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Diet, the Gut Microbiome and Cancer
Johanna W. Lampe, PhD, RD Fred Hutchinson Cancer Research Center,
Seattle, WA [email protected]
AICR Conference – Split Session A Dietary Modulation of the Microbiome and Cancer Risk
AICR Conference on Nutrition, Physical Activity, Obesity and Cancer November 14 – 16, 2016 • Bethesda North Marriott • North Bethesda, MD
Dietary Exposures and Cellular Processes Linked to Cancer
Diet
Differentiation
DNA repair
Carcinogen metabolism
Hormonal regulation
Inflammation Immune function
Apoptosis
Proliferation
Adapted from WCRF/AICR 2007 Expert Report
Diet and microbial metabolism
Involvement of Microbial Metabolism
Outline
How does diet affect gut microbial community? How does the gut microbiome affect components
of diet?
Gut Microbial Metabolism Obtain energy and nutrients to
live and reproduce
Microbiome: >100 times as many genes as human genome
Carry out reactions that human gut enzymes cannot Fermentation Denitrification Sulfate reduction Aromatic fission Hydrolysis/deconjugation
The indigestibles The leftovers
Food
Human digestion
Bacterial metabolism
Fermentation of Carbohydrates: Sugars, Dietary Fiber and Resistant Starch
Acetate Propionate Butyrate
>81 different glycoside hydrolase families
Gill et al, Science, 2006 Tremaroli & Bäckhed, Nature, 2012
Microbial Metabolism of Proteins & Amino Acids
Aromatic Amino acids
Other Amino acids
Sulfur Amino acids
Sulfur compounds
Phenols and indoles
Ammonia NH3
+/NH4
Amines H2, CO2, CH4 Organic acids
Proteins Peptides hydrolysis
α, β elimination deamination deamination &
fermentation decarboxylation
Adapted from Nyangale et al. J Proteome Res, 2012
Gut Microbiome and Dietary Fats
Joyce and Gahan, Ann Rev Food Sci Technol, 7:313, 2016
Metabolism of lipids Bile acid metabolism Primary to
secondary bile acids
Altered microbial community
Changes in signaling to liver
How does diet affect the gut microbiome? Evidence from:
Observational studies Globally distinct populations Long-term food pattern consumption
Short-term dietary interventions Low- vs high-fiber diets Animal vs plant food sources Macronutrient ratios
Reviewed in Arora & Bäckhed. J Int Med 280:339, 2016
Global Population Differences: Children in Rural Africa (BF) vs Urban Europe (EU)
De Filippo et al PNAS 107:14691, 2010
Global Population Differences: African-Americans in US vs Native South Africans
Ou et al, Am J Clin Nutr 98:111, 2013
Microbiota Change with Diet Switch in African Americans and Native South Africans
2-wk feeding study
US AAs fed: Fiber: 14→55g/d Fat: 35→16%
Native Africans fed: Fiber: 66→12g/d Fat: 16→52%
African Americans
Native Africans
Afric
an d
iet
Wes
tern
die
t
Wes
tern
die
t
Afric
an d
iet
O’Keefe et al, Nat Comm 6:6342, 2015
Diet Pattern Change and Gut Microbiome : Fat & Fiber and Colorectal Cancer Risk Factors
High-fiber, low-fat diet changed microbiome: Increased saccharolytic fermentation and
butyrate production Decreased secondary bile acid synthesis
Functional changes in gut microbiota were accompanied by colorectal cancer relevant changes in colonic mucosal proliferation and inflammation
O’Keefe et al, Nat Comm 6:6342, 2015
Short-Term Feeding of Plant- and Animal-Based Diets Alters Gut Microbiota
10 subjects tracked across plant- and animal-based diet treatments. Animal-based diet increased bile-
tolerant microorganisms and decreased microbes that metabolize plant polysaccharides. Bacterial metabolic gene
expression (RNA-seq) tends to cluster by diet.
Diet doesn’t always overcome inter-individual differences in GMC structure (16S rRNA).
12 David et al, Nature, 505:559 2014
Diet Patterns and Gut Microbiome: Controlled Low and High-Glycemic Load Diets
4-week randomized crossover feeding study in 12 healthy U.S. men and women.
Eucaloric diets with same macronutrient distribution, except: • Low GL: 55 g fiber • High GL: 28 g fiber
Discriminant analysis of microbiome distinguishes by diet
Neuhouser et al, J Nutr 2012
Hullar & Lampe, unpublished data, 2016
Martens E. Nature 529:158-159, 2016 Sonnenburg, E. et al. Nature 529: 212-215, 2016
Multigenerational Effects of Diet on Bacterial Diversity
How does the gut microbiome affect diet?
Alters exposure to nutrients and bioactives Generates new compounds, which: Serve as energy source Regulate metabolism Reduce inflammation Cause oxidative stress
Bacteria Can Produce New Compounds from Food Components
Food Component Bacterial Metabolite Dietary fiber Butyrate and other SCFAs Choline Trimethylamine Soy isoflavones Equol, O-desmethylangolensin Plant lignans Enterodiol, enterolactone Ellagitannins Urolithins A and B Anthocyanins Hippuric acid & small phenolics Glucosinolates Isothiocyanates Linoleic Acid Conjugated linoleic acid
Diet-Microbial Community Interaction Affects Exposure to Dietary Metabolites
Russell et al., Am J Clin Nutr 2011;93:1062–72.
Tota
l N-n
itros
o co
mpo
unds
(ng/
ml)
a
c
b
a,b,c significantly different p<0.001
17 obese men, randomized cross-over design
4 weeks of weight-reduction diets: high-protein; med carb high-protein; low-carb
HPLC diet resulted in decrease
in fecal cancer-protective metabolites (butyrate) and increased concentrations of hazardous metabolites (N-nitroso compounds).
Protein, % 13 28 29
Fat, % 37 37 66
Carb, % 50 35 5
NSP, g 22 9 13
Choline Metabolism, TMAO, and Cancer?
Shared risk factors with atherosclerosis: Oxidative stress
Inflammation
Insulin resistance
TMAO and aggressive prostate cancer in ATBC: OR: 1.36 (1.02–1.81), p=0.039
Choline metabolites and colorectal cancer in WHI: OR: 1.65 (1.17-2.34)
Tang et al. NEJM, 2013
Dietary phosphatidyl
choline
Choline
Trimethylamine
Trimethylamine N-oxide
Betaine
Atherosclerosis
Death Stroke Heart attack
Gut microbiota
Mondul et al. Int J Cancer, 2015 Bae et al, Cancer Res, 2014
Anthocyanin Metabolism by Gut Microbes
Higher consumption of high-anthocyanin foods inversely associated with risk of hypertension and CVD mortality.
Low bioavailability of parent compounds.
Microbial hydrolysis of glucosides and ring cleavage yield range of small phenolics detected in serum and urine.
De Ferrars et al, Br J Pharmacol, 2014
Metabolic Phenotypes: Microbial Production of Equol and ODMA From Soy Isoflavone Daidzein
O
O
HO
OH
OHO
OH
O
O
HO
OH
OH
O
HO
OH
OHO
OHOH
Daidzein Dihydrodaidzein
EquolO-Desmethylangolensin
Cis/Trans-isoflavan-4-ol
20-60% of individuals produce
80-90% of individuals produce
Daidzein-Metabolizing Phenotypes and Cardiovascular Risk among 595 Chinese Postmenopausal Women
Equol producers, compared to nonproducers, had: Higher fat-free mass
Lower systolic and diastolic blood pressure
Lower serum triglyceride), hs-CRP and FFA
O-DMA producers, compared to nonproducers, had: Lower BMI and %body fat
Lower total cholesterol
Habitual soy isoflavone intake had little relation to CVD risk factors in either metabolizing phenotype.
Liu Z-m, PLoS ONE 9(2): e87861, 2014.
Obese Adults More Likely to be ODMA-Nonproducer Phenotype
Frankenfeld et al., Eur J Clin Nutr, 2014
18 to <25 kg/m2
25 to 29.9 kg/m2
30+ kg/m2 P-trend
ODMA producers n (%) 142 (59.9) 71 (30.0) 24 (10.1) ODMA nonproducers 29 (48.3) 17 (28.3) 14 (23.3) OR* REF 1.0 (0.5, 2.1) 2.8 (1.2, 6.2) 0.032
Equol producers n (%) 77 (62.1) 32 (25.8) 15 (12.1) Equol nonproducers 94 (54.3) 56 (32.4) 23 (13.3) OR* REF 1.3 (0.7, 2.2) 1.1 (0.5, 2.2) 0.629
*n=297; adjusted for age (in years), race, and gender and menopausal status.
LEGEND: 1. O-deglycosylation 2. O-demethylation 3. dehydrogenation 4. dehydroxylation
Enterodiol (END) Enterolactone (ENL)
Secoisolariciresinol Diglucoside
Secoisolariciresinol)
1
2
4
3
4 3
Enterolignan Production by Gut Bacteria
Gut Microbial Diversity Differs by Tertiles of Urinary Enterolactone Excretion
05
10152025
no ENL Low ENL High ENL
Dive
rsity
Dive
rsity
b b
Low ENL (T1)
Medium ENL (T2)
High ENL (T3)
a
Hullar et al, CEBP, 2015
Gut Microbiome Associated with Urinary Enterolactone (ENL) Excretion
GMC composition is significantly different between high and low ENL excreters (MRPP, p<0.0005).
Association remains significant with adjustment for fiber intake and adiposity.
Low ENL clusters together
Hullar et al, CEBP, 2015
Low ENL
High ENL
Phylogenetic Distribution of Microbiome in High-ENL Excreters
Unique genera high ENL excreters
Distributed across Phyla
Firmicutes
Summary Diet can change the gut microbiome and its impact on
the host. Is it the microbe itself or a consortia of microbes? Is it the metabolites produced by microbes? Or the combination of both?
Availability of nutrients or bioactive substances important for health can be influenced by gut microbiota.
Metabolic phenotypes integrate diet and microbial action.
Better understanding the impact of the bacterial metabolites on regulatory pathways may help guide future diet and cancer prevention strategies.
Supported by: US National Cancer Institute Kellogg Corporate Citizens Fund Fred Hutch
J Lampe Lab
* Meredith Hullar Isaac Elkon Lisa Levy Fei Li Sandi Navarro Wendy Thomas Elizabeth Traylor Seth Yoder
Texas A&M University Robert Chapkin Ivan Ivanov
Hawaii Cancer Center Loic Le Marchand
University of Bristol Charlotte Atkinson
University of Helsinki Kristiina Wähälä
FHCRC and UW collaborators Mario Kratz Marian Neuhouser Tim Randolph Ali Shojae George Mason U Cara Frankenfeld