Post on 25-Jan-2019
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