Table of Contents

• Key Takeaways

• Gut Biology Key Terms

• Key Concepts

• Early Evidence of link between obesity and microbiome

• How does the microbiome cause or prevent obesity

  • Altered immune function

  • Altered adipose tissue biology

    • Healthy
    • Obese

  • Altered breakdown and absorption of nutrients

    • Stong potential cause of preferential storage: Leaky gut

  • Diet Increases Inflammation, Inflammation Drives Obesity

  • White fat vs Brown fat

    • Microbiom contributes to brown fat

  • Bacteria contribute to macro breakdown and absorption

  • Bacteria associated with obesity and leanness

• Summary

• Akkermansia muciniphilia

Key Takeaways

• Understand that obese and lean humans (and mice) have very unique microbiomes
• Remember the important “B to F” ratio
• Understand that adoptive transfer of the microbiome from an obese individual can drive obesity
• Explain, at a high level, the difference of immune infiltrates in fat from lean versus obese individuals
• Explain, at a high level, how leaky gut can drive obesity
• Understand the difference between white fat and brown fat
• Explain, at a high level, how the microbiome drives the activation of brown fat
• Understand conceptually how the microbiome can modify the breakdown and uptake of macronutrients
• Explain how Akkermansia may be a next generation probiotic for treatment of obesity

Gut Biology Key Terms

• Firmicutes/Bacteroidetes ratio
• Th1, Th2, Treg and CD8 T cells
• M1 and M2 macrophages
• Leaky gut
• LPS
• White fat
• Brown fat
• Mitochondria
• UCP1
• Akkermansia muciniphilia

Key Concepts

• The microbiome contributes to obesity through a number of different mechanisms Thinking of gaining/losing as just cals in vs cals out – massively simplifies everything

  The microbiome makes things much more complicated. Do types of calories matter? they do.. hormones

• Modulation of the microbiome is still an unproven method to treat obesity

• However, there are still steps we can take to alter the microbiome in an energetically favorable manner

Early Evidence of link between obesity and microbiome

Germ free mice accumulate significantly less body fat.. germ free mice have under developed guts though.

leptine - hormone that’s connected to weight gain.

studies have taking the gene out of a mouse and that mouse is much leaner compared to a mouse that has both copies of leptin. Firmicutes and Bacteroidetes ratio is out of wack. Firm. super high and Bact. much lower

More diversity in your microbiome, the healthier you are. and less obese. Western diet drives down the diversity of our microbiome

Twin studies of one being obese and the other not. The microbiome was much different. The microbiomes of each twin was put in germ free mice. The obese twins microbiome caused the mice to also become obese.

The microbiome itself can drive obesity

The lean microbiome is dominant over the obese one – atleast in mice

How does the microbiome cause or prevent obesity

Altered immune function

• The more proinflammatory the microbes, the more metabolic issues

igA has the ability to shape the microbiome. Can create Clostridia which can block the absorption of lipids

Altered adipose tissue biology

• A healthy microbiome activates brown fat to burn more energy

Healthy

The immune system is tightly linked to adipose tissue. You can tell what someone’s immmune system is like if you take a biopsy of their fat cells

large number of Tregs and Th2 T cells. Tregs are extremely anti-inflammatory. Leads to the generation of M2 macrophages Causes good lipase activity which causes fats to be used for energy.

Obese

In the case of obesity..

Presence of M1 macrophages which produce pro-inflammatory cytokines. convey insulin resitence to cells around them. much less likely to use the energy in your body and hold onto the adipose tissue you have. preferential storage of fat vs the release of it.

Altered breakdown and absorption of nutrients

• Certain bacteria are better/worse at the breakdown of specific macros, while others alter macronutrient uptake

Stong potential cause of preferential storage: Leaky gut

• Outgrowth of more proinflammatory bacteria in your small and large intestine. Have the ability to get in close to the epithelium and through the membrane.

  LPS now leaking into the body and trigger proinflammatory signals. Lipopolysaccharide, expressed by bacteria, is a powerful inflammatory factor that triggers obesity, insulin resistance, and diabetes

  Rich in dietary fiber and resistent starch -> diverse microbiome. Creates [Short Chain Fatty Acids], specifically acetate which activates GPR43 (Good white fat)

  Proinflammatory (high fat) diets increases LPS which triggers M1 Macrophages recuitment and drives up inflamation

  Cold exposure can impact brown fat

Diet Increases Inflammation, Inflammation Drives Obesity

Microbiome is connected to leaky gut!

• A 4-week high-fat diet chronically increased the proportion of an LPS

• containing microbiota as well as the plasma LPS concentration in mice by two to threefold

• This activates the innate immune system which leads to liver insulin resistance and heightened inflammatory markers within the adipose tissue

White fat vs Brown fat

• White fat stores energy as triglycerides, whereas brown fat burns extra calories to create heat.
• There are also beige adipocytes, which are an inducible form of brown adipocytes that are generated in response to various stimuli such as cold temperatures

Microbiom contributes to brown fat

• Antibiotic treated and Germ Free mice had DECREASED thermogenic activity of brown fat
  • Decreased expression of the key protein UCP1 Diverse microbiome somehow helps the function of the thermogenic activity
• Giving the mice butyrate restored the full capacity of brown fat butyrate drives the function of ucp1

Bacteria contribute to macro breakdown and absorption

• Colonization with a single bacteria species, B. thetaiotaomicron, produces a massive increase in total body fat content

  • This bacteria has an extraordinary capacity for acquiring and degrading plant polysaccharides

    Bacteria plays a much bigger role in accessing complex carbs than we thought

• High fat diets drive the expansion of Clostridiaceae bacteria
  • This bacteria upregulates lipid transport genes in the gastrointestinal tract

more lipids throughout the body

• Many additional examples exist

Bacteria associated with obesity and leanness

• Most studies indicate that the Bacteroidetes/Firmicutes ratio is critical

  • Want More B’s and Less F’s

• Akkermansia muciniphilia is inversely correlated with obesity related metabolic disturbances

  • Treatment of mice with this strain reduced insulin resistance, glucose dysregulation, steatosis and gut permeability issues
  • Even a purified protein from this bacteria induced this effect
  • Humans supplemented with the bacteria had reduced body weight, fat mass, liver dysfunction and inflammation

Summary

Healthy Microbiome creates a large number of downstream products.

SCFA, SFB -> anti inflamitory immune system Low inflamitory state allows for healthy fat tissue

Obesity starts from

1. Intestinal dysbiosis Diet, drugs, immune system can all play a factor in this

2. Intestinal barrier dysfunction translocation of bacteria into the blood stream -> liver and adipose tissue

   which drives metabolic activation (inflamation) ->

3. Metabolic dysregulation strong proinflammatory molecules which lead to M1 macrophages

   -> Atherosclerosis

Reduce the signal. Starts in the gut.

Akkermansia muciniphilia