persistent deficiency in substrate dietary fiber may result in a
deficiency in butyrate-producing bacteria fermentation of SCFAs increased risk of A-CRA
Limitations
Cross-sectional design: no cause-effect
Prospective human studies are required to determine whether an altered gut microbiome increases risk of colorectal cancer/adenoma or is an artifact of pre-existing disease
454 pyrosequencing identifies bacteria at genus, but not species level. Higher depth genomic techniques may be required to fully differentiate the colonizing groups and their subsequent functions
Fecal SCFA concentrations correlate with both formation and uptake throughout the gut, but do not necessarily reflect SCFA production
‘Food’ for Thought: Future Directions Transmissible and modifiable interactions between diet and microbiota
influence host biology and cancer development in mice: Intact uncultured and culturable bacterial component of Obese co-twin’s
fecal microbiota caused significantly greater increases in body mass and adiposity than those of lean communities (Ridaura, Science 2013)
Diet- or gene-induced obesity alters gut microbiota, thereby increasing the levels of metabolites that secrete inflammatory and tumor-promoting factors in the liver facilitating development of liver cancer (Yoshimoto, Nature 2013)
Potential for translation to humans…
Gut Microbiome
Obesity
Colorectal Cancer
Inflammation
Diet
Thank You!
In Conclusion
Gene Induced Obesity
Diet-Induced Obesity
Microbiome Induced Obesity
Mutation or polymorphism
High fat/high calorie diet
Disrupted microbial community
Microbe-dependent
effects
Increased Energy Harvest
Altered Metabolic Signaling
Altered Inflammation
Increased Adipose Tissue
Figure adapted from Blaser et al, Cell Press (2013)
- Microbe involvement in SCFA Metabolism & GPCR recognition- High Fiber diet- reduces insulin stimulation, increases gastric transit
time