Could Asian Diet and Gut

Microbiome have an Impact

on Diabetes?

Yuan Kun LEE

Department of Microbiology & Immunology

Yong Loo Lin School of Medicine

National University of Singapore

5 Science drive 2, Singapore 117597

Obesity is associated with metabolic disorder

implicated

Involvement of

gut microbiota:Intestinal microbiota help us to

digest what we can not digest:

Good or bad?

Hoper, Midtvedt, Gordon. How host-microbial interactions shape the nutrient

environment of the mammalian intestine. Annu. Rev. Nutr. 2002, 22: 283-307

Bacteroides sp, Methanobrevibacter smithii degrade

xylan, psyllium hydrocolloid

I am fat, eating too much!?

Microbes make us fat!

Weight Gain After Fecal Microbiota Transplantation Neha Alang , Colleen R. Kelly

Open Forum Infect Dis (2015) 2 (1): ofv004.

https://doi.org/10.1093/ofid/ofv004 01 February 2015

Abstract

Fecal microbiota transplantation (FMT) is a promising treatment for recurrent

Clostridium difficile infection. We report a case of a woman

successfully treated with FMT who developed new-onset obesity after receiving stool

from a healthy but overweight donor. This case may stimulate further studies on the

mechanisms of the nutritional-neural-microbiota axis and reports of outcomes in

patients who have used nonideal donors for FMT.

Eating too much vs Infection!

Viruses SMAM-1, adenovirus-36, -37 and -5 stimulate enzymes and transcription

factors causing accumulation of triglycerides and differentiation of preadipocytes into

mature adipocytes, causing obesity.

Regional Symposium on Diabetes - Current Science and Multi-Stakeholder Approaches to Prevention & Management, October 4-5, 2017, Singapore

According to the National Health Survey (2010),

29.3% of Singaporeans are overweight (BMI:

25.0kg/m2 – 29.9kg/m2) and 10.8% are obese

(BMI > 30.0kg/m2)

However

¼ metabolic disorder patients are “lean”?

Lean obsess!!

½ overweight & 1/3 of obese never develop

metabolic disorder?

Wildman RP, Muntner P, Reynolds K, McGinn AP, Rajpathak S, Wylie-Rosett J,

Sowers MF. The obse without cardiometabolic risk factor clustering and the

normal weight with cardiometabolic risk factor clustering. Arch Intern Med, 2008,

168: 1617-1624

WHY? Mechanisms in induction of Type-

2 diabetes-initiation of chronic inflammation:

Leptin-lipotoxicity

vs

Lipopolysaccharides (cell wall) of G- bacteria

Obesity not a direct risk factor

of diabetesNew Scientist 6 Oct 2012, pg 14

Mechanism of Type II diabetes:

Leptin-lipotoxocity

Roger H. Unger & Philipp E. Scherer. Gluttony, sloth and the

metabolic syndrome: a roadmap to lipotoxicity. Trends in

Endocrinology & Metabolism 2010, 21(6): 345-352.

They propose that obesity and hyperleptinemia protect

lipid-intolerant nonadipose organs against lipotoxic lipid

spillover during sustained caloric surplus. Metabolic

syndrome is ascribed to lipotoxicity caused by age-

related resistance to antilipotoxic protection by leptin.

Obese: Indicator of sustained caloric surplus

Fat deposit a protective mechanism for

metabolic disorder!

Functions attributes to micrbiome on high-fat diet causing type-2 diabetes:increased endotoximia (high plasma bacterial lipopolysaccharide) and changed intestinal microbiota. Cani et al. Diabetes 2007, 56: 1761-72.

Commensal strengthen epithelial layer tight-junction (increase expression of zonula

occludens-1 & myosin light-chain kinase), preventing crossover of pathogen and LPS,

chronic inflammation and type-2 diabetes.

chronic inflammation damage insulin producing B cells

in pancreas & insulin receptors on tissue cells

Filippo, C. D. et al. PNAS (2010) 107,

14691-14696

AlistipesBacteroidesAcetitomaculumFaecalibacterium

SubdoligranulumOthers

Roseburia

Bacteroidetes

Firmicutes

EU children (n=15, 1~6 y.)

PrevotellaXylanibacterAcetitomaculumFaecalibacteriumSubdoligranulumOthers

Bacteroidetes

Firmicutes

Children in

Burkina Faso

(n =14, 1~6 y.)

Linking long-term dietary patterns with gut microbial enterotypes Wu GD, Chen J, Hoffman C, et al.

Science 2011, DOI: 10.1126/Science 1208344

Enterotypes:Type 1: Consumed lots of

meat & saturated fat- more

Bacteroides

Type 2: People who consumed lots of alcohol &

polyunsaturated fats- Ruminicoccus prevailed

Type 3: Diet rich in carbohydrates- favored Prevotella

What have we learnt from microbiome studies

Regional Symposium on Diabetes - Current Science and Multi-Stakeholder Approaches to Prevention & Management, October 4-5, 2017, Singapore

Philippines

En

erg

y (

kca

l)

Baybay

(n = 24)

Ormoc

(n =16)

Leyte island

BaybayOrmoc

(A)

(C)

(B)

Ormoc

Carbohydrate Fat Protein

7118

11

6027

13

En

erg

y (

kca

l)

Impact of modern high-meat/-fat diet on gut microbiota

in children on Leyte island Philippines Redundancy analysis to correlate macronutrient intake alysis to correlate mac

with gut microbiota

-1.5 -1.0 -0.5 0.0 0.5 1.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

CAP1

CA

P2 B

B

B

BB

B

B

BB

BB

BB

B

BBB

B

B

B

B

BBB

O

O

O

O

O

O

O

O

OO

O

O

O

O

O

O

-10

1

Protein

FatCarbohydrate

Bacteroidetes

Actinobacteria

Firmicutes

B: Baybay

O: Ormoc

Bacteroides/Bifidobacterium-typePrevotella-type

Jiro Nakayama, Azusa Yamamoto, Ladie A. Palermo-Conde, Kanako Higashi, Kenji Sonomoto, Julie Tan,

Yuan Kun Lee (2017) Impact of high-fat diet on gut microbiota in children on Leyte island. Frontiers in Microbiology, doi: 10.3389/fmicb.2017.00197

Taipei

Taichung

Beijing

Yogyakarta

Bali

Bangkok

Khon Kaen

Fukuoka

Lanzhou

Tokyo

Bacteroidaceae

Lachnospiraceae

Ruminococcaceae

Bifidobacateriaceae

Ta

Seoul

MongoliaEnterotypes:Type 1: Consumed lots of

meat & saturated fat- more

Bacteroides?? Mongolian

A secondary dietary factor?

Prevotellaceae

J Nakayama, K Watanabe, JH Jiang,

K Matsuda, SH Chao, P Haryono, O

La-ongkham, MA Sarwoko, IN Sujaya,

L Zhao, KT Chen, YP Chen, HH Chiu,

T Hidaka, NX Huang, C Kiyohara, T Kurakawa, N

Sakamoto, K Sonomoto, K Tashiro, H Tsuji, MJ Chen,

V Leelavatcharamas, CC Liao, S Nitisinprasert, ES

Rahayu, FZ Ren, YC Tsai, YK Lee (2015) Diversity in

gut bacterial community of school-age children in Asia.

Scientific Reports, 5:8397/DOI 10.1038/srep08397.

1.1 1.20.9 1 0.6

1.10.8 0.3

Wheat

1.41

1.9 2.12.4 2.4

2.92.6

Rice

Food intake (Carbohydrate) frequency (per day)

> > > < < <<

<< << < > > >> >

>: higher than other cities (p<0.05); >>: higher than other cities (p<0.001)<: lower than other cities (p<0.05); <<: lower than other cities (p<0.001)>: higher than other cities (p<0.05); >>: higher than other cities (p<0.001)<: lower than other cities (p<0.05); <<: lower than other cities (p<0.001)

Resistant Starch

(6.6%)

Resistant Starch

(0.6%)

Japonica

Indica

Javanica

Regional Symposium on Diabetes - Current Science and Multi-Stakeholder Approaches to Prevention & Management, October 4-5, 2017, Singapore

Kill Prevotella +

bile sensitive species Less resistant starch ­ Bile acid in colon ¯Diversity

BB-type

Promote Prevotella +

bile sensitive species High resistant starch ¯ Bile acid in colon ­Diversity

P-type

WORKING HYPOTHESIS

Relative proportion of dietary fat & resistant carbohydrate determine enterotype

Over consumption of fat led to obesity

Pathogen-enriched

High fat ­ Bile acid/ fatty acids in colonKill commensal,

weaken tight junction ­Chronic inflammation

Does obesity plays any role in Type-2 Diabetes in Asia?

Over consumption of carbohydrate could lead to obesity!

Kill Prevotella +

bile sensitive species Less resistant starch ­ Bile acid in colon ¯Diversity

BB-type

Promote Prevotella +

bile sensitive species High resistant starch ¯ Bile acid in colon ­DiversityP-type

WORKING HYPOTHESIS

Relative proportion of dietary fat & resistant carbohydrate determine enterotype

Over consumption of fat led to obesity

Pathogen-enriched

High fat ­ Bile acid/ fatty acids in colonKill commensal,

weaken tight junction ­Chronic inflammation

Over consumption of carbohydrate led to obesity

High resistant starch Commensal remained

Strengthen tight junction No chronic inflammation¯ Bile acid/

fatty acids

Cell Metabolism 26, 539–546, September 5, 2017

A Ketogenic Diet Extends Longevity and Healthspan in Adult MiceMegan N. Roberts et al.

Calorie restriction, without malnutrition, has been shown to increase lifespan and is associated with a shift away

from glycolysis toward beta-oxidation. The objective of this study was to mimic this metabolic shift using low-

carbohydrate diets and to determine the influence of these diets on longevity and healthspan in mice. C57BL/6

mice were assigned to a ketogenic, low-carbohydrate, or control diet at 12 months of age and were either allowed

to live their natural lifespan or tested for physiological function after 1 or 14 months of dietary intervention. The

ketogenic diet (KD) significantly increased median lifespan and survival compared to controls. In aged mice, only

those consuming a KD displayed preservation of physiological function. The KD increased protein acetylation

levels and regulated mTORC1 signaling in a tissue-dependent manner. This study demonstrates that a KD

extends longevity and healthspan in mice.

Cell Chemical Biology 24, 935–943, August 17, 2017

Ketone Body Acetoacetate Buffers Methylglyoxal via a Non-enzymatic

Conversion during Diabetic and Dietary Ketosis

The a-oxoaldehyde methylglyoxal is a ubiquitous and highly reactive metabolite known to be involved in aging- and

diabetes-related diseases. If not detoxified by the endogenous glyoxalase system, it exerts its detrimental effects

primarily by reacting with biopolymers such as DNA and proteins. We now demonstrate that during ketosis,

anothermetabolic route is operative via direct non-enzymatic aldol reaction between methylglyoxal and the ketone

body acetoacetate, leading to 3-hydroxyhexane- 2,5-dione. This novel metabolite is present at a concentration of

10%–20% of the methylglyoxal level in the blood of insulin-starved patients. By employing a metabolite-alkyne

tagging strategy it is clarified that 3-hydroxyhexane-2,5-dione is further metabolized to non-glycating species in

human blood. The discovery represents a new direction within non-enzymatic metabolism and within the use of

alkyne-tagging for metabolism studies and it revitalizes acetoacetate as a competent endogenous carbon

nucleophile.

High dietary fat may be good!

Regional Symposium on Diabetes - Current Science and Multi-Stakeholder Approaches to Prevention & Management, October 4-5, 2017, Singapore

High fat-low resistant starch (wheat, potato) consumers eat more resistant

starch (Indica rice, bailey, oat, millet) to prevent type-2 diabetes.

High resistant starch-low fat consumers switch to low resistant starch or eat

more fat to prevent MCI/dementia and improve longevity.

(hypertension, cardiovascular diseases?!)

(Working hypothesis for intervention study!)

Could Asian ancient wisdom has a solution for Diabetes?

balance

Regional Symposium on Diabetes - Current Science and Multi-Stakeholder Approaches to Prevention & Management, October 4-5, 2017, Singapore