Foods for Health Institute Building the Science, Technologies and Education to Guide Diet and Health in the 21 st Century

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1 Foods for Health Institute Building the Science, Technologies and Education to Guide Diet and Health in the 21 st Century

2 Evolve Biosystems Metabolon MicroTrek Abbott Mars Nestle DSM GMCR Prolacta Arla Friesland-Campina CDRF & DMI Disclosures AgResearch NZ Food 4 Health Ireland Nutrigenomics Netherlands Food Network Canada BioInnovates Alberta NIH NSF USDA B&M Gates

3 Evolutionary Nutrition What evolved under the Darwinian Pressure to be Nourishing?

4 Darwin Awards: The willful removal of genetic material

7 MEN WOMEN MEN & WOMEN

8 Lactation The Darwinian Engine of Nutrition Maternal Optima Benefits B<C Costs Time Infant Optima B<(r)C Evolving a cost benefit solution for Katie Hinde UCLA Health

9 International Milk Genomics Consortium: Founded at UC Davis 2002

10 Katie Hinde UCLA Lactation The Darwinian Engine of Diet, Health & Sustainability Maternal Optima Benefits B<C Costs Time Infant Optima B<(r)C

11 Functions of Milk? The 3 rd most abundant class of biomolecule in human breast milk is un-digestible by humans! What are they?

12 Milk Oligosaccharides Carlito Lebrilla World s Leading Analytical GlycoChemist

13 Analytical tools for oligosaccharide analysis Biological sample to MS 1990 s -10 days PNGase F Glycan Release with Microwave Reactor 2000 s - 5 days Now - hours Microchip separation Automated SPE MALDI FTICR MS High performance MS

14 Human milk oligosaccharides - Human indigestible and highly variable Nearly 200 compositions in pooled breast milk Carlito Lebrilla UCD Chemistry Niñonuevo, et al. 2006

Human milk oligosaccharides HMOs Chain Length HMOs Proteins Lipids 4 5 6 7 Carlito Lebrilla UCD Chemistry 8 Lactose Nature 468 S5-S7 (23 December 2010) Garrido et al Microbiology

15 Human milk oligosaccharides HMOs Chain Length HMOs Proteins Lipids Carlito Lebrilla UCD Chemistry 8 Lactose Nature 468 S5-S7 (23 December 2010) Garrido et al Microbiology (2013) Other HMOs of longer lengths Human indigestible and highly variable Higher proportion of fucosylated (40-70%) than sialyated (4-38%) Nearly 200 species in pooled human milk

16 Functions of Milk? The 3 rd most abundant class of biomolecule in human breast milk is un-digestible by humans! Why?

17 Bacteria? David Mills Shields Endowed Chair Structure, Function and Health Benefits of Food Borne Bacteria

18 HMO utilization by Bifidobacteria

Bifidobacterium Infantis 1 2.5 Mb B. infantis 2,832,748 Mb 0.

19 Bifidobacterium Infantis Mb B. infantis 2,832,748 Mb 0.5 Mb Fucosidase Hexosaminidase Sialidase galactosidase 1.0 Mb Glc Gal GlcNAc Fuc Neu5Ac ESB?-

20 Bifidobacteria vs Bacteroides in situ Lacto-N-neotetrose supplementation of gnotobiotic mice with Bifidobacterium infantis and Bacteroides thetaiotaomicron Marcobal & Sonnenburg CHM 2011

Feces Oligosaccharides of Term Infant Vary With Bacterial

1878 1951 2097 % Bacteria 0 100% 80% 60% 40% 20% 0% Fecal

21 Feces Oligosaccharides of Term Infant Vary With Bacterial Population %Change in H/D Ratios Fecal HMO Profile FULL TERM INFANT Lorna de Leoz HMO neutral mass % Bacteria 0 100% 80% 60% 40% 20% 0% Fecal Bacterial Profile 0 Week 1 Week 1 2 Week 2 4 Week Age of Infant, in Weeks B. longum/infantis Bacteria Other Staphylococcaceae Enterobacteriaceae Coriobacteriaceae Streptococcaceae Bifidobacteriaceae Bacteroidaceae

Institute in Paris, isolated a bacterium characterised by a

22 Infant Gut Microbiome: what was typical? Bifidobacterium sp. In 1899, Henry Tissier, a French pediatrician at the Pasteur Institute in Paris, isolated a bacterium characterised by a Y-shaped morphology in the intestinal flora of breast-fed infants and named it "bifidus".

23 Infant fecal ph (before discovery/use of antibiotics) R.C. Norton MD and A.T. Shohl MD The Hydrogen Ion Concentration of the Stools of New-Born Infants ph measurements 27 infants

24 B. Infantis & Vaccination Bangladesh Infant Vitamin A Study International Center for Diarrhoeal Disease Research (Bangladesh) Charles Stephenson Western Human Nutrition Research Center (Davis, CA) Huda et al Pediatrics 2014

25 Neonatology: Translation Premature Infants Necrotizing Enterocolitis Combination of human milk oligosaccharides plus Bifidobacterium longum subsp. infantis: Mark Underwood

26 Forumla fed infant + B. infantis Human milk-fed infant + + B. infantis and then B. lactis HMO + B. infantis OD Mark Underwood HMO - B. lactis B. infantis B. lactis J. Pediatrics (2015)

27 If endotoxinproducing bacteria can t utilize HMO s why do premies get NEC?

28 Bacteroides sp. B. longum subsp. longum B. breve B. pseudocatenulatum B longum subsp. infantis Outside eater Inside eater Garrido Adv. Nutr 2012

29 Bacteroides thetaiotaomicron Degrades Sialylated Glycans Genome sequencing and phenotypic tests show they don t utilize sialic acid but consume sialylated glycans Frese et al Unpublished data

30 Who Consumes the Sialic Acid? E. coli UCD1381 Genome sequencing and phenotypic tests show they utilize sialic acid

From Scientific Discovery to NICU Applications www.evolvebiosystems.com Evolve BioSystems, Inc.

31 From Scientific Discovery to NICU Applications Evolve BioSystems, Inc. Headquartered in Davis, CA Founded by UC Davis scientists Bringing to market products to establish, restore and maintain a healthy newborn gut microbiome Products based on the unique partnership discovered between B. infantis and mammalian milk

32 Science: How does a microbial ecosystem work? Who is There What are they Eating What are they Making 3 Simple Principles All 3 are highly integrated 33

33 Ecosystems

34 The Truth of the Intestine Its dark, wet, competitive Who eats - wins

35 Practice: Milk directs this ecosystem in the baby Who is There What are they Eating What are they Making Milk Feeds the Intestinal Microbiota and guides its products 36

36 Where s the flaw

37 Mammals have embraced bacterial transfer

38 Modern Life has stopped microbial transfer

39 SHIT!

40 Healthy Breast fed infant Data from Ours & Other Studies 100% 90% Z. Lewis 80% 70% 60% 50% 40% 30% 20% 10% 0% All Others Proteobacteria Firmicutes Bacteriodetes Actinobacteria

microbiome composition, predictably ~40% of infants in vaginally delivered

42 The IMPRINT Study C-section delivered (N=21) Vaginally delivered (N=49) Vaginally delivered and Cesarean-delivered infants differed in initial gut microbiome composition, predictably ~40% of infants in vaginally delivered group had Bifidobacterium in higher numbers Days Frese et al submitted

43 The IMPRINT Study Unsupplemented Supplemented Days Days Frese et al submitted

44 EVC001 remodels fecal biochemistry Milk Oligos Fecal Milk Oligos Fecal SCFA Fecal endotoxin Frese et al (submitted)

45 Hi-Bif babies: a different colonic terroir ph = 6.0 Stools: 33% watery Frequency: 4.0/d ph = 4.5 Stools: 20% watery Frequency: 1.8/d

46 EVC001 remodels fecal biochemistry 1926 Fecal ph drops significantly after Imprint treatment Restores fecal ph to historical norms Frese et al (submitted)

47 What s Next?

48 Antibiotics eliminate commensals Gram negatives can multiply Restoration MUST consider the ecosystem and its fuels

49 Microbiota of Health Personal microbiome management: premature infants to weaning from athletes to hospitals

50 Any Microbiome as Target Who is There What are they Eating What are they Making Three complex variables: Are they Controllable? 51

51 Humans have a simple intestine Plant polysaccharides are Complex

52 Detailed Structure analysis of Plant Glycans

H + H + H + H + Transporter symbols EIIBC Glc EIIBC NAG fucose EIIA Glc ~P EIIA Glc ATP ADP ATP ADP ATP ADP EIIA NAG ~P EIIA NAG ATP ADP ATP ADP glucose HPr~P HPr HPr~P HPr galactose EI~P EI EI~P EI

53 H + H + H + H + Transporter symbols EIIBC Glc EIIBC NAG fucose EIIA Glc ~P EIIA Glc ATP ADP ATP ADP ATP ADP EIIA NAG ~P EIIA NAG ATP ADP ATP ADP glucose HPr~P HPr HPr~P HPr galactose EI~P EI EI~P EI oligosaccharide Pyruvate PEP Intracellular HMO hydrolysis Pyruvate PEP LNB GlcNAc Neu5Ac Glc Glycomic Gal symbols Lactaldehyde NADH NAD + L-fucose L-fuculose ATP ADP 22 Fuculose 1P 1,2 propanediol fucosidase β-galactosidase LNB phosphorylase β-hexosaminidase sialidase??? DHAP 23 2 ATP 2 ADP Galactose 2 Glucose F6P 3 GA-3P Ribose 5P 5 Ribulose 5P Leloir pathway 1 F6P 4 P i 2 NH 3 Erythrose 4P Sedoheptulose 7P 6 21 Xylulose 5P H 2 O glucosamine 6P 7 Acetate H 2 O Acetyl-P 8 3 Acetate 2 Acetyl-P 3 ADP 3 ATP 2 ADP 2 GA-3P Pyruvate 2 NAD + 2 NADH N-acetylglucosamine ATP ADP N-acetylglucosamine 1P 20 2 ATP NAG 6P 17 2 NADH 2 NAD + 2 L-Lactate Sialic acid N-acetylmannosamine ATP ADP N-acetylmannosamine 6P GlcNAc Fuc Neu5Ac Lac LNB LNT Metabolic symbols Intracellular GH activity HMO Glycosidic bond cleavage

54 For all the Moms, Babies, Scientists, Faculty, Students, Staff and Supporters Thank you

The Enigma of the Infant Microbiome

The Enigma of the Infant Microbiome 3 rd Microbiome R&D and Business Collaboration Forum Europe London, April 2016 David J. Kyle, CEO, Evolve Biosystems Inc Microbiome diversity is a good thing. Modern