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How your gut microbiome affects your metabolic health

Expert answers, Gut microbiome health, Type 2 diabetes

 How your gut microbiome affects your metabolic health

The Role of a Healthy Gut Microbiome in Metabolic Health
The instant you take a bite of food, your body begins the work of turning it into energy. After you swallow, the food travels further and further down into the dark recesses of your digestive tract and into the home territory of the microorganisms that live in your gut.
 
Recently, scientists have discovered that these tiny creatures are vital players in turning your food into energy. So while a healthy, balanced diet and regular exercise are essential for maintaining health, these lifestyle choices explain only part of the story. Your body's metabolism is also regulated by the hidden players in the digestive tract—referred to collectively as the gut microbiome. 


This relationship means that damage caused to our microbiome by a typical low-fiber, high-additive Western diet can impair our metabolic health in several ways, including reduced immune function and excess inflammation. However, there’s good evidence that we can also take a proactive role in improving our metabolic fitness by improving our metabolic health through diet and targeted probiotics. 
 
 
Why the gut microbiome is so important
 
There are trillions of microorganisms that reside on and inside our bodies. Most of them have evolved to live in harmony with humans over thousands of years—so much so that some critical functions of our system are dependent on these microorganisms’ presence and activities (Lee and Mazmanian, 2010). Unlike infectious germs, these microorganisms are partners to human cells, providing mostly harmless and often useful functions. 


Laboratory mice raised to be completely free of any microorganisms, called germ-free, show impairment in various metabolic and immune functions, demonstrating that the microbiome is crucial in developing and maintaining normal physiology (Bäckhed et al., 2007; Round and Mazmanian, 2009)
 
Researchers generally believe that the gut microbiome, the richest and most diverse of all the human body niches, is first seeded at birth. However, some suggest that we encounter trace amounts of microbes inside the mother’s womb (Aagaard et al., 2014). Our delivery method at birth, our initial feedings, and our early hygiene can all dynamically shape our infant gut microbiome. 


Microbiota growth tends to stabilize in adulthood, yet the composition is continuously influenced by environmental factors such as medications (especially antibiotics), geography, and diet. Studies of populations unaffected by the Western lifestyle, notably those with diets high in fiber, show that long-term dietary patterns result in fundamental differences in gut microbiome composition (Jha et al., 2018; Smits et al., 2017; Vangay et al., 2018). Dietary intervention studies also show that even short-term changes in diets can rapidly change the microbial makeup (David et al., 2014).
 
Significant changes in the diversity, composition, and density of the microbiome within the gastrointestinal tract are associated with many diseases. That’s because the gut microbiome essentially functions as an additional internal organ. 


Naturally, scientists have been investigating ways to maintain or, when damage occurs, to revert to a “healthy” microbiome. There is no quick solution to this challenge, as the definition of a healthy microbiome varies widely based on location and population. In the context of metabolic diseases, we see distinct pattern differences in the microbiome of lean versus obese people, and in individuals with type 2 diabetes (Karlsson et al., 2013; Ley, 2010; Turnbaugh et al., 2009) 


Moreover, successful interventions show that we can modulate the microbiome for metabolic benefits. These interventions include fecal matter transplant (Kootte et al., 2017; Vrieze et al., 2012), administering probiotics (live microorganisms that perform specific functions (Hill et al., 2014)) and prebiotics (substances, mostly fiber-derived complex carbs, that feed the bacteria that confer a health benefit (Gibson et al., 2017)) (Perraudeau et al., 2020; Sun and Buys, 2016)


In other words, changing your gut microbiome can change your metabolic health.
 
 
 
How the gut microbiome affects metabolic health
 
How can the gut microbiome, which is physically separate from human cells, influence human physiology?


The microbes speak the same language as human cells, and communicate by producing metabolites, or products of metabolism, that cells can read. One example is short chain fatty acids (SCFA), produced by the bacterial fermentation of dietary fiber in the gut. SCFA come in many forms—acetate, propionate, and butyrate are the most common—and support metabolic and immune functions, among others. 


Different types of fiber and bacteria present in the gut determine the types and amounts of SCFA produced. People with obesity and diabetes seem to have fewer bacteria that produce butyrate, which suggests a link between the lack of butyrate and the pathologies behind these conditions (Karlsson et al., 2013; Larsen et al., 2010; Qin et al., 2012). Other examples include bacteria-transformed bile acids, amino acids, neurotransmitters, vitamins, and more.


Here are some of the metabolic process directly and indirectly regulated by these microbial metabolites:
 

  1.         Secreting gut-derived metabolic hormones.

 

Our gut harbors sensor hormones, called incretins, that detect incoming food and signal our body to absorb, metabolize, and store nutrients by aiding communication between the gut and organs such as the brain, pancreas, liver, and muscles. Glucagon-like peptide 1 (GLP-1) is an incretin that signals the release of insulin, the hormone that controls the uptake of glucose from the blood. While not as famous as insulin, GLP-1 is just as important in maintaining a healthy level of blood sugar. 


Within minutes after we eat food, specialized cells in the gut lining called L cells begin releasing GLP-1. It also slows the rate of food leaving the stomach (so you stay full longer), decreases appetite, and improves insulin sensitivity. 


In addition to those direct benefits, one study showed that GLP-1 also decreases inflammation in fat tissue, which improves the tissue’s metabolic function and insulin sensitivity (Lee et al., 2012). Not surprisingly, people with diabetes and obesity suffer from impaired GLP-1 signaling, just like they suffer from impaired insulin secretion and signaling. And this could be due to the altered gut microbiome.


The gut microbiome affects GLP-1 in multiple ways. The most well-studied mechanism is that certain bacterial metabolites directly stimulate GLP-1 secretion from L-cells. SCFA, for example, metabolites of fiber fermentation, is a group  that has been reproducibly shown in animals to increase GLP-1 as well as improve glucose metabolism (Ducastel et al., 2020; Psichas et al., 2015; Yadav et al., 2013). In humans, eating more dietary fiber promoted SCFA-producing bacteria and improved glucose control in people with diabetes, along with increased GLP-1 production (Zhao et al., 2018). In addition, one study suggests that bacterial fermentation of fiber increased GLP-1 by increasing the number of GLP-1 secreting L-cells(Cani et al., 2007a). The effect can also go the other way: Some bacteria impair GLP-1 receptors, leading to GLP-1 resistance (Grasset et al., 2017)


Bile acids are another example. Produced by the liver and released into the small intestine, they are processed by gut bacteria, and can also stimulate GLP-1 secretion from the L-cells (Pathak et al., 2018; Ullmer et al., 2013)


So changes in the gut microbiome that reduce SCFA-producing bacteria or bile acid-processing bacteria may have consequences in GLP-1 signaling, which can impact  our ability to process glucose efficiently.
 

  1.         Strengthening of the gut barrier integrity

 

Chronic inflammation underlies many metabolic disorders. One pathway to that inflammation is when elements in the gut leak out and enter our system—a condition termed metabolic endotoxemia (Cani et al., 2007b). What prevents that leaking is the so-called gut barrier, a multi-layer physical and functional system separating the gut from the rest of the body. 


The gut barrier is lined with a single, intact layer of epithelial cells (similar to cells that cover the surface of the body, such as the skin) that absorbs nutrients and protects from invading pathogens. A layer of mucus covers the inside of that gut epithelium; on the other side are immune cells tasked with surveillance against microbes that may attempt to escape from the gut and enter the body.

 
Studies in animal models show that the microbiome regulates different components of this gut barrier defense mechanism. 
The mucus is created by specialized goblet cells in the gut lining to coat and protect the epithelial cells from microbes and digestive enzymes. This viscous layer is also infused with a diverse array of antimicrobial agents and antibodies as additional protection. Without a gut microbiome, germ-free mice have a thinner mucosal layer and fewer antimicrobial agents—traits often associated with metabolic and immunological diseases (Hapfelmeier et al., 2010; Jakobsson et al., 2015; Johansson et al., 2015). Similarly, a fiber-deprived diet shifts the gut microbiome to consume rather than build up the mucus, resulting in a compromised gut barrier (Desai et al., 2016). On the other hand, probiotic supplementation and fiber-rich dietary interventions can restore a healthy mucus barrier (Everard et al., 2013; Long et al., 2018).


Covered and protected by the mucosa is the selectively permeable barrier made of epithelial cells. The cells are bound together by specialized tight junction proteins that allow only desired nutrients to pass through. In many inflammatory diseases, these tight junction proteins are reduced or not functional, allowing harmful microbes and toxins to enter. The gut microbiome also influences tight junctions, which can, at least in animals, be restored by probiotics and dietary fiber (Ashrafian et al., 2019; Matt et al., 2018; Shang et al., 2016)


A blood biomarker, Lipopolysaccharide (LPS), allows us to measure a dysfunctional gut barrier. Probiotics, dietary fiber, and other nutritional interventions have been shown to lower the level of blood LPS, as well as markers of inflammation, in people with obesity and diabetes (Kopf et al., 2018; Krumbeck et al., 2018; Morel et al., 2015; Ott et al., 2017).
 

  1.         Development of the gut immunity

 

Beyond the gut barrier, the gut microbiome can also shape the immune system to be more resilient to fight invaders while being less damaging to the body. 


Inflammation is a double-edged sword; it protects the body from infection and injury, but excessive inflammation can be damaging. Therefore a balance, or immune homeostasis, is crucial. Unfortunately, the modern lifestyle puts the body under constant stress, and the result is a chronic low-grade inflammation that underlies many diseases. 


However, the gut is home to the largest number of immune cells within the body, and the gut microbiome and its metabolites are known drivers of the immune repertoire. In addition to the antimicrobial function at the mucosal barrier, commensal bacteria help develop immune cells that fight pathogenic microbes (Ivanov et al., 2009; Mazmanian et al., 2005). Other bacteria directly increase regulatory T cells, an important immune cell type that suppresses inflammation and keeps the body from attacking itself (Furusawa et al., 2013).


Again, microbially produced SCFA are important players behind this mechanism (Arpaia et al., 2013), along with vitamin A-derived retinoic acids (Sun et al., 2007). When the gut microbiome is missing the SCFA-producing bacteria—as it may be in an obese person’s gut—the inflammation-suppressing immune cells also diminish. On the flip side, dietary and probiotic-mediated gut microbiome changes have been shown to blunt inflammation, presenting possible microbiome-based solutions for inflammatory diseases.
 
So even though scientists haven’t found a sure-fire way to achieve a “healthy microbiome,” all of this science backs the idea that we can modulate the microbiome to support metabolic health.

  
How we can improve metabolic health through changes to the microbiome

 
Diet shapes the gut microbiome. The modern Western diet is low on fiber and high in unnatural additives—this combination reduces or removes certain groups of microbes from the gut. When those conditions persist, the weakened gut microbiome damages our immune and metabolic functions in the ways shown above, which further harms the microbiome, creating a negative feedback loop. While we need more controlled human-intervention studies, research thus far suggests that some simple interventions can reduce damages in microbiome-regulated metabolic and immune functions:

  1. Changing to a microbiome-friendly diet

 

The benefits of fiber-rich food are well known—fiber slows your digestion so you stay fuller longer, and it promotes blood-sugar and cholesterol control. We have seen above that the gut microbiome has everything to do with these benefits. Fiber-rich food—such as fruits, fresh vegetables, nuts and whole grains—are particularly good at supporting the growth of beneficial gut microbes that regulate metabolic hormones and reduce inflammation. 
In addition, polyphenol-rich foods, including green tea and berries, appear to modulate the gut microbiome and increase beneficial groups of bacteria.
 

  1. Taking prebiotic supplements

 

Prebiotic supplements pack specific types of fiber known to feed selective groups of bacteria that confer health benefits. Taking prebiotic supplements is an excellent way to ensure you foster the growth of these bacteria. Inulin, which occurs naturally in high concentrations in chicory root and Jerusalem artichokes, is a fiber source which supports the desirable microbes and is available in multiple prebiotic supplements. 
 

  1. Taking probiotics to restore the “missing” microbes

 

If your gut microbiome has already suffered from a prolonged Western diet, just adding back fiber in the short-term will not be enough to completely restore beneficial bacteria (Healey et al., 2018; Sonnenburg et al., 2016). But you can aid the “healing” process by taking targeted, medical probiotics designed to confer specific health benefits (e.g., increase butyrate production upon ingestion of dietary fiber, stimulate mucin production). 


Not all probiotics are the same--many “traditional” probiotic strains, especially those including Lactobacilli and Bifidobacteria, have been shown to convey modest improvements in metabolic parameters, but the underlying mechanisms are largely unknown. While both may be beneficial, it is important to understand that you can maximize the benefit by understanding the needs of your very unique gut microbiome.  These needs have been identified in studies that have profiled the microbiome changes associated with various diseases, and may sometimes be echoed in personal microbiome testing results. In the years ahead, more and more products will be available to “adjust” the microbiome to support individual microbial health.

 

 

 

 

 


Pendulum Therapeutics, Inc. has authored this review article, with editorial assistance from Levels. Pendulum commercializes Pendulum Glucose Control (PGC) - the first probiotic designed and developed based on an understanding of underlying mechanisms, enabling desired clinical outcomes. PGC is the only clinically shown probiotic providing dietary management of elevated glucose through the microbiome. The product helps improve glucose metabolism by decreasing blood glucose spikes and A1C levels. PGC contains novel bacteria that help to produce butyrate, the naturally occurring metabolite that is key for maintaining insulin and glucose balance. PGC helps to break down fiber and produce beneficial molecules that energize cells in the colon - functionalities that are not found in typical probiotics. Additionally, PGC supports gut health by helping protect the intestinal lining and preventing harmful bacteria from causing gut inflammation. PGC is non-GMO project verified, vegan, dairy-free and gluten-free.


Results of Pendulum’s double-blinded, placebo controlled, randomized clinical study, in which PGC lowered blood glucose spikes by 33% and reduced A1C levels by 0.6 (on top of metformin), were published in the BMJ Open Diabetes Research and Care medical journal in July 2020 https://drc.bmj.com/content/8/1/e001319.info
PGC is available for purchase online at pendulumlife.com
 

About Pendulum Therapeutics:
Pendulum Therapeutics is the first and only evidence-based microbiome company to apply the discoveries of high-resolution, long-read DNA sequencing to the development and commercialization of microbiome interventions targeting specific diseases. Its flagship product, Pendulum Glucose Control (PGC) is the only clinically shown probiotic providing dietary management of elevated glucose through the microbiome for individuals with T2D taking metformin. Pendulum's proprietary innovation platform enables identification of microbiome mechanisms of action and rapid translation from discovery and development through human clinical validation. Founded in 2012 by a diverse team of scientists with deep microbiology, biochemistry, computational and clinical expertise, Pendulum’s investors include Sequoia Capital, Mayo Clinic, True Ventures, Khosla Ventures, AME Cloud Ventures and others. Formerly Whole Biome, Pendulum Therapeutics is headquartered in San Francisco.