
#283 ‒ Gut health & the microbiome: improving and maintaining the microbiome, probiotics, prebiotics, innovative treatments, and more | Colleen Cutcliffe, Ph.D.
The Peter Attia DriveSun Dec 17 2023
Gut Microbiome:
- The gut microbiome comprises bacteria, viruses, fungi, and yeast residing in the gut, playing a crucial role in human health.
- Initial seeding of the microbiome occurs during delivery through consumption of fecal matter in the vaginal canal.
Microbiome Diversity:
- Gut microbiome diversity peaks at a relatively young age, typically during teenage years, and decreases as individuals age, leading to a reduction in key functions within the microbiome.
Bacterial Functionality:
- Bacteria exhibit different functionalities based on their location within the body. For instance, bacteria in the mouth are exposed to oxygen while those in the distal colon exist strictly anaerobically.
- Strains living in different parts of the gastrointestinal tract have distinct metabolic activities and roles.
Characteristics of Bacteria:
- Bacteria can be classified based on their genomic makeup and functionality. DNA sequencing has enabled detailed examination of bacterial strains and their actions.
- Methylation, used for silencing certain genes, is a topic of interest when considering bacterial genomes' characteristics and post-modifications that may influence strain identity.
Viruses in Microbiome:
- Viruses also form part of the microbiome; however, their role and significance are not yet fully understood. They might play a role in accelerating gene transfer between bacteria.
Gut Microbiome and Evolution:
- Gut microbes constantly evolve in response to changes in the environment, particularly diet and antibiotic use.
- The microbiome optimizes for its environment, primarily influenced by the food received and the host's created environment.
Impact of Fiber on Gut Health:
- A high-fiber diet plays a crucial role in sustaining a thriving gut microbiome by promoting the production of butyrate, an important short-chain fatty acid.
- Butyrate has significant implications for gastrointestinal health and metabolic well-being as it triggers G-protein coupled receptors to release GLP-1 from L-cells.
Measurement Methods for Microbiome:
- DNA sequencing techniques like shotgun sequencing and quantitative PCR are used to understand microbial composition and function.
- Longitudinal data is essential due to the dynamic nature of the microbiome, rapidly changing in response to factors such as diet, travel, antibiotics, etc.
Fecal Microbiota Transplant (FMT) for C. Difficile Infection:
- FMT involves transferring feces from a healthy donor into a recipient's colon to restore a diverse microbial ecosystem, showing remarkable success rates when conventional antibiotic treatment fails.
- Initially considered unorthodox, FMT has shown incredible success rates in treating Clostridium difficile infections when conventional antibiotic treatment fails.
Role of Insoluble Fiber in Carbohydrate Metabolism:
- The gut microbiome metabolizes insoluble fiber found in vegetables and fruits into short-chain fatty acids like butyrate through carbohydrate metabolism.
- Strains such as clostridial strains, bifidobacterium strains, and Akkermansia muciniphila play pivotal roles in this process.
Fecal Microbiota Transplant (FMT) Safety and FDA:
- The cautious approach of the FDA towards fecal microbiota transplants reflects the early stage of understanding microbiome science and the need to ensure safety.
- Initially, FMTs were not approved by the FDA due to safety concerns, but patient advocacy led to a reversal of this decision.
Gut Microbes and Weight Regulation:
- The gut-brain connection can influence food cravings and behavior through neurotransmitter production, impacting metabolic health.
- Changes in an individual's microbiome may lead to altered food cravings, potentially contributing to weight gain or obesity.
Influence on Vaginal Microbiome:
- Factors such as diet, pregnancy, menopause, and hormonal fluctuations significantly influence the vaginal microbiome.
- Maintaining an acidic environment through certain bacteria like lactobacillus is essential for vaginal health and protection against infections.
Microbiome Depletion and Health Implications:
- Factors like aging, stress, disrupted circadian rhythms, and intense stress can lead to depletion of specific strains with vital functions in the gut microbiome.
- Low levels of beneficial strains like acromantia have been associated with various health issues ranging from obesity to immunological disorders.
Dietary Impact on Microbiome Composition:
- Geographic diversity may play a role in shaping different microbial compositions based on varied diets across cultures.
- Further research is needed to understand how stable an individual's microbiome composition remains regardless of dietary variations.
Gut Microbiome and Probiotics:
- Flow cytometry is crucial for accurately assessing probiotics in supplements, as the majority of them are often dead.
- The freeze-drying process involves growing lactobacillus and bifidobacterium strains in culturable media, harvesting them at a certain density, and then freeze-drying them into a powder form.
- Freeze drying results in a significant loss of cells (up to 90%), leading to the exploration of cryoprotectants that aid in preserving cell viability during this process.
Microbiome Impact of Antibiotics:
- Antibiotics have broad-spectrum effects on the microbiome, potentially altering its composition and diversity.
- Post-antibiotic treatment presents an opportunity to improve gut health by adopting a high-fiber diet as the microbiome adapts and reconstitutes itself over time.
Acromantia Cultivation:
- Acromantia, a strain within the gut microbiome, requires a strict anaerobic environment for cultivation due to its extreme sensitivity to oxygen.
- Companies developing next-generation strains for gut microbiome therapy have had to build their own manufacturing plants due to the need for an end-to-end closed system that excludes oxygen.
Challenges in Production:
- Growing acromantia necessitates a pure nitrogen environment and the pumping in of multiple other gases to maintain its viability as a product.
- The process involves operating small-scale cultures within an anaerobic chamber with careful handling using gloves, ensuring an entirely closed system while continuously excluding oxygen.
Stability and Viability:
- Freeze-dried acromantia remains stable at room temperature but must be kept away from moisture and oxygen. Desiccants are used to maintain stability during storage.
- After freeze-drying, acromantia can remain stable without requiring freezing or refrigeration until hydration occurs.
Rigorous Development Process:
- Pendulum Therapeutics heavily invested in research and development, raising $150 million for building a manufacturing plant and conducting preclinical and clinical work.
- A pivotal decision was made by the company to sell directly to consumers rather than through prescription-based channels based on the belief in democratizing access to naturally occurring strains for optimal health support.
Gut Microbiome and Probiotics:
- The study focused on the impact of probiotics, particularly a five-strain formulation including Acromantia and four strains for propionate conversion into butyrate.
- The trial showed a significant reduction in hemoglobin A1c levels by 0.6% compared to placebo over 90 days, indicating the potential metabolic benefits of the probiotic intervention.
- The efficacy of the five-strain formulation was higher than that of formulations without Acromantia, highlighting its significance in gut health improvement.
- Stool samples collected during the trial revealed that every participant experienced an increase in all strains post-intervention, demonstrating successful delivery of the probiotic formulation.
Challenges in Clinical Trials:
- Recruiting participants for clinical trials is challenging, as seen in this study where individuals had to undergo frequent blood draws and other invasive procedures.
- It took six years of basic science leading up to the trial, emphasizing the extensive time and effort required for rigorous scientific investigation.
- This particular trial was considered a do-or-die moment for the company, signifying the high stakes involved in such research endeavors.
Commercialization and Product Development:
- The company faced challenges with product pricing and logistics due to the need for cold shipping and storage, impacting accessibility for consumers.
- In response to customer feedback about pricing concerns, they introduced a lower-dose version at a more affordable price point ($49/month) while maintaining all five strains present in their original product.
- They also released single strains based on market demand, such as pure Acromantia, which became one of their best-selling products despite being challenging and expensive to manufacture.
Clinical Trial Data and Future Research:
- Predictive modeling based solely on microbiome composition or levels of specific bacteria was not sufficient to predict individual responses to the intervention.
- Post-trial washout period results indicated sustained increases in strain presence even after discontinuation of probiotic intake.
Gut Microbiome Intervention:
- Discussion about the impact of microbiome intervention on maintaining acromantia levels during the 90-day study period.
- Consideration of implementing diet logs to monitor fiber intake for a better understanding of dietary impact on gut health.
- The need for a more direct approach, such as providing high-fiber meals, to assess the benefits of added fiber.
Challenges in Study Design:
- Lack of diet logs in clinical trials due to potential inaccuracies from participants and the perceived unreliability of self-reported data.
- Emphasis on not wanting participants to undergo behavioral changes during the study but facing uncertainty regarding whether participants changed their diets.
Exploring New Avenues:
- Considering delivering high-fiber meals alongside the microbiome intervention to measure the impact of added fiber on gut health and its role in promoting microbial diversity.
- Discussing the potential of microbiome interventions in various health conditions like depression, ADHD, obesity, and type 2 diabetes.
Future Research and Development:
- Interest in exploring dose response and optimal dosages for colonization ratio in microbiome interventions that influence overall metabolic well-being.
- Exploring specific strains or species beyond acromantia that offer promise for investigation based on existing literature.