Postbiotic Metabolites: How Probiotics Regulate Health

The purpose of this article is to present the latest information on postbiotic metabolites, which are compounds that are produced by bacteria as they digest fiber-rich foods in the intestinal tract. Gradually over the past two decades, scientific studies have been gradually unraveling the mystery of how probiotic bacteria influence human health. We are learning that different types of postbiotic metabolites regulate different aspects of human health. The emerging new ‘story’ in microbiome science is that postbiotic metabolites are increasingly being understood to be master health-regulating compounds for human health.

Historical Background

Probiotics are defined as live bacteria, which when administered in sufficient amounts, exert beneficial effects to the gastrointestinal tract. The previous century of microbiome science was largely devoted to identifying and naming different strains of bacteria and observing their appearance and characteristics as they were grown on petri dishes in microbiology laboratories. However, over 99% of the bacteria in the human intestinal tract are anaerobic, which means those bacteria die immediately when exposed to oxygen. Hence, during most of the 20th century, scientists were only able to study about 1% of the human microbiome (in this article, the term microbiome refers only to the bacteria that reside in the gastrointestinal tract).

A Revolution in Microbiome Science

The Human Genome Project was a 13-year (1990-2003), $3 billion-dollar project that resulted in the first successful sequencing of the human genome. One of the major goals of the Human Genome Project was to find cures for the chronic degenerative diseases that currently plague mankind. Unfortunately, that goal was a complete failure because to date, sequencing the human genome has not led to successful treatments for any diseases.

Although cures for diseases did not materialize, scientific advancements during the 1990s and the first two decades of the 21st century resulted in the development of vastly faster, more powerful gene sequencing technologies along with huge reductions in cost. The speed of these technological advancements is unprecedented in the history of science.

Here’s a summary of these remarkable achievements. The sequencing of the first human genome took 13 years and cost nearly $3 billion dollars. In January 2017, Illuminia, which is the world’s leading producer of next-generation sequencing (NGS) technology, announced that their new NovaSeq™ machine can sequence an entire human genome in less than one hour for $100.¹ How’s that for mindbogglingly fast scientific advancement? What originally took over a decade and cost billions of dollars can now be done is less than an hour for $100. These exponential increases in gene sequencing technology have ushered in a revolution in microbiome science.

The Human Microbiome Project

The amazing power and speed of the new gene sequencing technologies were partly responsible for the funding of the Human Microbiome Project (2007-2012).² Funding from The Human Microbiome Project has resulted in the publication of over 350 studies. This “flood” scientific publications on probiotics and microbiome science is viewed as the “birth” of the modern era of microbiome science.

The National Microbiome Initiative

In May 2016, the White House Office of Science and Technology (OSTP) committed to continue research into the vast new frontier in microbiome science by announcing funding for the National Microbiome Initiative. This program is sponsored with $121 million in funding from Federal agencies and an additional $400 million from non-government institutions.³

The Genome Complexity Conundrum

The successful sequencing of the human genome revealed that humans have about 23 000 genes. This number much smaller than the number of genes scientists expected to find in the human genome. This resulted in a perplexing puzzle that is called the Genome Complexity Conundrum.⁴

The puzzle was due to the fact that whereas humans have about 23,000 genes, the common rice plant (Oryza sativa) has about 45 000 genes. Experts were shocked when they realized that the common rice plant has nearly twice as many genes as humans. Scientists began scratching their heads and wondering, “If we humans are as complex and evolved as we think we are, how can it be that we only have half as many genes as the common rice plant”?

The solution to the Genome Complexity Conundrum began to emerge when studies began to reveal that the human intestinal microbiome consists of an estimated 100 trillion bacteria, and on average, humans harbor from 500-1000 different species of bacteria in their GI tract. These intestinal bacteria contain approximately 3.3 million non-repeating genes, compared to the 23 000 genes in the human genome. It is amazing to realize that over 99% of the DNA in your body is the DNA of your bacteria. This helps explain why humans only need 23 000 genes, because massive amount of DNA in the genes of your probiotic bacteria regulate a great deal of your biological activity.

In the past two decades, an increasing number of studies are revealing that probiotic bacteria utilize the information contained in their DNA produce a wide range of compounds that play key roles in directing and regulating many aspects of human health. These compounds are referred to as postbiotic metabolites.

The emerging understanding of postbiotic metabolites is redefining what it means to be human. It is not just our human genes that make us human. Instead, a human being is a symbiotic, bacteria-controlled Superorganism. We are not just “us”.…we are “us” plus “them.”

Postbiotic Metabolites: The New Frontier in Microbiome Science

For decades, we have known that probiotic bacteria play important roles in the regulation of health. However, until recently, the mechanisms that explain how probiotic bacteria regulate so many aspects of human health have remained elusive.

In the past several decades, scientists have been discovering that probiotic bacteria are amazingly complex little chemical manufacturing plants. The primary function of probiotic bacteria is to digest and ferment dietary fibers, which results in the production of a wide range of health-regulating compounds that known as “postbiotic metabolites.”

The terms “postbiotics”^5,6 and “postbiotic metabolites”⁷ are increasingly appearing in the title of scientific studies. In The Mind-Gut Connection, author Emeran Mayer, MD states that our bacteria utilize the information in their millions of genes to transform the food into “hundreds of thousands of metabolites.”⁸ This is the vast new frontier in microbiome science.

Microbiome diversity

Microbiome diversity is a critical factor related to overall health. Microbiome diversity refers to the number of different strains of bacteria present in the intestinal tract. Numerous studies report that a more diverse microbiome equates to better health.^9,10 A more diverse microbiome promotes better health because different strains probiotic bacteria produce different kinds of postbiotic metabolites. In all types of ecosystems, such as lakes, forests, grasslands and the human microbiome, greater diversity equals greater balance, strength and resilience.¹¹

The FIBER GAP: America’s #1 Nutritional Deficiency

Fiber is the required food for probiotic bacteria. Dietary fibers contain carbohydrates that our human digestive system cannot metabolize. Hence, these dietary fibers pass through the small intestines unchanged. However, when they arrive in the large intestines, fibers become the primary “food” for probiotic bacteria. Anaerobic probiotic bacteria that reside in the large intestines produce specialized enzymes which enable them to breakdown plant-based fibers, resulting in the production of postbiotic metabolites.

A book titled The Good Gut¹² provides a much deeper discussion of how important dietary fiber is to the maintenance of a diverse microbiome. The book’s author Justin Sonnenburg suggests that “dietary fiber” is an imprecise term and he proposes using the term, “microbiota accessible carbohydrates” or MACs. Thus, a “BIG MAC diet” is a diet that contains fruits, vegetables, legumes and unrefined whole grains, which are rich in the fibers required by various strains of probiotic bacteria.

An article titled The Fiber Gap and the Disappearing Gut Microbiome: Implications for Human Nutrition discusses how low fiber diets are affecting people’s microbiome and ultimately, their health. The authors report that an alarming 90% of children and adults in America DO NOT consume the recommended amount of daily dietary fiber.¹³ Scientific studies provide solid evidence that the microbiome is the very foundation of health.^14,15 It is becoming alarmingly clear that the Standard American Diet, known as the SAD diet, is more than just SAD, it is killing people.¹⁶ Most Americans lack both quantity and diversity of dietary fiber.

The quantity of fiber in the American diet is not the only fiber issue. A wide diversity of fiber-rich foods is required to promote the growth of a diverse microbiome. How many different types of multi-colored, fiber-rich foods are you feeding your probiotic bacteria today?

Many people take probiotics. However, since most Americans are not consuming fiber-rich diets, it is likely that many people don’t get much benefit from the probiotics they are taking.

For an easy way to increase the diversity of fiber-rich foods in your daily diet, I suggest you watch my 8-minute YouTube video which teaches people how to save an enormous amount of time making salads that contain a wide variety of fiber-rich vegetables. Just Google: Ross Salad Buzz.

Microbiome Balance

In addition to diversity, microbiome balance is also a critical factor that influences microbiome health. People who purchase probiotics frequently have the mistaken belief that more is better. It is now common to see products claiming to be superior because they contain 50 billion bacteria or even 100 billion bacteria per dose. The fact is, massive doses of just one or several strains of probiotic bacteria does not promote microbiome balance, they actually work against balance. Probiotics that deliver very high doses of just one or several strains of bacteria can cause the immune system to trigger an alarm reaction. The authors of one study made the following statement in their conclusion, “Probiotics can be ineffective or even detrimental if not used at the optimal dosage for the appropriate purposes.”¹⁷

Balance and greater diversity are imperative because these factors result in the production of a broader range of postbiotic metabolites. Some of the benefits of various types of postbiotic metabolites include reducing inflammation, regulating the acid/base balance in the GI tract, directly fighting pathogens, regulating digestion and absorption of nutrients, detoxification, regulating the immune system, gut-brain communication, and much much more. Remember, in The Mind-Gut Connection, Dr. Meyer stated that your bacteria would produce “hundreds of thousands of metabolites.” This is why postbiotic metabolites have become the new frontier in microbiome research.

A Healthy Microbiome: Two Pieces to the Puzzle

The ONLY way you can achieve a diverse microbiome is to consume a diverse range of fiber-containing foods. Dietary fiber is the food for your probiotic bacteria. Different strains of bacteria require different types of fiber, which results in the production of a diverse range of postbiotic metabolites. Thus, it takes more than probiotic bacteria to create and maintain a healthy microbiome. It takes bacteria + fiber. If you don’t learn how to feed your probiotic bacteria well, they will not thrive and survive.

An Analogy: Manufacturing vs Microbiome

The auto manufacturing industry produces vehicles such as cars, trucks, SUVs and vans. The workforce consists of many hundreds of employees with a wide variety of skills and talents. However, this workforce is largely ineffective if they don’t have on hand the thousands of parts that are required to produce different kinds of vehicles.

Similarly, the human microbiome contains between 500 to 1000 species totaling an estimated 100 trillion bacteria.¹⁸ The probiotic bacteria are like the skilled employees in a manufacturing plant, but your probiotic “workers” must have a wide variety fiber-rich food available (the parts) in order to create the desired end products, which are the postbiotic metabolites. Probiotic bacteria are primarily a “workforce,” and their “job” is to build or create postbiotic metabolites.

The Benefits of Bacterial Fermentation

Fermentation has been used for centuries as a method of preserving food.¹⁹ During fermentation, bacteria break down sugars, carbohydrates and fibers in foods and convert them into a class of postbiotic metabolites named short-chain fatty acids (SCFAs). These slightly acidic compounds suppress the growth of pathogens, which preserves the food. The same process takes place in the human gut. Bacteria ferment dietary fibers, which results in the production of weakly acidic compounds that suppress the growth of pathogens. Hence, probiotic bacteria regulate an important part of our immune system.²⁰

Studies in microbiome science continue to discover new kinds of postbiotic metabolites with varying health-regulating effects. In fact, human clinical trials have revealed strong associations between consumption of fermented foods and improved health for conditions such as obesity²¹, type 2 diabetes²², hyperlipidemia²³, hypertension²⁴, osteoporosis²⁵, and depression.²⁶ These studies emphasize that postbiotic metabolites in fermented foods or that are created when probiotic bacteria ferment dietary fibers in the an individual’s GI tract, have important health-regulating effects far beyond just gut health.

Seismic Shift in Microbiome Science

Much of the emphasis in microbiome science is shifting from Who Is There to What Is Done There.²⁷ Scientist continue to discover new postbiotic metabolites and the way these compounds function. Thus, we are learning that postbiotic metabolites are the mechanism(s) of action by which probiotic bacteria regulate a wide range of human functioning.

Metabolomics and Metagenomics

These two scientific disciplines, which are barely twenty years old, are developing very fast, in large part, due to the fundamental importance of the microbiome. Microbes rule the world. Metagenomics is unlocking the genetic secrets of our microbial planet. Metagenomics, which is defined as the genomic analysis of microorganisms, is elucidating which genes in bacteria are responsible for the production of various postbiotic metabolites.²⁸ Rapid advances in metabolomics have resulted in the discovery of thousands of bacteria-produced small-molecule metabolites, or postbiotics.²⁹

The number of postbiotic metabolites discovered to date is far too large to list in this article. However, examples of some of the better known postbiotic metabolites include the following:

• Essential nutrients: B-vitamins,³⁰ vitamin K,³¹ and aromatic amino acids.³²

• Short-chain fatty acids (SCFAs): acetic, propionic and butyric acid.³³

• Glutathione: synthesized by Lactobacillus fermentum ME3.³⁴

• Antimicrobial peptides (AMPs)³⁵ classified as bacteriocins and defensins³⁶

• Phenyllactic acid³⁷

• D-amino acids³⁸

• Hydrogen peroxide³⁹

• Volatile organic compounds (VOCs)⁴⁰

• Phytoestrogens: equol, enterolactone, enterodiol⁴¹ • Urolithin A and urolithin B^42,43

• Fulvic acids⁴⁴

Postbiotic Metabolites: Master Health-Regulating Compounds

The emerging understanding of postbiotic metabolites is ushering in a new frontier in microbiome science and an important new understanding of human health. An increasing number of scientific studies are explaining how postbiotic metabolites are compounds that are master regulators of human health. Postbiotic metabolites influence and regulate every organ system⁴⁵, including the brain⁴⁶ and the immune system⁴⁷.

Good vs Bad Postbiotic Metabolites

In this article I am only focusing on postbiotic metabolites produced by beneficial probiotic bacteria. However, pathological bacteria also produce postbiotic metabolites. The difference is that the postbiotic metabolites produced by probiotic bacteria have beneficial health-regulating effects, whereas the postbiotic metabolites produced pathological bacteria have toxic effects. That’s why certain strains of bacteria are pathological, it is their postbiotic metabolites that are toxic.

This is why it is so important for people to learn how to create and maintain a healthy microbiome. A healthy microbiome consists of predominantly beneficial probiotic bacteria. The postbiotic metabolites from strains of probiotic bacteria create a microbiome ecosystem that supports the growth and proliferation of probiotic bacteria and inhibits the growth of pathogens.

Ingesting Probiotics vs Postbiotics

Commercial probiotic products simply contain one or several strains of probiotic bacteria that are delivered in a capsule, tablet or in foods such as yogurt or kefir. However, in order to be effective, those bacteria must survive transit through the harsh acidic environment in the stomach. Then, when they arrive in the small intestines, they must locate fiber-rich foods and begin the process of digesting/fermenting those fibers into postbiotic metabolites. This process takes a substantial amount of time. And, remember, most Americans don’t consume nearly enough fiber-containing foods, which compromises the probiotic bacteria’s ability to produce postbiotic metabolites.

Directly Ingesting Postbiotic Metabolites

When people directly ingest postbiotic metabolites, those compounds immediately begin to exert their health-promoting effects when they arrive in the small intestines. Here are some of the better-known health effects of postbiotic metabolites:

• Anti-inflammatory activity⁴⁸

• Antimicrobial peptides kill pathogens; critical aspect of immune system⁴⁹

• SCFAs play important roles in regulating the immune system⁵⁰

• Weakly acidic compounds create the optimal intestinal acid/base balance⁵¹

• Hydrogen peroxide suppresses the growth of fungi and yeasts like candida⁵²

• Fulvic acids bind and transport minerals into cells.⁵³

• SCFA butyrate is the primary energy source for epithelial cell growth⁵⁴

• Glutathione (only produced by Lactobacillus fermentum ME-3) has powerful antioxidant, detoxification & immune system enhancing effects⁵⁵

• Phytoestrogens equol/enterolactone/enterodiol bind to estrogen receptors: lower menopausal symptoms & risks to many diseases⁵⁶

• Probiotic-produced nutrients (B-vitamins & amino acids): wide range of benefits associated with these nutrients⁵⁷

Dr. Ohhira’s Probiotics^®: Directly Delivering Postbiotic Metabolites

Dr. Ohhira’s Probiotics is a fermented food product that is produced utilizing a multi-year fermentation production process under strict cleanroom conditions. Dozens of different kinds of organically grown foods (vegetables, fruits, seaweeds and mushrooms) are shredded and added to large 80-gallon fermentation vats along with 12 strains of carefully selected synergistic strains of probiotic bacteria.

There are two versions of this fermented food probiotic. Dr. Ohhira’s Probiotics: Original Formula undergoes three years of fermentation and this product is sold at the retail level in fine health food and vitamin stores throughout the United States. Dr. Ohhira’s Probiotic: Professional Formula undergoes an additional two years of anaerobic fermentation, for a total of five years of fermentation. Over 99% of your microbiome consists of anaerobic bacteria that reside in your large intestines and colon. The additional two years of anaerobic fermentation results in the production of larger amounts of the postbiotic metabolites from the anaerobic bacteria. The Professional Formula is primarily marketed to healthcare professionals.

Recent research conducted by an independent laboratory in Japan reported that Dr. Ohhira’s Probiotics contain over 500 different postbiotic metabolites.⁵⁸ Each capsule contains live probiotic bacteria, some of the prebiotic foods used during the fermentation process, which continue to support the bacteria, and most importantly, a multitude of postbiotic metabolites.

This explains why Dr. Ohhira’s Probiotics has achieved such a favorable world-wide reputation. Directly ingesting postbiotic metabolites produces rapid improvements in dysbiosis-related intestinal symptoms such as gas, bloating, diarrhea and/or constipation, pain and inflammation. No other probiotic in the world is produced utilizing a multi-year fermentation process that enables the production of a multitude of postbiotics.

Rapid Microbiome Restoration: This is The Dr. Ohhira’s Difference.

Biography

Ross Pelton, RPh, PhD, CCN, is currently the Scientific Director for Essential Formulas, Inc, based in Dallas, TX. As a pharmacist, he is an expert on pharmaceutical drugs and their life-altering side effects. As a certified clinical nutritionist (CCN), he counsels clients on diet, nutrition and natural therapies for a wide range of health issues. As a health care professional, Ross helps clients and other healthcare professionals utilize and integrate natural therapies and life extension technologies into their lives and/or practices to achieve a healthier, longer life.