#283 ‒ Gut health & the microbiome: improving and maintaining the microbiome, probiotics, prebiotics, innovative treatments, and more | Colleen Cutcliffe, Ph.D.
Colleen Cutcliffe, CEO & co-founder of Pendulum Therapeutics, discusses the microbiome's role in health, how it's measured, and its impact on metabolic well-being. She covers the importance of fiber, probiotics, and mitigating antibiotic damage to foster a healthy gut.
Deep Dive Analysis
17 Topic Outline
Colleen Cutcliffe's Scientific Background and Pendulum Therapeutics
Defining the Microbiome and its Early Colonization
Characteristics of Bacteria and Their Rapid Evolution
Methods for Measuring and Understanding the Microbiome
The Role of Fiber and Butyrate in Gut Health
Fecal Microbiota Transplant (FMT) for C. diff Infections
Microbiome's Influence on Obesity and the Gut-Brain Connection
Factors Affecting Microbiome Diversity and Function
Vaginal Microbiome and its Health Implications
Common Probiotic Strains and Manufacturing Challenges
Probiotics, Prebiotics, Postbiotics, and Symbiotics Defined
Mitigating Antibiotic Effects on the Microbiome
Impact of Artificial Sweeteners on the Gut Microbiome
Akkermansia Mucinophila: A Keystone Strain for Metabolic Health
Pendulum Therapeutics' Clinical Trial and Product Development
Mechanisms of Akkermansia in Glucose Control and Satiety
Pendulum's Product Line and Future Research Directions
10 Key Concepts
Microbiome
The microbiome refers to all the microbes, including bacteria, viruses, fungi, and yeast, that reside in and on our bodies. These organisms are a significant part of our body mass and functions, particularly in the gut, where they play a crucial role in metabolism and overall health.
Prokaryotes vs. Eukaryotes
Our human cells (eukaryotes) need other cells and organs to survive, whereas bacterial cells (prokaryotes) are self-sufficient living organisms that can replicate and perform functions independently. Bacterial cells divide very rapidly, sometimes as quickly as every 10-15 minutes, allowing for quick evolution.
Short-Chain Fatty Acids (SCFAs)
These are important small molecules, such as butyrate, propionate, and acetate, produced by gut microbes when they metabolize fibers. Butyrate, in particular, is a crucial energy source for colon cells and plays a role in gut health and metabolic regulation by triggering GLP-1 release.
Strict Anaerobes
These are bacteria that cannot grow or survive in the presence of oxygen, as even a single molecule of oxygen can kill them. Many beneficial gut microbes, like Akkermansia, are strict anaerobes, posing significant challenges for their manufacturing and preservation.
Probiotic
A probiotic is the living organism itself, typically bacterial or yeast strains, that are consumed for health benefits. Examples include the lactobacillus and bifidobacterium strains commonly found in yogurts and supplements.
Prebiotic
A prebiotic is the food that feeds beneficial microorganisms in the gut. Fibers, inulin, and polyphenols are primary prebiotics that gut strains metabolize to produce beneficial compounds like short-chain fatty acids.
Postbiotic
A postbiotic refers to the beneficial molecules or substances produced and secreted by probiotics as a result of their metabolic activity. Butyrate, for example, is a key postbiotic.
Colony Forming Units (CFU)
CFU is a metric used to quantify viable bacterial cells in a probiotic product by counting how many colonies grow on a Petri dish. However, it only measures cells capable of forming colonies and does not account for dead or non-colony-forming cells, which can still have functional roles.
Active Fraction Units (AFU)
AFU is a more accurate metric for probiotic products, determined using flow cytometry, which measures live, dead, and in-between cells based on membrane integrity. This provides a more comprehensive understanding of the total viable and functional components within a product.
Depleted Microbiome
A depleted microbiome refers to a state where there is a loss of specific beneficial bacterial strains and their associated functions. This can be caused by aging, intense stress, circadian rhythm disruption, or antibiotic use, and is linked to various health issues.
11 Questions Answered
The primary initial seeding of the microbiome occurs during vaginal birth through the consumption of fecal matter. Diversity is minimal in infants, grows significantly as one starts eating solid foods and gains environmental exposure, peaks around the teenage years, and then starts to decline with aging.
Unlike human cells which depend on the entire body system, each bacterial cell is an independent living organism capable of replication and function. They also divide extremely rapidly, allowing for very quick evolution in response to their environment.
The Human Microbiome Project was a large-scale observational study that surveyed the microbiomes of over 10,000 people across different ages and demographics, demonstrating the vast person-to-person differences at the strain level, though functional redundancies were observed.
Gut bacteria, particularly in the distal colon, metabolize insoluble fibers into short-chain fatty acids (SCFAs) like butyrate, propionate, and acetate. Butyrate is vital for colon cell energy and stimulates GLP-1 secretion, impacting metabolic health and satiety.
An FMT involves transplanting feces from one person into another to re-establish a healthy gut ecosystem. It has an incredible success rate of about 99% for treating severe Clostridium difficile infections, which can be fatal.
The microbiome can influence food cravings and behavior through the gut-brain connection, by generating neurotransmitters (like serotonin, dopamine, GABA) and influencing GLP-1 secretion, which induces satiety and reduces cravings.
The two biggest modifiable factors are antibiotics and nutrition. Other factors include intense stress, disruption of circadian rhythms (e.g., from travel), and for women, menopause.
CFU (Colony Forming Units) measures only the live bacteria capable of forming colonies, often overlooking the majority of dead cells in a product. Flow cytometry provides a more accurate count of live, dead, and compromised cells, offering a complete picture of the product's contents.
While the antibiotic course is ongoing, it's suggested to 'double down' on probiotics, as some studies indicate this can lead to a healthier microbiome post-antibiotic. After the course, focusing on a high-fiber, high-polyphenol diet is crucial for reconstituting beneficial microbes.
Akkermansia mucinophila is a bacterial strain whose depletion is consistently associated with metabolic syndrome, obesity, and type 2 diabetes across various populations. It's considered a keystone strain because it plays a crucial role in regulating the mucin layer and stimulating GLP-1 secretion, which impacts glucose control and satiety.
Akkermansia stimulates GLP-1 secretion through multiple mechanisms: its surface protein AMUK1100 and secreted protein P9 bind to L-cells, and it produces propionate, which is converted to butyrate, further stimulating L-cells. GLP-1 helps the body secrete insulin, metabolize sugars, and induces satiety by slowing GI transit and reducing food cravings.
22 Actionable Insights
1. Acromantia for Glucose Control
For individuals with type 2 diabetes, a multi-strain probiotic formulation including Acromantia mucinophila has been shown to lower A1C by 0.6% and reduce blood glucose spikes by 34% over 90 days. This works by stimulating GLP-1 production and improving gut metabolism.
2. Optimize Post-Antibiotic Diet
Following antibiotic treatment, seize the opportunity to reset your gut microbiome by consuming a diet rich in high-fiber and high-polyphenol foods. Avoid high-fat, high-sugar foods to foster the growth of beneficial microbes.
3. Take Probiotics with Antibiotics
To support gut health during and after antibiotic treatment, consider taking probiotics. Research indicates this practice may help maintain a healthier microbiome by providing a “seeding” effect for beneficial strains, even if some are killed by the antibiotic.
4. Boost Butyrate for Colon Health
Increase butyrate production in your gut, as it is a crucial short-chain fatty acid that serves as the primary energy source for colon cells. Sufficient butyrate levels are linked to good GI health and may reduce the risk of colon cancer.
5. Consume Insoluble Fiber
Increase your intake of insoluble fiber from vegetables and fruits, as it acts as a crucial prebiotic, feeding gut bacteria that metabolize it into short-chain fatty acids like butyrate, essential for gut health.
6. Acromantia for Gut Lining
Ensure sufficient levels of Acromantia in your gut to support the regulation of the mucin layer, which is vital for maintaining a healthy gut lining and preventing conditions such as “leaky gut” and other gastrointestinal issues.
7. Reduce Sugar Cravings with Acromantia
To help manage sugar cravings, consider a probiotic supplement containing Acromantia, as pilot studies indicate it can lead to a significant reduction in food cravings, likely by influencing GLP-1 and satiety.
8. Harness Microbiome Mutability
Understand that your microbiome is highly mutable and can be changed through various factors, offering a significant opportunity to impact your health. Focus on modifiable factors to drive positive changes.
9. Evaluate Probiotics Beyond CFU
Do not solely rely on Colony Forming Units (CFUs) when choosing probiotics, as this metric only counts live, culturable cells and often overlooks the majority of dead cells and their functional contributions (postbiotics). Focus on products with demonstrated efficacy and transparent manufacturing.
10. Screen FMT Donors Carefully
Before undergoing a fecal microbiome transplant (FMT), confirm that the stool donor has been rigorously screened to avoid transmitting pathogens or potentially altering your metabolism negatively, such as inducing obesity.
11. Bank Autologous Stool Sample
To mitigate risks associated with donor stool for potential future needs, consider banking your own stool sample for an autologous fecal microbiome transplant. This could be a smart strategy for gut microbiome reconstitution after events like antibiotic courses.
12. Optimize Fiber Supplement Delivery
If using fiber supplements, choose enteric-coated capsules to ensure the fiber reaches the distal colon, where gut bacteria primarily metabolize it. This targeted delivery may enhance impact and allow for smaller effective doses.
13. Pair Probiotics with Inulin
To improve the colonization of specific probiotic strains in your gut, consider taking them alongside a small amount of prebiotic such as inulin. This provides immediate food for the strains upon capsule dissolution.
14. Maintain Vaginal Acidity
To support a healthy vaginal microbiome and protect against pathogens like yeast, focus on maintaining an acidic environment. This is achieved through the actions of beneficial bacteria like lactobacillus.
15. Diet Affects Vaginal Microbiome
Understand that the foods you consume can impact the composition of your vaginal microbiome. Consider dietary choices that support its health, such as cranberry juice for urinary tract health.
16. Protect Microbiome from Depletion
Be aware that aging, intense stress, and disrupted circadian rhythms (e.g., from travel) can deplete your microbiome’s diversity and function. Women should also note significant changes during menopause.
17. Understand Microbiome-Cravings Link
Recognize that your gut microbiome can influence your food cravings via the gut-brain connection, potentially altering your dietary preferences. This awareness can be a tool for managing eating behaviors.
18. Choose Precision Antibiotics
When possible, discuss with your physician the use of precision antibiotics rather than broad-spectrum options. Broad-spectrum antibiotics can severely deplete your gut microbiome, impacting overall health.
19. Refrigerate Probiotics Properly
Always refrigerate probiotics if the product specifies it, as this is crucial for maintaining the viability of the live bacterial strains. Improper storage can cause the bacteria to die, reducing product efficacy.
20. Keep Acromantia Dry
To preserve the viability of Acromantia probiotics, store them in a dry environment, utilizing desiccant packets if provided. Moisture can reactivate the dormant strains, leading to their death due to oxygen exposure.
21. Comprehensive Microbiome Analysis
For a thorough understanding of your microbiome, utilize shotgun sequencing for strain identification, quantitative PCR for abundance, and longitudinal studies to track changes and functional shifts. This approach provides a more complete picture than a single snapshot.
22. Monitor Microbiome Diversity with Age
Recognize that your gut microbiome’s diversity naturally decreases as you age, which can lead to a loss of key functions. This understanding can inform proactive health strategies.
6 Key Quotes
So much of the work that I've seen around the microbiome has been interesting, but it's been very difficult for me to understand how one could operationalize and make real causal effect from the science that is being presented.
Peter Attia
The microbiome is essentially all of the microbes. So the bacteria, the viruses, fungi, yeast that reside in and on us.
Colleen Cutcliffe
A good bacteria can become a bad bacteria in a certain situation. And likewise, bad bacteria can become beneficial in a different context.
Colleen Cutcliffe
The microbiome is incredibly mutable, and we're doing it all the time. And so when you think about the ability to change it and to have real health implications, that's where it's at. That's why it's an exciting field.
Colleen Cutcliffe
When you take an antibiotic, that's essentially almost like a nuclear bomb to your microbiome. It kills everything in there.
Colleen Cutcliffe
I mean, everybody is a marketing genius that's selling a probiotic. There are people who make you feel like what they're selling is super innovative. And you've never seen anything like this before. But when you really look at the ingredients, it's literally the same thing that everybody else has been selling.
Colleen Cutcliffe
2 Protocols
Mitigating Microbiome Damage from Antibiotics
Colleen Cutcliffe- Take probiotics during the antibiotic course to potentially seed the gut, even if some are killed.
- After the antibiotic course, focus on consuming a high-fiber, high-polyphenol diet to provide food for beneficial microbes and aid in reconstitution.
Manufacturing Strict Anaerobic Probiotics (e.g., Akkermansia)
Colleen Cutcliffe- Start with a heavily characterized freezer master stock of the bacterial strain to prevent genetic drift.
- Grow the strain in an entirely closed, anaerobic system, continuously pumping in specific mixes of gases (e.g., nitrogen) to keep all oxygen out.
- Operate in anaerobic chambers for small-scale cultures, using specialized glove systems.
- Transfer cultures through closed systems (e.g., bags) into larger vats for scale-up, maintaining anaerobic conditions.
- Harvest the cells (e.g., via slow centrifugation for sensitive strains) and remove the media.
- Freeze-dry the cell paste using lyophilizers, incorporating cryoprotectants to maximize cell viability during the harsh process.
- Store the freeze-dried powder in moisture-free conditions (e.g., with desiccant packets) to keep the bacteria dormant and stable at room temperature or refrigerated, depending on the strain's stability.