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Primer (tm) Ingredients -- Science Preface

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Par Deus

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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).

For references, see "View Full Science Write-Up" here: http://neobium.org/product-line/primer/

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