Thursday, April 23, 2020

Role of Gut Microbiota in the Aetiology of Obesity

AHN - Discussion Paper

- aetiology (cause) of obesity attributed to several factors such as env, dietary, lifestyle,
host and genetic factors; don't fully explain the increase in prevalence of obesity
worldwide
- gut microbiota, located the interface of host and env in the gut are new area of
research being explored to explain excess accumulation of energy in obese
individuals - potential target for therapeutic manipulation to reduce host energy
storage
- suggested mechanisms in the role of gut microbiota in the aetiology of obesity include:
- SCFA production

- hormone stimulation

- chronic low grade inflammation

- lipoprotein and bile acid metabolism

- Increased endocannaboid receptor system tone

- current human and animal studies indicate controversies in determining cause/effect
relationship ; metagenomics studies indicate functionality of gut microbiota may be
important than the composition.

1. Introduction - Initial Evidence of the Role of Gut Microbiota in Obesity

gut microbiota - metabolic organ that ferments non-digestible dietary components (non-
digested CHOs) to SCFA

• in 2004, gut microbiota’s role as significant env factor affecting host adiposity through
integrated host signaling pathway was explored
- suggested that the gut microbiota induced adiposity by:
1. stimulating hepatic de novo lipogenesis and triglyceride storage
through ChREBP (CHO response element binding protein) 1
(SREBP1)

2. suppressing fasting induced adipocyte factor (fiaf) - inhibitor

of adipocyte lipoprotein lipase - accumulation of fat ; emerging

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regulation, kind of gene, affect the ability of body to deposit fat -
obesity

- the group proposed that this ‘ intestinal high efficiency bioreactor’

in certain individuals might promote energy storage (obesity); ‘low efficiency bioreactor’
would promote leans due to lesser energy harvest from CHO fermentation

(differences b/w obese and lean people were worthy of further exploration)

- Fermicutes to Bacteroidetes ratio was suggested to be associated

w/ increased energy harvest from food facilitated by gut microbiota

- no evidence shown of increased gene expression

related to bacterial metabolic activity and how it could be affected by diet, lifestyle nor
whether these changes could be seen in humans

• in human study, obese adults were randomized onto fat/CHO restricted diets, followed
up for one year

• obese people, prior to restricted calorie intake:

- lower relative abundance of Bacteroidetes
- higher relative abundance of Fermicutes
• over follow up period, relative abundance of Bacteroidetes sig. increased -
+vely correlated w/ % weight loss and not the caloric content of diet

• suggested that the gut microbiota restructured, changed their

metabolic priorities to support coexistence in a changed env.

• study did not explore the same relationship w/ parallel lean group to see
if they had the same response to dietary intervention.

• while that of Fermicutes sig. reduced

• in mice study, evidence suggested the presence of gut microbiota as necessary

for development of obesity
- germ-free mice were resistant to obesity even when they
consumed more calories from a normal chow/ high fat diet
compared w/CONV mice.

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2. Proposed mechanisms for role of gut microbiota in Obesity

- differences in gut microbiota of lean and obese people suggests a link b/w gut
microbiota and energy homeostasis (still a debate as to whether the differences are
casually related to obese/lean phenotype)

Mechanisms for the role of gut microbiota in the aetiology of obesity

1. Metabolic: Increased production of short chain fatty acids [1]

Muscle fatty acid oxidation [1]

Bile acid circulation [19]

Expression of liver

ChREBP/SREBP-1 [1]

2. Inflammatory: Chronic low-grade inflammation [9]

increased endocannabinoid (eCB) system tone [10, 20]

3. Hormonal: Suppression of Fiaf

Increased PYY [21]

Expression of G protein coupled receptors 41 and 43 (GPR41 and

GPR43)

2.1 Energy Harvest from Diet (SCFAs)

gut microbiota in the colon ferments undigested dietary polysaccharides and proteins
into SCFA mainly 1. acetate propionate

2. butyrate

amount of energy harvested hypothesized to be influenced by gut microbiota

composition - up to 10% of daily energy req. and 70% of energy for cellular respiration
for colonic epithelium may be derived from SCFA.

- chronic excess energy harvest may cause long term fat

accumulation in the body

- whether the production of SCFA results in increased energy harvest from

diet in obese phenotypes, depends on several factors:

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1. substrate availability

2. gut transit

3. mucosal absorption

4. gut health

5. production by the gut microbiota

6. symbiotic relationships b/w diff groups of gut microbiota

2.2 Gut microbiota and fasting induced adipocyte factor

Inhibition of fiaf by gut microbiota with resultant increase in LPL - one mechanism for gut
bacterial induced host adiposity.

for angiopoitein-like protein 4 is a target gene for peroxisome receptor activated

proteins (PRAPs) - produced by L.I epithelial cells and liver

- inhibits LPL lipoprotein lipase > accumulation of fat in peripheral tissues.

2.3 Gut Microbiota and FAO (fatty acid oxidation)

gut microbiota thought to reduce muscle and liver FAO by supperssing AMPk (adenosine
monophosphate kinase) - liver and muscle cell enzyme that monitors cellular energy
storage.

- inhibition of AMPk > reduced muscle and liver FAO > excess fatty acids storage
in these tissues.

2.4 Gut Microbiota and Bile Acids Circulation

- bile acids are ligands for farnesoid x receptor (FXR) which plays a key role in the the
control of hepatic de novo lipogenesis - metabolic pathway that synthesizes fatty
acids from excess carbohydrates, VLDL triglyceride export, and plasma triglyceride
turnover > improved lipid and glucose metabolism

- bile acids bind to FXR in ileal cells - stimulate expression of genes which helps in
absorption, intracellular transport, and transport of bile acids into liver by
enterohepatic circulation.

how does this affect obesity? -

figure 1 - modulation of bile acid circulation by gut microbiota - improves glucose

metabolism - improved insulin sensitivity, improves lipid and glucose metabolism
in the liver by ↓ lipogenesis ↓ VLDL export ↓ TG turnover

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2.5 gut microbiota and changes in satiety

- by changing the hormonal milieu in the intestine and other visceral organs.
- bifidobacteria inversely associated w/ development of fat mass, glucose intolerance,
and bacterial lipopolysaccharides (LPS) in the blood via SCFA induced stimulation of
PYY and gherlin

- intervention w/prebiotics - dietary fructans/oligosaccharides stimulates

bifidobacterial growth > reduces weight accompanied by increased PYY and
reduced gherlin consistent w/ lower food intake in the prebiotics group.

- intervention w/ 16 g fructose/day or 16 g nextrin maltose/day for 2 weeks

was associated w/ an increase in breath hydrogen - marker for colonic fermentation
and increase production of PYY

These hormonal changes bring a change in satiety, food intake, and overall metabolic status of
an individual that could affect host adiposity. Whether this relationship is causal needs further
investigation.

2.6 Gut Microbiota and Instestinal Permeability: Chronic Low-Grade Inflammation

2.6.1 Bacterial Lipopolysacharide and Inflammation

- absorption of bacterial LPS by gut microbiota contributes to chronic low grade
inflammation - a hallmark of obesity
- 2007 study demonstrated the link b/w LPS and metabolic disease by infusing bacterial
LPS subcutaneously into germ free mice for 4 weeks - produced the same level of
metabolic endotoxemia as by high fat diet.
- Mice lacking functional LPS receptors were resistant to those changes
- feeding high fat diet to mice mucosal immune dysfunction for 4 weeks
resulted in 2-3 times increased systemic LPS level in liver, adipose tissue
and muscles higher body fat mass - “metabolic endoteoxemia”
- Inflammatory status associated w/ lower bacteriorides, Bifidobacterium
species, and Eubacterium rectale C coccoides group

2.6.2 Gut Barrier Integrity anf Inflammation

alteration in the gut microbiota is linked to changed gut barrier function - may promote
release of bacterial endotoxins through damaged and leaky gut

2007 - significant reduction in Bifidobacteria w/high fat diet in male C57BL/6J mice

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- supplementation w/oligofructose - restored the bifidobacterium
population, improved gut barrier, decrease in endotoxemia

2.6.3 High Fat Diet and Inflammation

clear evidence that suggests consumption of high fat diet is associated w/metabolic
endotexemia and 2-3x increase in bacterial LPS levels in the blood - 2-3 times increased
systemic LPS level in liver, adipose tissue and muscles higher body fat mass

Figure 3

Proposed model for the role of LPS in generating inflammation and its relationship with
obesity.

• Altered mucosal barrier function due to reduced expression of glucagon like

peptides 1 and 2 (GLP-1 and GLP-2) leads to altered mucosal function and
reduced synthesis of tight junction proteins, Zonula Occludin-1 and Zonula
Occludin-2 (ZO-1, ZO-2), increasing gut permeability.

• This allows LPS to enter the systemic circulation inducing the release of
proinflammatory cytokines. Proinflammatory cytokines result in activation of a
family of kinases JNK and IKK (inhibitor of NFkB kinase) that increase the
expression of inflammatory and lipid metabolism genes.

• Subcutaneous administration of LPS, hyperglycaemia, and insulin resistance

induces the same pathway by increasing the endoplasmic reticulum and
mitochondrial stress. Type-2 diabetes, hyperglycaemia, and insulin resistance
also cause macrophage infiltration and inflammatory cytokine release leading to
the same process. HF: high fat diet - increasing the expression of inflammatory and
lipid metabolism genes.

3. Review of Animal Studies relating gut microbiota w/obesity

- gut microbiota located at the interface of env and host
- effect of env factors esp diet, highly significant, and contributes to changes in gut
microbiota composition, function and phenotype
- ingestion of high fat western diets may play an important role in modifying the gut
bacterial population > alters the energy harvesting capability, showing a tendency
towards increase in populations of firmicutes and reduction in Bacteriodetes after
feeding w/high fat western diet

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3.1 Conclusion from animal studies: controversy as to whether these changes are
attributable to diet itself or caused by the gut microbiota.

- studies in germ free mice suggest that gut microbiota are the critical player in
inflammation, development of immunity, and host metabolic regulation; diet is also
considered a co-founding factor that determines change in gut microbiota and obesity.

4. Review of Human Studies relating gut microbiota w/obesity

evidence is inconclusive and controversial could be due to marked inter individual

variations in the gut microbiota, and metabolic activity in humans with age, diet, use of
antibiotics genetics and other env factors.

5. Conclusion

None of the factors fully explain the aetiology and pathogenesis of obesity ; search for
possible causes continues

gut microbiota - one factor affecting host entry homeostasis through several
mechanisms investigated in mice and human studies

several studies suggested profound effect of diet of diet on gut microbiota which
modifies host metabolism towards lean/obese phenotype

evidence linking gut microbiota to increasing epidemic of obesity is too contradictory and
inconclusive to prove a cause/effect relationship > differences in methodology, study
design, control of diet, genetic propensity of individuals to obesity, other lifestyle factors

Moreover, faecal samples are the usual source of gut microbiota which may not
represent the true picture of the colonic microbial population. Access to the full length of
the gut is restricted for medical or ethical reasons. In addition, differences between
animals and human beings including intestinal microbiota, metabolic rate, and length of
intestine, caecal fermentation, coprophagy, and genetic variability limit
the extrapolation of results from animal studies.