Symbiotic Metabolism: New Insights into Functional Food Ingredients

"Dis-moi ce que tu manges, je te dirai ce que tu es."

Tell me what you eat and I will tell you what you are

Anthelme Brillat-Savarin, Physiologie du Gout, ou Meditations de Gastronomie Transcendante, 1826

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Agenda for Today

• Prebiotics–why?

• Lignins to phenolics-novel signaling?

• The entero-endocrine axis-what does it mean?

• DNA sequencing and personal genetics-what is its impact?

Age

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Searching for Proper Physiology: Diets through the Years

Weight watchers

1963

1992

Atkins diet

Brillat-Savarin publishes Physiology of Taste, 1826

John Rollo publishes An Account of Two Cases of the Diabetes Mellitus, 1797

Lord Byron: Vinegar and water diet

1820

1925

Slimfast

1977

1080 William the Conqueror creates the liquid diet

1930

Grapefruit

Scarsdale diet 1978 ? 2000

The search for weight optimized diet has historically focused on ingredients, combinations of ingredients, and intake

quantity

Savarin: Father of the Low Carb Diet!

• Sure enough, carnivorous animals never grow fat (consider wolves, jackals, birds of prey, crows, etc.). Herbivorous animals do not grow fat easily, at least until age has reduced them to a state of inactivity; but they fatten very quickly as soon as they begin to be fed on potatoes, grain, or any kind of flour. ...

• The second of the chief causes of obesity is the floury and starchy substances which man makes the prime ingredients of his daily nourishment.

• As we have said already, all animals that live on farinaceous food grow fat willy-nilly; and man is no exception to the universal law. Brillat-Savarin, Jean-Anthelme The Physiology of Taste. trans. Anne Drayton. Penguin Books (1970). pp. 208–209. ISBN 978-0-14-044614-2.

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Resistant Starch

From MGP Ingredients

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Example: Sex-specific RS2 Effects

• Men with BMI >35 improved insulin sensitivity with 15 g/day for 4 weeks

• No effect observed with women

• Maki et al speculate that higher Si baseline or hormonal/menstrual cycle effects may alter RS2 sensitivity

KC Maki et al., J. Nutr. 142: 717–723, 2012.

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Example: RS4 Effects

• Hydroxypropyl distarch phosphate[HPD]; widely used RS4 chemically modified starch

• Reduction in body weight gain and white adipose tissue growth when added to high fat diet

• HPD from tapioca and waxy corn starch used in mice studies

• RS4 can ameliorate weight gain induced by high fat diets

Ashimotoyodome et al. AJP-Endocrinol Metab 298: E652-662, 2010

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Additive Effects of RS and Beta-glucan in women

• Test of post prandial glucose challenge with lean and obese women

• Low (0.71g)-medium (2.57g)-high (5.06g) high amylose resistant starch combined with 1, 2.5, 10% (w/w) betaglucan provided in muffins

• Combination of high RS and high betaglucan reduced plasma glucose and insulin in both lean and obese women

Behall KM et al. Dia Care 2006;29:976-981

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Resistant Starch Conclusions

• Resistant starches though undigestible by the human body; can positively affect weight gain and disease state

• Modified starch market expected to grow to $15.2B by 2017 at ~3% CAGR

• Dietary fiber expected to grow at 14% CAGR to >$3B in 2017

[source: MarketsandMarkets]

• Prediction: Growth accelerates with increasing discoveries in human metabolic physiology

• Market segmentation

• Sex

• Physiological state

• Region/ethnicity

• Combinations of different fibers to maximize desired outcome

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Lignins to Phenolics

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A Few Plant ‘AntiOxidants’

Quercetin

Catechin

Salicylic acid Gallic acid

Resveratrol

Resorcinol

Coumaric acid

Caffeic acid Ferulic acid

Sinapic acid

Quinic acid Guaiacol Vanillin

Chlorogenic acid

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Ferulic acid

• Antibacterial in plants and part of lignin wall

• Ono K, et al, Ferulic acid destabilizes preformed beta-amyloid fibrils in vitro. Biochem Biophys Res Commun. 2005 Oct 21;336(2):444-9

• Suzuki A, et al, Short- and long-term effects of ferulic acid on blood pressure in spontaneously hypertensive rats. Am J Hypertens. 2002 Apr;15(4 Pt 1):351-7

• Hou YZ, et al, Ferulic acid inhibits vascular smooth muscle cell proliferation induced by angiotensin II. Eur J Pharmacol. 2004 Sep 19;499(1-2):85-90.

• Ardiansyah et al, Novel effects of a single administration of ferulic acid on the regulation of blood pressure and the hepatic lipid metabolic profile in stroke-prone spontaneously hypertensive rats. J Agric Food Chem. 2008 Apr 23;56(8):2825-30

• Pathak et al., Natural polyphenols in the management of major depression, Expert Opin Investig Drugs. 2013 Jul;22(7):863-80

• Mori et al., Ferulic acid is a nutraceutical β-secretase modulator that improves behavioral impairment and alzheimer-like pathology in transgenic mice. PLoS One. 2013;8(2):e55774

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Chlorogenic acid

• Lipoxygenase inhibition in leaves, antibacterial and antifungal activity in plants

• Shimoda et al., Inhibitory effect of green coffee bean extract on fat accumulation and body weight gain in mice, BMC Complement Altern Med. 2006; 6: 9

• Vinson et al., Randomized, double-blind, placebo-controlled, linear dose, crossover study to evaluate the efficacy and safety of a green coffee bean extract in overweight subjects, Diabetes Metab Syndr Obes. 2012; 5: 21–27

• Lee et al., Chlorogenic Acid Attenuates High Mobility Group Box 1 (HMGB1) and Enhances Host Defense Mechanisms in Murine Sepsis, Mol Med. 2012; 18(1): 1437–1448

• Van Dijk et al., Acute Effects of Decaffeinated Coffee and the Major Coffee Components Chlorogenic Acid and Trigonelline on Glucose Tolerance, Diabetes Care. 2009 June; 32(6): 1023–102

• Antitumor Molecular Mechanism of Chlorogenic Acid on Inducting Genes GSK-3β and APC and Inhibiting Gene β-Catenin, J Anal Methods Chem. 2013, Article ID 951319

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Resveratrol

• Phytoalexin and anti-fungal in plants

• Baselga-Escudero et al., Resveratrol and EGCG bind directly and distinctively to miR-33a and miR-122 and modulate divergently their levels in hepatic cells, Nucleic Acids Res. 2013 Oct 27

• Liang et al., Resveratrol as a therapeutic agent for renal fibrosis induced by unilateral ureteral obstruction, Ren Fail. 2013 Oct 24

• Ding et al., Mechanism of resveratrol on the promotion of induced pluripotent stem cells, J Integr Med. 2013 Oct 15

• Miao et al., Phytonutrients for controlling starch digestion: Evaluation of grape skin extract, Food Chem. 2014 Feb 15;145:205-11

• Smoliga et al., A healthier approach to clinical trials evaluating resveratrol for primary prevention of age‐related diseases in healthy populations, Aging; 2013 Jul;5(7):495-506

• Desquiret-Dumas et a., Resveratrol Induces a Mitochondrial Complex I Dependent Increase in NADH Oxidation Responsible for Sirtuin Activation in Liver Cells, J Biol Chem. 2013 Oct 31

• Dash et al., High-Dose Resveratrol Treatment for 2 Weeks Inhibits Intestinal and Hepatic Lipoprotein Production in Overweight/Obese Men, Arteriosclerosis, Thrombosis and Vascular biology, Nov 2013

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Anti-Oxidants are not JUST Anti-Oxidants

• Being an anti-oxidant is just one property of phenolics

• Phenolics perform important signaling functions in plants; often in response to pathogen attack

• As humans have evolved to consume these plants, might not we evolve too, mechanisms and pathways that take advantage of these plant phenolics?

• Increasing evidence shows that plant phenolics can perform discrete signaling functions in mammalian systems

• Regulate metabolism

• Inflammation

• Stimulate cell death

• Regulate gene expression

• Stimulate/inhibit enzyme activity

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The Alternative Fuel Industry Produces Polyphenolic Source

• Example: U.S. targets 30% replacement of transportation fuel with biofuels by 2030

1.5 billion pounds of biomass

60 billion gallons of EtOH

Burned for fuel Additives for

animal feedstock

Specialty chemicals

According to PNNL and NREL studies, using this resultant lignin for purposes other than power, improves overall revenue potential by $12 billion to $35 billion

225 million tons

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Incretin Concept: The act of eating is itself a signal

• Taste receptors for sweet, bitter, and umami are G-protein coupled receptors

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Taste receptors are everywhere!

From Asclafani, PNAS (104): 38, 2007

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So what came first? Tasting or……… Tasting?

Perhaps our olfactory/gustatory tasting evolved to attract us to ingredients that our physiological tasting/sensing indicates is

good for us?

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Some Scenes from Molecular Psychiatry

• C-1291G polymorphism in the promoter region of the gene coding the a2A-adrenoceptor (ADRA2A) influences fasting glucose levels and is also important in insulin secretion [Maestu et al. Molecular Psychiatry (2007)

12, 520–521]

• Functional polymorphism of the of 5-HT receptor subtype, 5-HT2A – T102C, reported to be associated with eating disorders such as anorexia nervosa and bulimia nervosa [Prado-Lima et al. Molecular Psychiatry (2006) 11, 889–891]

ADRA2 polymorphisms: Double recessive GG variant increases intake of sugary foods in Caucasian children

5HT-2a polymorphism associated with increased amino acid intake in an elderly Brazilian population

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The Impact of DNA Sequencing on Food and Beverages

• ‘Third generation’ [Electronic] DNA sequencing driving towards the $1K genome

• Ubiquitous sequencing; everything gets sequenced

• Revolution in personalization potentials

Moore’s Law The number of transistors on

integrated circuits doubles approximately

every two years

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While many bacteria cannot be cultured, we can detect and correlate them with human health…thanks to sequencing

Source: Ben de Jourdan

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The Symbiotic Metabolism Revolution

• In 2006 Jeff Gordon’s team at Washington University show that swapping the intestinal flora [microbiome] between ‘skinny’ [wild type] and genetically obese [Ob/Ob] swapped the obese phenotype

• Clearly metabolism is both organism plus microflora; the two ‘collaborate’ to determine overall metabolic physiology

• Food and Beverage: in the context of health and wellness, need to take into account what is good for the body and the microflora

Turnbaugh, et al. Nature 2006; 444:1027

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Extension to Humans: Diet Influences Microflora

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Ley et al. NATURE Vol 444: 21/28 December 2006

• Bacteroidetes is decreased in obese people

• Its relative population % increases with increasing weight loss

• And is influenced by diet

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Symbiotic Metabolism: Coevolution?

• Children between 1-6 y.o.a. compared between Boulpon, Burkina Faso [west Africa] and Milan, Italy

• Ratio of Bacteriodetes and Firmicutes found almost completely reversed

• Results suggest correlation between polysaccharide-degrading microbiota and total calories that the host can extract from diet as, potentially directly influencing survival and fitness of the host

• De Filippo et al postulate that gut microbiota coevolve with region-specific polysaccharide diet, in order to maximize caloric efficiency, indicating relationship between human genetics, regional diet, microbiome, and population health

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De Filippo et al., PNAS 107: 14691-14696, 2010].

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Businesses for direct-to-consumer genetic testing are still in the early stages but growing rapidly

Company Test offerings Region

23andme Medical, health/wellness, ancestry USA

ancestry DNA Ancestry USA

Atlas Sports Genetics Athletic genetic advantage USA

deCODE genetics Medical, health/wellness Iceland

DNA Plus Paternity, prenatal, forensic USA

Eastern Biotech & Life Sciences

Medical, health/wellness, ancestry, prenatal

UAE

Genelex Medical, health/wellness USA

GeneLife2012 Medical, health/wellness Japan

Genelink Biosciences Medical, health/wellness USA

Interleukin Genetics Medical, health/wellness USA

Lumigenix Medical, health/wellness, ancestry USA

Navigenics (Life Technologies)

Medical, health/wellness USA

Pathway Genomics Medical, health/wellness USA

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Adding up the Ideas: Health and Wellness is the Future

Plants with their starch and polyphenols provide selective nutrition and signaling

Evolution selects for maximizing caloric intake efficiency

Humans co-evolve with their microbiome and the environment

We can harness genetics to manipulate our metabolic destiny

Health and Wellness

In the future, food and beverages will be local, personalized

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The End

-Anthelme Brillat-Savarin

“The discovery of a new dish does more for human

happiness than the discovery of a new star”

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Thank you!

Kevin Pang, Ph.D., MBA | Director | Lux Research Inc.

234 Congress St., 5th Floor | Boston, MA 02110

Direct: +1 (857) 284-5691

kevin.pang@luxresearchinc.com | www.luxresearchinc.com