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Full Notes
Circadian Rhythm and Gut Microbiome
- Gut bacteria have their own circadian rhythms
- Timing of diet impacts composition and function of gut microbes
- Microbes change activity based on when we eat or don’t eat
- Disrupting microbial circadian activity can lead to obesity and type 2 diabetes
- Shift workers at higher risk due to disrupted wake-sleep patterns
- Time-restricted feeding can restore disrupted microbial behavior
- May not be practical for shift workers
Diet Composition and Gut Microbiome
- Diet composition is the most dominant factor impacting gut microbes
- Macronutrients can affect gut microbes in various ways:
- Serve as an energy source for microbes
- Influence bacterial communication within the gut ecosystem
- Affect host behavior and conditions, which in turn impact microbial composition and function
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Different diets around the world can lead to different gut microbiomes
- E.g., African diets with consistent complex carbohydrates vs. Western diets with more variety and processed foods
Stability of the Microbiome and Diet Changes
- E.g., African diets with consistent complex carbohydrates vs. Western diets with more variety and processed foods
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Microbiome stability depends on the resolution being observed
- In healthy adults with stable lifestyles, the microbiome appears very stable
- However, at a closer look, the microbiome is “stably unstable,” oscillating throughout a 24-hour cycle
- Environmental factors such as diet, location, health status, and medications can impact the microbiome
Vegetarian vs. Carnivore Diet Impact on Microbiome
- Abrupt changes in diet can cause reproducible changes in the microbiome composition
- However, even within the same diet, people react differently to dietary components
- Personalized nutrition approach takes into account unique responses to dietary components
Microbiome Diversity and Metabolic Responses to Food
- Loss of diversity in the microbiome has been linked to modern risks of developing diseases such as obesity, type 2 diabetes, fatty liver, and cancer
- Causal role of microbiome diversity reduction in disease development is still under investigation
Microbiome Changes Throughout Lifespan
- First three years of life are a critical window for shaping the adult configuration of the microbiome
- Factors such as breast milk, diet, antibiotic use, and environmental exposure to bacteria can influence the development of a child’s microbiome
- Overly sterile conditions may harm children by not allowing their microbiome to develop properly, increasing the risk of diseases such as asthma and obesity later in life
Mother’s Microbiome Affecting Child’s Microbiome
- The mother’s microbiome can indeed affect the child’s microbiome
- There is evidence suggesting that early life exposure to environmental factors, such as dirt and bacteria, can be protective against the development of asthma and autoimmune diseases later in life
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More research is needed to establish a causal link between the mother’s microbiome and the child’s health outcomes
Microbiome Acquisition in Neonates -
Children acquire their microbiome during the neonatal period from their immediate surroundings, mainly their parents
- A child’s microbiome is heavily influenced by their parents, especially their mother
Genes vs. Environment in Shaping Microbiome
- Study with 500 healthy individuals compared the influence of human genome and environment on microbiome composition and function
- Results:
- 1.9% of microbiome variability explained by differences in human genes
- 99% of microbiome variability explained by environmental factors
- Environment can be modulated, allowing for potential reversal of unhealthy microbiome configurations
Human Traits Affected by Microbiome
- Some human traits only impacted by human genes (e.g., height)
- Microbiome and human genes have independent and substantial effects on metabolic parameters (e.g., weight, waist-to-hip ratio, cholesterol levels)
Artificial Sweeteners and the Microbiome
- Study on mice found that exposure to saccharine led to disturbances in glycemic responses, driven by the microbiome
- Suggests that modern dietary compounds, previously thought to be inert, may impact the body indirectly through their effects on the microbiome
- Further research needed to determine if these findings are applicable to humans
Emulsifiers and the Microbiome
- Some studies on mice used levels of emulsifiers similar to those observed in humans
- Mice are not humans, but studies provide intelligent hypotheses that need to be tested in human studies
Personalized Responses to Artificial Sweeteners
- Preliminary small-scale study suggested personalized responses to saccharine in humans
- Larger controlled trials needed to determine potential personalized effects and how to predict them
Natural Non-Nutritive Sweeteners
- Stevia and monk fruit extract are popular natural non-nutritive sweeteners
- Research is ongoing to determine their effects on the microbiome and metabolism
Omega‑3 Fatty Acids and the Gut
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Effects of omega‑3 fatty acids on the gut microbiome are of interest, but not directly related to the discussed research
Omega‑3 and Gut Microbiome -
Omega‑3 has beneficial effects on the human body and gut microbiome
- Different people have different microbiomes, which can affect outcomes of omega‑3 consumption
- Individual reactions to food components, including fatty acids, vary due to host factors, lifestyle, and microbiome
Recurrent Obesity (Yo-yo Obesity)
- Affects up to 80% of obese individuals worldwide
- Pattern: weight gain, dieting, weight loss, and weight regain within 12 months
- Little understanding of the molecular mechanisms driving yo-yo obesity
Gut Microbiome and Obesity
- Study in mice showed gut microbiome remained disturbed after successful dieting
- Post-dieting microbiome stored a metabolic memory of past obesity, predisposing mice to exaggerated weight regain
- Microbiome drove weight regain by altering its ability to degrade dietary compounds called isoflavonoids
Flavonoids and Obesity
- Flavonoids like apigenin (found in parsley) and naringenin (found in grapefruit) are important
- Obesity causes a decrease in bacteria that degrade these flavonoids
- Resupplementing mice with missing metabolites helped avoid or treat exaggerated weight regain
Microbiome Transplantation and Obesity
- Replacing the “bad memory microbiome” with a healthier one through fecal microbiome transplantation helped reset mice to avoid yo-yo obesity
- Ongoing trial in humans to study the effects of metabolite supplementation and microbiome impact on recurrent obesity
Caloric Restriction and Gut Microbiome
- Caloric restriction may have beneficial effects on the microbiome and metabolism
- Periodic food restrictions (e.g., 16:8 diets) may have positive metabolic effects, potentially mediated by the microbiome
Microbiome Metabolome
- Gut microbiome acts as a biochemical factory, generating/modulating thousands of small molecules (metabolites)
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These metabolites can have unique chemistry and can impact distant cells and organs in the body
Microbial Secreted Molecules and Health Effects -
Microbial secreted molecules can impact health and disease processes in distant areas
- Example: gut microbes affecting the brain or joints
- About 50% of small molecules in peripheral blood may originate or be modulated by gut microbes
- Microbes can be considered a “neglected organ” with distant effects
Beneficial and Harmful Metabolites
- Beneficial metabolites: short-chain fatty acids (e.g., butyrate, propionate, acetate)
- Modulate the immune system, affect T regulatory cell activity/production
- Harmful metabolites: contribute to leaky gut/intestinal permeability
- Can play a role in cardiovascular disease risk
Leaky Gut and Disease
- Leaky gut: disruption of the gut barrier, allowing foreign molecules to enter the body
- Can contribute to heart disease, cancers, autoimmune disorders
- Gut barrier composed of:
- Lining epithelial cells with tightly regulated connections
- Mucus layer separating bacteria and food molecules from epithelial cells
- Barrier function can be influenced by food, microbial molecules, medications, and toxins
Environmental Factors and Leaky Gut
- Food composition can have individualized effects on gut permeability
- Example: celiac disease caused by immune reactivity to gliadin protein in genetically susceptible individuals
- Lack of certain dietary components (e.g., fermentable fiber) can also play a role
Prebiotics, Probiotics, and Postbiotics
- Prebiotics: dietary fibers aimed to make the microbiome healthier
- Probiotics: supplementation of exogenous microbes to impact the body favorably
- Postbiotics: supplementation of small bioactive molecules (metabolites) to bypass the microbial ecosystem
Probiotic Effectiveness and Individual Variability
- Probiotic effectiveness varies among individuals due to the indigenous microbiome
- In some cases, the indigenous microbiome is hostile and does not allow probiotics to colonize the gut
- In other cases, the indigenous microbiome is more welcoming, allowing probiotics to colonize and have significant impacts
- Colonization of exogenous probiotics is highly individualized and determined by the composition and function of the indigenous microbiome
Factors Regulating Probiotic Colonization
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Exact factors regulating probiotic colonization are not fully understood
- May involve the types of bacteria present and their interactions with each other
- Other factors may also play a role in determining available “residential space” for probiotics
Microbiome and Probiotics
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Microbiome interactions are complex and poorly understood
- Microbes can compete for space or food
- Some microbes secrete antimicrobial peptides (natural antibiotics) to inhibit others
- Some interactions are hostile, while others are supportive
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Disrupting the indigenous microbiome with antibiotics can allow probiotics to colonize the gut
- However, this can lead to a chronic disturbance in the gut microbiome composition
- Probiotics may aggressively colonize and prevent the indigenous microbiome from repopulating
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More research is needed to understand the function, personalized effect, and long-term influences of probiotics
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High doses of probiotics may have a transient therapeutic effect, but more evidence is needed to recommend them for specific conditions
Bacteriophages
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Bacteriophages are viruses that only infect bacteria
- They are common in nature and are in an arms race with bacteria
- Bacteria develop defense mechanisms against phages, such as CRISPR
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Bacteriophages could be used to target specific bacteria in the microbiome without harming the entire microbial community
- Phages are specific in their targets and can attack certain families of bacteria
- Using cocktails of phages can prevent bacteria from developing anti-phage defense systems
Targeted Bacterial Treatments and the Microbiome
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Clinical trials underway for targeted bacterial treatments
- Aim to target specific bacteria without damaging the entire microbiome
- Potential for combining bacteriophage cocktails with commensal bacteria
- Precision probiotics to replace harmful bacteria with beneficial ones
- Personalized medicine approach for future treatments
- Combining probiotics, phages, and dietary interventions
Timeline for Replacing Antibiotics
- Antibiotics have greatly improved human health and lifespan
- New precision treatments may not replace antibiotics, but complement them
- Microbiome field still in its infancy, but advances are being made
- Within the next decade, some interventions may mature for clinical use
Role of the Virome in Human Health
- Virome, fungal, and parasitome kingdoms within the microbiome are understudied
- These kingdoms may have significant impacts on human health and the microbiome
- More research needed to understand their roles and interactions
TMAO and the Microbiome
- TMAO is a compound associated with atherosclerosis and heart disease
- Produced from precursors like L‑carnitine and choline found in red meat and eggs
- Microbiome plays a role in the production of TMAO
- Combination of risk factors, not just one, contribute to atherosclerosis
Lifestyle Modifications for Gut Health
- Healthy sleep patterns have profound effects on the microbiome
- Consuming fibers generally beneficial for gut health
- Not all fibers are created equal; some may be better than others
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Personalized nutrition and precision medicine approaches needed for optimal health
Effects of Smoking on the Microbiome -
Smoking is universally bad for many reasons
- Cigarette-related chemicals reach systemic circulation, penetrate the gut, and impact the microbiome
- Disturbed microbiome composition and function can increase the risk of developing obesity after attempting to quit smoking
Personalized Nutrition Project
- Started in 2012 by Eran Elinav and Eran Segal
- Analyzed data from 1,000 individuals in Israel
- Collected microbiome and host-related data, including continuous glucose measurements
- Used machine learning and AI technologies to generate predictive algorithms for each individual
- Able to accurately predict a person’s sugar responses to any given food
- Tested in different contexts, including a long-term randomized human trial
- Showed that personalized, science-driven approach outperformed the one-size-fits-all diet in a large group of prediabetic individuals
Day Two
- Spinoff company that licensed the technology from the Weitzman Institute of Science
- Performed over 100,000 tests on 100,000 people
- Allows individuals to provide a stool sample and some clinical parameters to receive accurate predictions of their glycemic responses to food
- Recommendations are specific to each person
Continuous Glucose Monitors
- Can provide valuable information on how the body responds to different foods
- Can help individuals tweak their diet to reduce sugar responses after meals
- Some scientists and physicians are against continuous glucose monitors, claiming they may discourage people from eating healthy foods that elevate blood glucose levels
- Elinav believes in the benefits of measurement and using science and technology to improve daily lives
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