Primer Write-Up

Primer™Microbiomic Superfuel™Bacteria need to eat, too. Pamper them. A well fed microbiome is a happy and healthy microbiome. Give them the gourmet shit. Primer is a generously portioned blend of 11 prebiotic dishes and desserts meticulously chosen to entice the good bacterial denizens and citizens of your gut to feed and breed, prodigiously, while starving and poisoning unwelcome pathogenic bacterial inhabitants. Grow your own, right at home.

Currently, probiotics are mostly thought of and used in relation to a healthy digestive system (reducing upset stomach, gas and bloating, diarrhea, and IBS type symptoms) and the immune system (coughs, colds, and general sinus and respiratory health). While they certainly are indeed useful for such applications, the ramifications of an unhealthy gut and microbiota go far, far beyond that.

The gut and its microbiome are essentially a massive endocrine organ, controlling and influencing basically your entire body and brain. And, given that all of the trillions of bacteria that call it home originally came from outside your body – and entered without your permission – it is by far the most important organ in which we can take steps to manipulate and take back control.

We will first look at some basic science and data on how this all works. Then, we will look at studies that have shown alterations in the microbiotic make-up of the gut, and the correlations they display in health and disease, suboptimal and optimal fitness, and just general things that everyone would consider part of good or bad life outcomes.

It is a massive subject, far too much to discuss in complete depth, here, so we’ll do our best to keep it as short and sweet as possible while still giving you enough background in this field to understand the shocking reality, scope, and importance of this microscopic invasion.

Subsequently, we will get down to business and specifically get into the science of Shock Treatment™, the first step in the process of making yourself king or queen of your own castle, again. We’ll show you how it can immediately ameliorate symptoms, while preparing the gut for a permanent fix, with special emphasis on a lean, healthy body.

Deus Vult!

The BasicsIt basically works like this. The Western lifestyle, including diet, lack of exercise, and alcohol use (and, in all likelihood, genetics, though the data just isn’t there, yet) leads to an imbalance of the bacterial composition of the gut (1,2). This results in the excess production and release of inflammatory signals,

such as Lipopolysaccharide, TNF-alpha, interleukins, and prostaglandins, which subsequently escape the gut and enter the rest of your body (3).

Though, they all contribute to the pathologies we will cover in various ways, it is Lipopolysaccharide (LPS) that we will focus on the most. Within the gut, this leads to the general digestive issues and inflammatory bowel syndromes like IBS and colitis that you have commonly known probiotics as being used to alleviate (4).

While fixing digestive disorders will come along for the ride, our primary focus is going to be on body composition and metabolic health. In other words, we want to make you leaner, protect against diabetes, and help keep you from having a heart attack or stroke. However, there really is so much more to it than that, as a few quotes from the literature aptly demonstrate:

“Changes in the composition of the gut microbiota (dysbiosis) may be associated with several clinical conditions, including obesity and metabolic diseases, autoimmune diseases and allergy, acute and chronic intestinal inflammation, irritable bowel syndrome (IBS)…” (5)

“In this milieu… disturbance of the gut microbiota balance and the intestinal barrier permeability is a potential triggering factor for systemic inflammation in the onset and progression of obesity, type 2 diabetes and metabolic syndrome.” (6)

“Through these varied mechanisms, gut microbes shape the architecture of sleep and stress reactivity of the hypothalamic-pituitary-adrenal axis. They influence memory, mood, and cognition and are clinically and therapeutically relevant to a range of disorders, including alcoholism, chronic fatigue syndrome, fibromyalgia, and restless legs syndrome… Nutritional tools for altering the gut microbiome therapeutically include changes in diet, probiotics, and prebiotics.” (7)

As you can see, alterations in the microbiota can affect basically everything, but that there is also hope for change.

Getting back to the gut and body composition, the aforementioned Lipopolysaccharide (LPS) leads to overactivation of cannabinoid receptor 1 (CB1) within the gut, which causes an increase in intestinal motility (speed of food going through) in the proximal parts of the intestine. This leads to less absorption of nutrient feedback signals that tell the brain you are well fed, and that it is time to stop eating (8). Concurrent with this is an increase in transit time in the colon, which results in a greater total harvest of caloric energy from your food (9, 10).

In other words, the signal your brain is getting is that you are not getting enough food, while you are actually extracting more calories from what you eat. This not only directly leads to more fat accumulation from harvesting more calories, it lends itself to over-eating. This aggravates the cycle further, as overeating and increased adiposity are themselves inflammatory. So, what you have is more inflammation, more dysfunction, greater food intake, greater extraction of food, more fat accumulation, then REPEAT!

The carnage does not even end here. Along with this inflammatory state is a disruption in the intestinal barrier. Intestinal permeability is increased and these inflammatory agents spill out systemically. This is often called a “leaky gut”. This results in a low-level inflammatory state in the entire body. The biggest

culprit here is, once again, LPS (11).

LPS activates CB1 receptors in the body and brain, just as in the intestine. In the fat tissue, this leads to activation of PPAR-gamma, and an upregulation of triglyceride synthesis, fat cell formation, and fat storage (12). In the brain, activation of CB1 increases orexegenic pathways, thus increasing appetite, hunger, and ultimately, food intake (13). This should not much as much of a surprise considering “the munchies” that accompany intake of famous cannabinoid receptor agonist, marijuana.

And, LPS is not done yet, not at all. It also activates Toll-like Receptor 4 which, along with other inflammatory signals (TNF-alpha, interleukins), promotes both insulin and leptin insensitivity, peripherally and centrally (14, 15). At this point, your adipostat (the thermostat for your body fat level) is wrecked. Your ability to control food intake is gone, and you are a fat storing machine. Obviously, this is not what you want your body doing to itself. It is not what you want it doing to you. It is not what you want it doing to your life.

Oh, and to top it off, atherosclerosis, heart disease, and stroke are promoted by these same inflammatory pathways. Combined with the increased body fat and insulin resistance, you officially have all of the perfect ingredients for the dreaded Metabolic Syndrome (16, 17).

And, it is just a bunch of microscopic bacteria that call your gut “home” causing all of this devastation.

General DataThe most well-known genera of bacteria in commercial probiotics are Lactobacillus and Bifidobacterium. They are also among the most common in the body, along with several other ones which are not commercially available, but which we can manipulate with supplementation. We will talk about these in length in the SupraBiotic™ and Primer™ write-ups.

Unfortunately, Lactobacillus belong to the Firmicutes phylum which has been found to be associated with weight gain and obesity (18-20). Just a 20% increase in Firmicutes (which Lactobacillus is usually the primary genus) with an equal decrease in Bacteroides results in an increased energy harvest of 150 calories per day in humans (21). That is equal to 15lbs of fat per year! The Western style diet promotes these negative changes in microbial proportions (22). Thus, one can plainly see why it can be so difficult to get lean, as well as how easily obesity has become an epidemic.

Interestingly, smoking cessation produces the same negative changes in bacterial composition, while gastric bypass surgery improves it (23-24). The well-known effects on weight with both of these further highlights the negative body compositional effects of this intestinal dysbiosis.

In addition, probiotic treatment with several Lactobacillus species that are in a great number of commercial formulations, including Lactobacillus acidophilus, Lactobacillus fermentum, and Lactobacillus ingluviei , have been directly associated with weight gain and obesity (25). Type-2 diabetics had significantly more Lactobacillus, with L. acidophilus being particularly bad in this

regard (26). Further, L. reuteria and L. sakei have been found to be positively associated with obesity and body mass index (27-29). They probably don’t tell you that on the label.

More powerful evidence of the profound effect of the microbiota on body weight and metabolism come from studies on “fecal transfer”. And, yes, that is exactly what it sounds like – transferring poop from one subject’s intestine to another’s.

In twins, transfer of an obese microbiota to lean mice was accompanied by an increase in bodyweight, fat mass, and a dysbiotic alteration of the Firmicutes:Bacteroides ratio to reflect that of the obese model (30). A similar transfer replicated the obese phenotype with increased weight gain, lipogenesis, adipogenesis, overeating, and lower satiety, as well as inflammation and hyperglycemia in formerly lean, healthy subjects (31, 32).

On the other side of the coin, transferring the intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome, as well as reversing obesity and gastrointestinal issues (33). It also reduced markers of metabolic syndrome, inflammation, and oxidative stress in animals challenged with high-fructose diets (34).

Obviously, while it highlights the science, doing a fecal transfer is not terribly practical, appetizing, or readily available -- unless maybe you are in California.

Fortunately, there is good news. While several species and strains of lactobacillus have been found to promote weight gain, several have also been found to protect against it. And, of course, we only used the good ones. Furthermore, Bifidobacterium have shown only positive effects to a remarkable extent.

Bifidobacterium are anti-obesity and lipid lowering, decreasing fat weight, blood glucose, cholesterol, and triglyceride levels (35). They are higher in lean subjects, as well as being lower in obese (36, 37). They are significantly lower in type-II diabetics and have been shown to improve glucose tolerance as well to decrease inflammatory signaling (38-40). In addition, they increase levels of EPA, DHA, and CLA in fat tissue and the brain (40). They have also been found to decrease with aging (41).

We can also readily manipulate levels of the good bacteria that are not commercially available such as Bacteroides species, Akkermansia Muciniphilia, Faecalbacterium Prausnitzii, and Roseburia via supplementation of ingredients that ARE available.

So, let’s get to it.

You may have noticed that almost no probiotic formulas contain just a single species of bacteria, nowadays. And, if you did not, I will just say that it is for a good reason. They work better in combination. This applies to the prebiotics that feed them as well. You need a variety of prebiotics to grow a variety of probiotic bacterial species.

First of all, microbial diversity seems to be good, in and of itself. Essentially, a diverse gut is a healthy gut (42). Obesity has been associated with a lack of microbial diversity and, as you might expect, lean subjects have greater microbial diversity in the gut (43-45). Insulin sensitivity is also improved along with

diversity increases (46). Finally, in the interesting but not terribly shocking category, exercise increases microbial diversity (47, 48).

Increased diversity also works to specifically create an environment where probiotic bacteria can thrive, thus enhancing their ultimate performance (49). Compared to individual strains alone, this diversity increases adhesion to intestinal mucus, which is necessary for most survival, growth, and activity (50, 51). Conversely, bacteria inhibit adhesion of pathogenic bacteria better when in combination (52, 53).

However, you do not want to just try to have every single species and strain in existence growing inside of you. It needs to be done rationally. If not, they can interfere with each other’s actions and compete for space and resources (54-56).

But, maybe the most interesting benefit of supporting a combination of bacteria is through cross-feeding. This is when one bacterial species produces metabolic substrates the other species and strains use for fuel (57, 58). Bifidobacterium adolescentis is the most interesting and important species in this regard as it functions as THE archetypal cross-feeder for several of the most important and impressive strains of bacteria. And, those strains are not commercially available. B. adolescentis produces acetate and oligosacharrides which are then consumed by these acetate utilizing, butyrate and propionate producing bacteria (59).

The Best Bacterial Species That Money Can’t Buy.Unfortunately, several species of bacteria with some of the very best data are not available commercially, due to regulatory issues and well as practical challenges such as stability and viability of the bacteria themselves. We are working on these, as are several other groups, but it will happen later rather than sooner, at best.

Fortunately, there are a myriad of ways to specifically target and increase these strains using methods that ARE available. And, that is exactly what we have done. So, let’s take a look at these novel wonder-bacteria, and then we will get to the data on B. adolescentis as the ultimate cross-feeding probiotic.

Genus Bacteroides

Bacteroides are butyrate and propionate producing. Levels were 6-fold higher in lean vs. obese subjects, as well as being reduced in obese patients, in general, compared to control populations (60-63). The Firmicutes:Bacteroides ratio was also significantly worse in obese patients, even in comparison with the merely overweight (65, 66). It has a negative correlation with fat mass and waist circumference (66, 67). It was also 60% lower in obese pigs – yeah, apparently that is a thing (68).

Bacteroides levels in Type-2 diabetes were only half that of those with normal glucose tolerance (69). Lower Bacteroides was correlated with increased energy intake (70). Additionally, it was decreased after smoking cessation similar to differences in obese compared to lean subjects suggesting a link between Bacteroides and the weight gain of smoking cessation (71).

Among various species in the Bacteroides genus, B. uniformis reduced bodyweight gain, triglycerides, and adipocyte volume while improving insulin and leptin sensitivity. It also lowered LPS and other inflammatory signals (72). Bacteroides acidifaciens decreased bodyweight and fat gain, while increasing fatty acid oxidation via PPAR-alpha (73). In addition to an elevated Firmicutes:Bacteroides ratio, B. vulgatus levels were found to be lower in the obese (74).

B. fragilis releases a symbiotic immunomodulatory anti-inflammatory factor called Polysacharride A (75). This activates TLR-2, which releases anti-inflammatory interleukins. PSA is basically the opposite of LPS, and TLR-2 the opposite of TLR-4 (76). This has been shown not just to prevent but to cure experimental colitis, an extreme version of a leaky, inflammatory gut (77). It has also been shown to prevent demyelination of neurons in the central nervous system, indicative of protection against inflammation well outside of the gut (78).

A few of the Bacteroides species bind to mucins for colonization and consume these mucin polysaccharides (79, 79b). Bacteroides species also have greater glycan degrading capability than Firmicutes, thus they are preferentially increased by polyphenols (80). Primer™ contains both mucin and polyphenols.

Faecalibacterium prausnitzii

Faecalibacterium prausnitzii is butyrate producing and is considered a physiological sensor and marker of human health (81). It does not get much more important than that. It is lower in the obese and type-2 diabetics (82-84). Conversely, it is higher in normal glucose tolerance vs. prediabetic subjects (85).

Faecalibacterium prausnitzii is also negatively correlated with inflammatory markers and sharply decreased in inflammatory bowel diseases (84, 86). It is greatly reduced in ulcerative colitis and less abundant in Crohn’s disease (87, 88). As would be expected from the above, it improves intestinal barrier function (89).

Akkermansia muciniphilia

Akkermansia muciniphilia is mucin degrading, meaning it feeds on mucins (90). Levels are higher in lean subjects than the general population (91). It is also decreased in obesity and type-2 diabetes. Its administration reduced fat mass, adipose tissue inflammation, and enhanced insulin sensitivity. Along with this, improved gut barrier function and increased intestinal endocannabinoid levels were seen (92).

This species is also inversely related to fasting glucose, waist-to-hip ratio, subcutaneous adipocyte diameter, plasma triglyceride levels, visceral adipose tissue mass, and insulin resistance (93). Along with enhanced glucose tolerance, it reduced adipose tissue inflammation (94). Akkermansia levels are higher in normal glucose tolerance vs. pre-diabetic subjects (95). It decreased inflammatory cytokine production and protected intestinal barrier function in experimental colitis (96). Finally, its levels are reduced in ulcerative colitis (97).

Roseburia Species

Roseburia species are butyrate producing (98). An increase in this species is associated with decreased body weight, fat mass, insulin sensitivity, and triglycerides -- independent of calorie intake (99). Increased Roseburia correlated with reduced body weight, improved profile of lipid and obesity related gene expression, along with a normalized inflammatory status (100). It is also lower in type-2 diabetes (101). Levels are increased by a Mediterranean diet, as is insulin sensitivity (102). Roseburia is enriched in healthy populations vs. those with atherosclerosis (103). And, its levels display an inverse correlation with disease activity in ulcerative colitis (104).

High protein/low carbohydrate diets, which are so effective and popular, reduce Roseburia and SCFA levels (105, 106). This does not mean don’t use them, it just means make sure you make a point to get fiber/prebiotics to feed your good bacteria that produce SCFAs. Butyrate is especially important amongst the SCFAs, as it the preferred energy source, along with Glutamine, for epithelial cells in the colon (107). Butyrate is basically the fat to Glutamine’s protein and carbohydrate as far as feeding these cells. We will talk more on Glutamine in the Primer™ write-up.

Bifidobacterium adolescentis as Cross-Feeder

As mentioned, B. adolescentis is hugely important in helping to feed other bacteria, specifically the really good ones that we just talked about, which we cannot get commercially.

B. adolescentis is superior to other potential cross-feeding Bifidobacterium in that it provides a slow, steady degradation of oligosaccharides for a long, continuous release of substrate for these various bacteria to feed on. It is essentially time-released, allowing acetate feeding, butyrate producing bacteria to grow and thrive throughout the entire length of the gut (108).

Faecalibacterium prausnitzii is almost fully dependent on acetate, which B. adolescentis supplies. F. prausnitzii converts it to butyrate with 85% efficiency, and its growth is enhanced by co-culture with B. adolescentis (109, 110).

Roseburia is also an acetate user (111). It is, in fact, generally required for growth (112). In addition to acetate production, B. adolescentis increases Roseburia via partial breakdown of oligosaccharides, which it can then utilize (113).

Cross-feeding with Bifidobacterium modulates the prebiotic effect of inulin and arabinoxylan-oligosaccharides on Roseburia and F. prausnitzii by making acetate available (114). Roseburia was able to grow in pure complex carbohydrate cultures, which it cannot metabolize on its own, owing to cross-feeders (115).

Short Chain Fatty Acids (SCFAs)

One of the primary ways that probiotic bacteria work their magic is by fermenting prebiotics and producing SCFAs (primarily acetate, butyrate, and propionate), so we are going to talk about those, and how they work.

They primarily work through two mechanisms: 1) activation of free fatty acid receptors, FFA2 and FFA3. 2) Decreasing inflammation and permeability in the gut.

SCFAs protect against obesity and insulin resistance. Butyrate and propionate induce anorectic gut hormones, while acetate does so without reducing food intake (Supplementary 1). FFAR2 deficiency results in obesity on a normal diet, whereas with overexpression, subjects remain lean, even on an obesity promoting high-fat diet. Activation of FFAR2 suppresses insulin signaling in adipocytes, which inhibits fat accumulation in adipose tissue and promotes the metabolism of lipids and glucose in other tissues such as muscle (S2).

Propionate and butyrate activate intestinal gluconeogenesis. Butyrate does so through AMPK, while propionate works through a gut-brain neural circuit involving FFAR3 (S3). Propionate is sensed in the portal vein walls via FFAR3, initiating intestinal gluconeogenesis. This glucose then triggers a signal to the brain to modulate hunger sensations and normalize whole body glucose homeostasis (S4). In a fasting state, as much as 62% of infused propionate is converted to glucose, accounting for 69% of total glucose production (S5). This is quite applicable to lower carb diets. Basically, it makes your brain think you are plenty fed with carbs/glucose, so it signals not to eat more, as well as not to produce or pump out more glucose into the blood.

SCFAs also stimulate the release of anorectic and satiey inducing peptides like GLP-1 and PYY via FFAR2/3 (S6, S7). Activation of FFAR3 by SCFAs inhibits insulin secretion and increases sympathetic outflow. This raises energy expenditure and help to protect against obesity (S8, S9). Acetate has been found to increase brown adipose tissue, UCP1, and mitochondrial biogenesis via FFAR2 (S10).

Short-chain fatty acids also improve intestinal barrier function via activation of AMPK (S11). Sodium butyrate has been specifically found to be an AMPK agonist (S12). And, butyrate increase tight junction assembly, thus improving barrier function, specifically through AMPK (S13, S14).

This seems like as good of a place as any to add a bit more about AMPK, as it is one of the major targets in all of this.

AMPK

AMPK is a primary signaler in the maintenance of tight junction integrity and intestinal barrier function. It is one of the most important pathways in preventing the “leaky gut” we have spoken of earlier in regard to LPS and other inflammatory and infectious molecules escaping into the body to wreak havoc (S15, S16). Modern food processing and the Western diet is a particularly egregious malefactor in this (S17).

In addition to its involvement in barrier function, AMPK activation is extremely positive for the great bacteria that we can’t get commercially.

Metformin increased Akkermansia 18-fold through AMPK activation. Also, against a high-fat diet, it restored Bacteroides levels and the Firmicutes:Bacteroides ratio to that of lean subjects (S18-S20). It inhibited LPS induced inflammation and gut permeability increases, while improving glucose uptake and insulin sensitivity (S19). Akkermansia increases are likely at least partially due to greatly elevated production of its favorite food, mucin, which is stimulated by AMPK. It also reduces insulin resistance and adipose tissue inflammation in a high-fat diet (S20).

Primer™ IngredientsAs Primer™ is primarily a prebiotic, let’s start with those. Prebiotics have come a long way since oat bran and psyllium husks. Beginning with inulin, a huge array of oligosaccharide and glycan type compounds have been found to be fermented and fed on by intestinal bacteria. These newer prebiotics tend to be basically tasteless and dissolve effortlessly, which is quite handy.

With the importance of microbial diversity for optimal gut and body health, we want a number of different prebiotics for them to feed on. Likewise, we want to choose the ones that best increase the bacteria we want to increase, rather than just randomly feeding all of them.

Galacto-oligosaccharides (GOS)GOS reduced fat mass, food intake by 14%, and elevated expression of pro-satiety peptides. Combining them with Calcium increased propionate formation (116). In addition to reductions in food intake, appetite, bodyweight, and inflammation are also decreased (117). GOS increase beneficial bacteria, particularly Bifidobacterium, with 5-10 fold increases in some subjects being noted (118-121). They also raise Bacteroides levels (121). They are long-acting, providing prebiotic effect throughout the entire length of the colon, while strongly inhibiting pathogenic bacteria (122). This owes to high resistance to conditions early in gut digestion (123).

GOS provide direct enhancement of intestinal barrier function through interaction with goblet cells, separate from SCFA or anti-inflammatory mediated mechanisms. They also showed a 2-4 fold mucin elevation, which would create a positive environment for mucin feeders such as Akkermansia and Bacteroides (124). They inhibited inflammatory responses, augmented protein junction assembly by 85%, and prevented loss of barrier function (125). GOS displayed a microbiota independent increase in tight junction assembly and improved barrier function (126). Finally, they mitigate LPS induced inflammation and protect against stress induced LPS activity (127, 128).

Arabinoxylan-oligosaccharides (AXOS)AXOS are strongly Bifidogenic. They increase satiety inducing peptides, while decreasing weight gain, fat mass, and insulin resistance (129). They raise butyrate levels along with Bifidobacterium suggestive of subsequent cross-feeding to butyrate producing bacteria (130). They also reduce protein fermentation in the gut (130, 131). This spares amino acids for more useful purposes as well as preventing toxic breakdown products.

AXOS are long-acting, with bacterial fermentation occurring throughout length of colon. They significantly promote Bacteroides as well as Lactobacillus (132). They are even better than inulin at providing fermentation products to the distal portions of the colon (133). AXOS elevated Roseburia and butyrate levels, with total SCFA increases as high as 2-3 fold (134, 135). Finally, they increase tight junction proteins, improve barrier function, and inhibit inflammation in adipose tissue (129).

Xylo-oligosaccharides (XOS)XOS increased Bifidobacterium along with acetate and butyrate. Combining with inulin further augmented butyrate formation, as well as increasing propionate, suggesting cross-feeding to butyrate and propionate producing bacteria like Roseburia and Bacteroides (136, 137). And, XOS have indeed been found to promote both Roseburia and Bacteroides, as well as improving the Firmicutes:Bacteroides ratio (138, 139). Bacteroides possess special xylan degrading enzymes, making them a preferred fermenter of XOS (140). Elevated Bacteroides and butyrate from XOS protected against genotoxicity in a colonic simulator (141). They also decreased LPS and increased epithelial cell proliferation (137, 142).

Lactulose Lactulose inhibits adipogenesis and fat accumulation, down-regulates adipogenic genes, and reduces caloric extraction efficiency, while increasing energy expenditure and lipolysis (143). It also improves post-prandial blood glucose and insulin levels (144, 145). Lactulose raises Bifidobacterium counts, particularly of the ideal cross-feeder B. adolescentis, as well as Akkermansia (146-148). Finally, it decreases intestinal permeability and proteolysis of amino acids in the gut (147, 149).

Inulin Inulin improved glucose uptake in insulin resistant cells, and activated AMPK (150). It increases Bifidobacterium and butyrate, while reducing protein fermentation (151, 152). It has a prolonged Bifidogenic effect, with more distal fermentation and SCFA production vs. fructo-oligosaccharides, particularly of butyrate and propionate – again, suggestive of cross-feeding (153, 154). In fact, it was found to increase B. adolescentis more than 4-fold and F. Prausnitzii by 50% (155). It also increased

Roseburia, while augmenting mucin production 6-fold, leading to large elevations in Akkermansia and propionate, distally (156).

Resistant Starch 3 (RS3)Resistant Starch 3 is formed when starchy foods such as potatoes and rice are cooked and then cooled. This turns formerly digestible starches into resistant starches via a process called retrogradation. RS3 is particularly, and somewhat uniquely, highly prebiotic for Ruminococcus bromii, with increases up to 4-fold (157-159). R. bromii has superior ability to degrade this resistant starch, which is the most prevalent fermentable carbohydrate in the average diet, making it a “keystone species” by acting as a cross-feeder for other species (160, 161).

It was also found to be readily consumed by Bacteroides, elevating faecal propionate, rather than butyrate as is often observed following resistant starch feeding of other types. This propionate formation reflects a gut community dominated by the Bacteroides, and it actually became the primary lineage in this study (162).

Amylopectin Amylopectin was found to be superior to several other prebiotics for increasing butyrate, as well as butyrate producers F. prausnitzii and Roseburia (163). It also raises Bacteroides, with increases in Roseburia and Bacteroides being found to be proportional to the amylopectin content of barley and oats (164, 165).

Mucin Mucin is the glycoprotein constituent of the mucus which lines the wall of the intestines and protects it. Several species of bacteria, including some of the really good ones, feed off of it. Akkermansia is the most well characterized mucin consumer (166, 167). Verrucomicrobia, of which Akkermansia is the primary genus, was increased from .03% to 5.25% by mucin, and in combination with inulin, Bacteroides was raised as well (168).

Bacteroides thetaiotamicron is a known mucin degrading specialist (169-171). Bacteroides fragillis consumes mucins as well (172, 173). Roseburia intestinalis also colonizes the mucosal layer and feeds on mucins (174).

With these bacteria colonizing the mucus and being close to the epithelium, particularly with the butyrate producers, bioavailability for epithelial cell regeneration and barrier function is enhanced.

RhamnoseRhamnose is a preferred sugar for the propanediol pathway of propionate production by Roseburia inulinivorans (175, 176). It is quite selectively metabolized to propionate (177, 178). It is much more selective for propionate formation than lactulose or glucose, which utilize different, less selective pathways, resulting in 4 times more propionate than with lactulose or glucose (179). Rhamnose was also found to decrease triglyceride synthesis and serum triglyceride levels, likely due to propionates effects on the SCFA receptors FFAR 2/3 (180).

Glutamine Glutamine is the primary substrate of rapidly diving cells, a category to which the epithelial cells of the digestive tract belong. It increases tight junction protein production (181). It does so by activating the mammalian target of rapamycin (mTOR) cell signaling in enterocytes. It enhances intestinal growth, enterocyte proliferation and survival, and regulates intestinal barrier function in injury, infection, stress, inflammation, and other catabolic conditions (182). It is basically both the leucine (protein) and the glucose (carbohydrate), to go along with butyrate as the fat, for the fueling of survival, growth, and reproduction of the enterocyte. This makes it quite possibly the most important nutrient for intestinal barrier health and function.

Glutamine also reduces utilization of other amino acids (asparagine, aspartate, serine, lysine, leucine, valine, ornithine, and arginine) in the gut, preserving them for more useful things while reducing toxic metabolites (183, 184). It decreases intestinal permeability and enhances intestinal mucosa and barrier function (185). Glutamine improves intestinal barrier impairment and quells the LPS mediated inflammatory cascade (186). It also prevents mucosal injury and promotes recovery from LPS induced inflammatory damage, as well as downregulating TLR-4 expression (187, 188).

Inflammatory conditions increase the requirements for Glutamine to maintain the intestinal barrier (189). It has specifically been shown to protect the intestinal barrier against processed, Western diet style foods (190). AMPK mediates its enhancement of tight junction integrity and barrier preservation (191).

Conversion to glutamate and subsequent cellular uptake is a pivotal step in its protective effects (192). Monosodium Glutamate has been found to promote the colonization of F. prausnitzii and Roseburia (193). And, finally, L-glutamate enhances barrier function (194).

Calcium Phosphate Increasing dietary Calcium produced a reduction in weight gain and fat pad mass of 26-39% with a 51% inhibition of adipocyte fatty acid synthase expression and activity, while stimulating lipolysis by 3 to 5-fold (195). In another study, an almost 50% increase in weight loss was found (196). A high-Calcium diet decreased fat gain by 55%, stimulated adipose tissue uncoupling protein (UCP2) and skeletal muscle UCP3 expression, increased thermogenesis and lipolysis, while lowering fatty acid synthase expression

and activity (197, 198). Calcium also elevated peptides GLP-1 and GLP-2, which increase satiety and decrease food intake (199, 200).

Calcium improves intestinal permeability, strengthens the mucosal barrier, reduces inflammation, and alleviates colitis (201). Prebiotics have actually been found to have negative effects on intestinal permeability and inflammation without Calcium Phosphate rather than the positive effects produced when it is present (202, 203). This protection is dependent on Phosphate, thus Calcium likely pulls it into the colon, improving luminal buffering capability (204). This is because SCFAs produced by prebiotic fermentation could lower pH too much in its absence.

Finally, Calcium is necessary for the Calcium/Calmodulin-dependent Protein Kinase Kinase 2 (CaMKK2) mediated AMPK signaling and barrier maintenance produced by Glutamine (205).

Multi-Berry Powder

Multi-berry powder has the power of berries!! A day’s worth of Primer™ is equal to ¼ cup of mixed berries. It has the polyphenols and fiber and such that berries have, but it is mostly in here because it gives it a nice, subtle berry flavor.

ConclusionPrimer™ takes the concept of prebiotic far beyond where anyone has previously taken it before. It starts by carefully and selectively feeding the most beneficial bacterial species, including novel probiotic species that you cannot attain, anywhere. It does so in a way that no other product comes even close to doing. It protects against dysfunction of the gut and microbiota to promote better health, better appetite control, better metabolism, and better fat loss. Finally, its supporting ingredients go to work on making your inflamed and leaky gut as good as new, leaving your body functioning in the optimal way it is intended to.

Primer™ is a gourmet meal for your microbiota and a happy-ending massage for your gut. It is a one of a kind product that fits in perfectly with and enhances any diet and exercise program, any supplement regimine, any lifestyle.

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