NM504 Technology

GI Microbiome Dysbiosis Associated with Impaired Glucose Regulation

Modern diets largely contribute to the pandemic of type 2 diabetes (T2D) and prediabetes.  The incidence rate of new cases is rising at such an alarming rate that an effort to intervene with a lifestyle-intervention program or the administration of metformin began in 2002 to determine if early intervention could prevent or delay the development of T2D (1).  Recently, this Diabetes Prevention Program (DPP) demonstrated that altering diet along with increased physical activity reduced the incidence of progressing to T2D by 34% in the 10 years following initiating the intervention (2).  Moreover, participants in the DPP who returned to normal glucose regulation just once had a significantly lower risk of developing T2D during the following years (3).

The GI microbiome present in type 2 diabetics (4) and prediabetics (5) is characterized by a less rich microbiome, a state known as dysbiosis. This dysbiosis is likely driven by contemporary diet choices and results in:

  • reduced nutrients for the GI microbiota population to feed on to produce short chain fatty acids (SCFAs), and
  • an overabundance of nutrients that stimulate blooms of gram-negative bacteria that contain endotoxin as a component of their cell wall, which cause inflammation and increased intestinal permeability, called leaky gut.
  • This dysbiosis in the microbiome is also associated with other functional changes, including increased methane metabolism, which is associated with weight gain and stimulation of hydrogen sulfide, also associated with leaky gut syndrome.

NM504, A GI Microbiome Modulator (GIMM) to Complement Lifestyle Intervention

 NM504 is specifically formulated for the nutritional management of the blood glucose response to a meal and is designed for individuals who may need additional support in controlling their glucose.  It delivers important nutrients to the GI microbiome in a manner to restore or augment gut action in those who have insufficient levels of nutrients, such as prebiotic fibers, in the lower intestine. It contains concentrated food-derived ingredients selected to expand and nurture the richness of the GI microbiome.  This GIMM was tested in two successful clinical trials (6,7).

Microbiome SCFA levels

Short chain fatty acids (SCFAs) are small molecules that are produced in large quantities in the lower GI by certain groups of bacteria which feed on complex carbohydrates.  Individuals with abnormal glucose responses to a meal are recommended to follow diets that are low in carbohydrates.  NM504 contains two active complex carbohydrate ingredients, ß-glucan and inulin.  These fibers are molecules linked together by bonds that cannot be digested.  Therefore, when consumed they travel through the GI track unabsorbed into the blood, until they become in contact with the microbiota.  Collectively, dietary fiber is a term used to describe these types of carbohydrates that are resistant to digestion.  These micronutrients are only metabolized in the lower GI by microbiota.  The byproducts of microbial fermentation do not contribute to calorie load, as do typical carbohydrates such as sucrose, fructose and starches (8).  These byproducts are not sugars or carbohydrates; they are SCFAs that signal secretion of certain peptides (9, 10). Some of these peptides signal satiety and also decrease gastric emptying and increase insulin release (11).

Leaky Gut

The physical barrier protecting cells of the intestines is the mucus.  Mucus is largely composed of sugar molecules that may also serve as nutrients for some of the microbiota. If low levels of carbohydrates are present in the biome, such as during fasting or when following a carbohydrate restricted diet, microbiota may feed on components of mucus reducing the protective GI barrier (12). NM504 contains inulin and ß-glucan, which are preferred food sources for those microbiota and thus serve to protect the mucosal barrier.

If the physical barrier is compromised, the GI track contains specialized immune systems to neutralize potentially harmful invaders.  The ability of the immune system to quickly recognize and respond to an invading pathogen is essential for controlling infection. Interestingly, fungi, oat and barley contain ß-glucan in their cell walls that are similar to the cell wall glycans of pathogens but only alert the immune system; they do not launch an immune response (13). Thus, the ß-glucan in NM504 primes or readies the GI immune system to defend if breaches in the mucosal barrier occur.

Oat β–glucans increase viscosity within the GI microbiome impairing the interaction of microbiota and toxins from engaging with the protective mucosal barrier of the intestines.

Methane and Hydrogen Sulfide in the Microbiome

A byproduct produced by many microbiota when they forage on nutrients is hydrogen.  In turn, there are three groups of microbiota that use this hydrogen to produce hydrogen sulfide, methane and acetate (14).  The microbiome of prediabetics and T2Ds has an increased ability to produce hydrogen sulfide and an increased ability to produce methane (4,5).  The methanogens that produce methane appear to favor fat absorption (15) and the sulfur reducing bacteria that produce hydrogen sulfide contribute to increased gut permeability and lower GI pathologies (14). Of these three groups, only the acetogens thrive on polyphenolic molecules like those found in blueberries and in NM504 (16).   The polyphenols of NM504 stimulate a bloom in acetogens that use hydrogen to produce acetate (one of the SCFAs) in the lower GI (17). These SCFAs serve to stimulate release of satiety hormones.  Since only the acetogens are capable of feeding on polyphenolic molecules, they have a selective advantage over the other two hydrogenotrophs.

Bile Acids

Bile acids (BAs) are released from the gall bladder into the small intestine when fat is ingested.  BAs are toxic to some microbiota in the GI microbiome and are toxic to intestinal cells. Conversion of bile acids to bile salts is performed by groups of microbiota in the GI microbiome, a mechanism that reduces this BA toxicity (18). The presence of bile salts in the intestine is a process that can improve insulin sensitivity (19) and improve glucose tolerance (20).  The quantity of bile salt present is sensed by the intestine and regulated so that the liver does not overproduce bile acids.  An overproduction of bile acids could lead to diarrhea (21).  β–glucans have been shown to interact with bile salts in the small intestine (22), interfering with the bile acid sensing mechanism and resulting in overproduction of bile salts in the small intestine.  This produces positive effects in glucose regulation.  At the same time, the β–glucan-bile salt binding neutralizes the action in the lower GI, preventing diarrhea.

Recommended Dietary Fiber Intake

 Dietary fiber is a term used to collectively describe all carbohydrates that are not digested in the human GI track.  Each serving of NM504 contains 5g soluble dietary fiber and 3.8g insoluble fiber (8.8g total dietary fiber). The American Dietetic Association (ADA) recommends 14g total dietary fiber per 1,000kcal consumed for children, adolescents, adults and elderly persons (23). The average daily caloric consumption for adults is 2,000 kcal, translating to 28g of recommended daily fiber. Soluble fiber, especially ß-glucan, has been sufficiently studied for the FDA to authorize a health claim that foods containing 0.75g to 1.7g per serving can reduce the risk of heart disease (24).

Insoluble fibers (like inulin) are linked to laxation. They increase the water content of stool. The greater the amount of added dietary fiber, the better defecation frequency is normalized to one bowel movement daily (25).

Although the health consequences of consuming sufficient quantities of dietary fiber are established by the ADA, recent discoveries of microbiome function will undoubtedly expand the nutritional biology of fibers in the near future.  Two servings of NM504 can help bridge the dietary gap between the typical fiber intake and that recommended by the ADA.

 

References

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  2. Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes study.  Lancet 374(9702):1677-1686.
  3. Perreault L, et al. Effect of regression from prediabetes to normal glucose regulation on long-term reduction in diabetes risk: results from the Diabetes Prevention Program Outcomes Study. 2012. Lancet 379(9833):2243-2251.
  4. Oin J, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. 2012. Nature 490: 55-60.
  5. Karlsson FH, Tremaroli V, Nookaew I, et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. 2013. Nature 498:99-103.
  6. Burton JH, et al. Addition of a gastrointestinal microbiome modulator to metformin improves metformin tolerance and fasting glucose levels.    J Diabetes Sci and Technol. 9(4):808-14.
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  17. Bain J, et al. Dissecting the in vivo metabolic potential of two human gut acetogens. 2010. J Biol Chem; 285: 22082-22090
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