presenting the microbiota–gut–brain axis in obesity article by Cristina Torres-Fuentes, Harriët Schellekens, Timothy G Dinan, John F Cryan

1. THE MICROBIOTA–GUT–
BRAIN AXIS IN OBESITY
PRESENTED BY DANA MATBOULI
Torres-Fuentes, C., Schellekens, H., Dinan, T. G., & Cryan, J. F. (2017).The microbiota–gut–brain axis in obesity.The Lancet. Gastroenterology & Hepatology, 2(10), 747-
756. https://doi.org/10.1016/S2468-1253(17)30147-4
Cristina Torres-Fuentes, Harriët Schellekens, Timothy G Dinan,
John F Cryan

2. THE HUMAN MICROBIOME
HTTPS://WWW.YOUTUBE.COM/WATCH?V=YB-8JEO_0BI

3. INTRODUCTION
Human intestines host tens of trillions of microorganisms
Dominated by bacteria from the phyla Firmicutes and Bacteriodetes
Gut bacteria have a symbiotic relationship with the human body:
• Protecting and supporting the structure of intestinal mucosa
• Key regulators of host physiology and pathophysiology

4. INTRODUCTION
The composition of the human gut microbiota is altered in:
Metabolic disorders Neuropsychiatric
disorders
Obesity
Diabetes
Eating
disorders
Depressi
on
Anxiety

5. ROLE OF GUT MICROBIOTA
Regulate fat
storage
Harvest
energy from
the diet
Affect
inflammatio
n
Affect
insulin
Metabolism
Affect
glucose
metabolism
Affect
hepatic lipid
metabolism
Affect the CNS via modulation of endocrine signaling
pathways of the microbiota–gut–brain axis (glp-1,
peptide YY signaling, or activation of reward
pathways)
Alterations in the composition of the microbiota, especially early in life,
might cause obesity and diabetes by substantially modifying the host’s
metabolism and affecting homoeostasis and the central appetite mechanism

7. OBESITY ASSOCIATED MICROBIOTA
• Germ free mice were protected against obesity and were significantly
leaner than were control mice (despite consuming more calories)
• They had altered plasma lipid metabolic markers and lower
concentrations of ghrelin and leptin (indicating an energy deficit)
Bacteroidet
es Bacteroidet
es
Firmicute
s
Firmicute
s

8. OBESITY ASSOCIATED MICROBIOTA
Alterations in the gut
microbiota following envi
ronmental reprogramm
ing ameliorates the dev
elopment of metabolic sy
ndrome in different
strains of mice
Genetics:
monozygotic twins
had a more similar
gut microbiota
composition than
did dizygotic twins

9. OBESITY ASSOCIATED MICROBIOTA
• Metagenome-wide association study found a decreased abundance of a
glutamate-fermenting commensal bacteria in obese individuals  This
abundance was increased after bariatric surgery, which highlights further
unknown links between intestinal microbiota alterations, circulating
amino-acids, and obesity

10. BARIATRIC SURGERY
• RYGB affects the composition of gut microbiota, leading to increased
diversity
• After bariatric surgery, patients and mice have an increased abundance of
Gammaproteobacteria and Verrucomicrobia and a decrease in Firmicutes
• FMT from mice that had RYGB into germ-free mice resulted in weight loss
in the recipient animals (potentially due to altered microbial production of
SCFAs) bariatric surgery leads to specific changes in the gut microbiota,
causing changes in the composition of SCFAs and thus influencing host
metabolism, including gut hormone secretion and insulin sensitivity

11. METABOLISM AND APPETITE REGULATION
• The intestinal microbiota produce bioactive metabolites in a diet-
dependent manner (short-chain fatty acids & conjugated fatty acids)
• These metabolites have peripheral effects but also modulate the brain
via direct or indirect mechanisms, which modifies host metabolism and
the central regulation of appetite and food intake

12. METABOLISM AND APPETITE REGULATION

13. METABOLISM AND APPETITE REGULATION
Peripheral metabolic signalling
• An obesity-associated microbiota increases the efficiency of calorie
uptake from ingested foods  provide more energy to the host from
otherwise indigestible carbohydrates and proteins
• The gut microbiota changes the composition and relative abundance of
bile acid species, which might explain its effect on glucose and insulin
homoeostasis
• A reduced bile acid concentration in the gut has been associated with
bacterial overgrowth and inflammation

14. METABOLISM AND APPETITE REGULATION
• Some gut bacteria metabolise bile acids and their conjugates for a
source of energy, causing activation of bile acid receptors (FXR and
TGR5) which are essential receptors for maintaining glucose tolerance
and insulin sensitivity
• Obese patients and type 2 diabetics have altered bile acid metabolism
• Gut microbiota also affect serotonin metabolism might also influence
host glucose homoeostasis (stimulation of 5-HT1B or 5-HT4 receptors
increased plasma active GLP-1 concentrations)

15. METABOLISM AND APPETITE REGULATION
The gut microbiota might also affect fat storage and hepatic lipid
metabolism
• A circulating lipoprotein lipase inhibitor is selectively suppressed by
intestinal bacteria, inducing triglyceride deposition in adipocytes
• Gut bacteria affect the bioavailability of choline (an essential nutrient for
synthesis of VLDL) which affects triglyceride storage in the liver
• Gut microbiota-mediated activation of the bile acid FXR receptor
increases adiposity

16. METABOLISM AND APPETITE REGULATION
The gut microbiota is also associated with inflammation in obesity
• Increased plasma levels of lipopolysaccharide (an endotoxin in the cell wall of
Gram-negative bacteria) causes metabolic endotoxemia  inducing a strong
immune system response and contributing to obesity-related low-grade
inflammation
Note: Dietary fat increases intestinal lipopolysaccharide absorption by
incorporation into chylomicrons
• Metabolic endotoxemia might also result from impaired intestinal barrier
integrity HOWEVER, some gut bacteria could prevent this by protecting
intestinal barrier integrity which leads to thickening of the mucus layer or up-

17. METABOLISM AND APPETITE REGULATION
Microbiota and obesity—from gut to brain
• Some bacterial strains can modify gut hormone secretion (PYY, GLP-1,
leptin, ghrelin)  thus affect appetite and satiety via hypothalamic
neuroendocrine pathways
• Microbiota-derived metabolites(SCFAs) can bind to receptors on
enteroendocrine cells, modifying the release of enteric hormones into the
systemic circulation
• HENCE fermentation of non-digestible carbohydrates by the intestinal
microbiota has been shown to increase the production of SCFAs and

18. METABOLISM AND APPETITE REGULATION
• Acetate, the main SCFA secreted by intestinal bacteria, directly suppresses
appetite via central hypothalamic mechanisms
• HOWEVER an increase in acetate concentration caused by altered microbiota
leads to activation of the parasympathetic NS, promoting glucose-stimulated
insulin secretion, increased ghrelin secretion, and obesity
• Absence of microbiota in germ-free mice substantially decreased expression of
intestinal satiety peptides and increased expression of the oral fat taste
receptor resulting in an increased calorie intake from fats

19. METABOLISM AND APPETITE REGULATION
• In EEC, different taste receptors (eg, sweet, fat, bitter, and umami
receptors) are expressed and their activation leads to secretion of GLP-
1, cholecystokinin, and ghrelin
• A study in germ-free mice showed alteration in the intestinal sweet
signaling protein, T1R3, which led to increased consumption of nutritive
sweet solutions

20. METABOLISM AND APPETITE REGULATION
• Gut bacteria produce neuroactive metabolites, including serotonin and γ-
aminobutyric acid (GABA), which affect the central control of appetite
• Serotonin mediates its appetite-suppressant effects by modulating
melanocortin neurons
• GABA, the main inhibitory neurotransmitter in the CNS stimulates
feeding, and its synaptic release by agouti-related protein-expressing
neurons in the ARC is required for normal regulation of energy balance

21. METABOLISM AND APPETITE REGULATION
Pathways related to mood, reward, and feeding
• Some bacterial species interact with host metabolism through stimulation of
systems outside of the GI tract such as the endocannabinoid system, which
affects gut barrier function, host metabolism, & homoeostatic and hedonic
control of appetite and food intake
• Increased propionate reduces anticipatory reward responses to high-energy
foods
• Gut microbiota affects mood and behavior via:
 Vagal nerve stimulation
 Immune activation
 Production of microbial metabolites

22. METABOLISM AND APPETITE REGULATION
• Increases in psychological stress activate the hedonic signaling pathway,
stimulating intake of calorie-dense (comfort) foods
• FMT from either anxious or obese mice, or patients with depression, produces
an anxious phenotype in the recipient rodent
• Modification of the gut microbiota via prebiotic administration has anxiolytic-like
and antidepressant-like effects
• Gut microbiota might affect mood and ultimately affect brain circuits linked to
feeding behaviors

23. DIET AS MODIFIABLE FACTOR OF MICROBIOTA IN
OBESITY
• Changes in diet could explain 57% of structural variations in total gut
microbiota
• Western diets, especially low dietary fiber, have possibly reduced the diversity
of microbiota over generations
• Populations with traditional diets that are high in fiber and low in sugar and fat,
will have increased microbiota diversity
• Diet-induced obesity in mice following a high fat and high sugar western-style
diet was associated with an increase in some Firmicutes (caused by their
competitive advantage in processing simple sugars) and a substantially lower

24. DIET AS MODIFIABLE FACTOR OF MICROBIOTA IN
OBESITY
• The composition of the microbiota changes substantially with age(less diverse)
• The microbiome contributes to accelerated post-dieting weight regain
• Since diet is a key determinant in short-term and long-term composition,
diversity, dynamics of the intestinal microbiota, and subsequent microbiota-
driven host metabolic functioning, interest is in designing diets that enhance the
growth of specific beneficial anti-obesity gut microbiota

25. DIET AS MODIFIABLE FACTOR OF MICROBIOTA IN
OBESITY
• High-fiber diets are associated with different positive metabolic effects
and a diverse, healthy microbiota
• Dietary fat might also indirectly modulate the gut microbiota through bile
acid secretion and composition
• Bile acids have selective antimicrobial activity and could therefore
mediate the fat-induced effects on the gut microbiota

26. DIET AS MODIFIABLE FACTOR OF MICROBIOTA IN
OBESITY
• 90–95% of polyphenols accumulate in the large intestine and act as
energy substrates for some beneficial bacteria while inhibiting the growth
of pathogenic bacteria
• Proteins are the major source of nitrogen, which is essential for
fermentation of carbohydrates and production of beneficial products
such as SCFAs
• Although a high-protein diet seems to lead to weight loss, it can also
cause detrimental health effects, such as increased risk of colonic

28. THERAPEUTIC STRATEGIES
Probiotics
• Live microorganisms that, when administrated in adequate amounts, confer
beneficial health effects on the host
• Different bacterial strains have shown beneficial anti-obesity effects
• Akkermansia muciniphila has the capability to reverse high-fat diet-induced
metabolic effects such as fat-mass gain, metabolic endotoxaemia, adipose
tissue inflammation, and insulin resistance
• Beneficial bacteria interact with different components of the diet, mainly
insoluble fibre, releasing bioactive metabolites that signal to the host via the
gut–brain axis

29. THERAPEUTIC STRATEGIES
Prebiotics
• Prebiotics are non-digestible compounds that modulate composition, activity, or
both, of the gut microbiota:
 oligosaccharides
 fructo-oligosaccharides
 galacto-oligosaccharides
 polyphenols
• Fiber rich diets increases the abundance of beneficial bacteria in the gut
(Bifidobacterium &Lactobacillus spp) causing anti-obesity effects, including
reduction of endotoxaemia and enhanced intestinal barrier function and
decreased circulating pro-inflammatory cytokines

30. THERAPEUTIC STRATEGIES
FMT
• FMT from healthy donors into the patient’s intestinal tract (colonoscopy or
duodenal endoscopy) results in the restoration of normal gut microbial
community
• Donor microbial strains in human beings can colonize the recipient gut
microbiota and persist for at least 3 months
• Donor–recipient compatibilities are important for success (a greater chance of
prospering if the species were already present in the recipient)
• FMT has successfully been used to treat Clostridium difficile infections (>90%
efficacy)

31. NEGATIVE MODULATORS OF GUT
MICROBIOTA

32. NEGATIVE MODULATORS OF GUT
MICROBIOTA

33. NEGATIVE MODULATORS OF GUT
MICROBIOTA

34. NEGATIVE MODULATORS OF GUT
MICROBIOTA

35. CONCLUSION
• Host–microbe interactions are key for optimal health
• Commensal bacteria exert many structural and protective effects on
intestinal mucosa, but also affect host metabolism
• Evidence highlights the central role of the gut microbiota in the gut–brain
axis and its implication on central appetite modulation
• The association between the composition of the intestinal microbiota and
metabolic dysfunction or obesity has been extensively reported

36. CONCLUSION
Modulation of the gut microbiota might be a potential therapeutic target for
the treatment of obesity and other metabolic diseases
Strategies include:
• The use of prebiotics and probiotics (most commonly used)
• The use of polyphenols
• Bariatric surgery
• FMT

37. THANK YOU