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 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).
Pomegranate Extract is an extremely rich source of polyphenols. Polyphenols are generally prebiotic for good bacteria (Bifidobacterium, Akkermansia, Bacteroides, and Roseburia), and antibacterial for less favorable and pathogenic ones (189-191). Fruit/berry based polyphenols seem to be particularly favorable toward Bacteroides, the Firmicutes:Bacteroides ratio, and Akkermansia compared to other polyphenol sources. Lactobacillus (Firmicute) lack glycan degrading enzymes, thus do not grow on them particularly well compared to the others (192).
Strawberry polyphenols elevate Bifidobacterium and Bacteroides, butyrate and propionate, as well as decreasing Firmicutes (193). Red wine polyphenols raise Bifidobacterium and Bacteroides as well (194, 195). Polyphenols improve the Firmicutes:Bacteroides ratio, while also increasing Roseburia (196, 197).
Akkermansia REALLY loves polyphenols (198). Grape polyphenols gave a 10-fold increase in Akkermansia and decreased the Firmicutes:Bacteroides ratio, while also reducing weight gain, triglyceride storage, insulin resistance, LPS, and inflammation (199). Cranberry polyphenols produced a 30-fold increase in Akkermansia and decreased weight gain, visceral adipose tissue, triglyceride synthesis, insulin resistance, LPS, and inflammation (200).
Finally, Pomegranate Extract, itself, produced a massive 33 to 47 fold increase in Akkermansia (201). Caffeic acid, a component of Pomegranate Extract, increased Akkermansia 15-fold vs control and several hundred fold vs. subjects with induced colitis! It also improved the Firmicutes:Bacteroides ratio (202).
Polyphenols activate AMPK, enhancing intestinal barrier function (203). They increase tight junction proteins, decrease tight junction pore formation, and ameliorate inflammatory bowel disease (204). Pomegranate Extract activates AMPK at 2 times the potency of metformin (205). It also displayed extremely potent alpha-glucosidase inhibitory activity (this is an ezyme that metabolizes carbohydrates to glucose), being 10 times as potent as acarbose, lowering blood glucose after sucrose intake, but not after glucose (206, 207). It consistently decreases glucose levels, as well as being anti-inflammatory (208, 209).
Fermentation of herbs results in much higher concentrations of active compounds compared to unfermented (210). This same fermentation is done in the body, but it is highly dependent upon the microbial make-up of the individual’s gut, so it can vary widely from person to person (211, 212). As just one example, a fermented herb preparation inhibited LPS mediated inflammatory damage, while the unfermented was ineffective (213, 214)
Kudzu is a group of polyphenol rich plants belonging to the pea family. Its administration reduced body weight, fat mass, and lipogenesis while stimulating lipolysis and thermogenesis (215). It also lowers body mass index and visceral fat (216). Kudzu increased fatty acid oxidation, and decreased weight gain, triglyceride levels, and visceral adipose tissue on a high-fat diet (217). In addition, it improves insulin sensitivity and lipid metabolism (218).
Kudzu is anti-inflammatory, with components inhibiting LPS, TNF-alpha, and ROS induced inflammation (219, 220). It is also a potent inhibitor of COX-2 (221). In addition, Kudzu reduced intestinal permeability and improved intestinal barrier function (222, 223). Finally, it reduces expression of the dreaded TLR-4 (224, 225).
The anti-obesity effect of unfermented ginseng was shown to be dependent on bacterial make-up of the microbiota (226). It increased mucins (the Akkermansia and Bacteroides food) by 50% (227). It is metabolized by Bifidobacterium as well as Bacteroides. There is a dramatic difference in levels of those bacteria between metabolizers and non-metabolizers, suggesting strong prebiotic specificity toward them (228). And, it was indeed found to enhance growth of Bacteroides (229).
Absorption of one of its main active ingredients, Compound K, is increases by prebiotics (230). And, there are plenty of those in Primer™. Fermented Ginseng decreased bodyweight, fat mass, and food efficiency, while improving insulin and leptin sensitivity (231, 232). In addition to reduced body weight, decreases in fat mass, adipocyte size, and glucose uptake were also observed. And, all of these effects were superior with fermented vs. regular ginseng (233, 234). Finally, it decreases inflammatory cytokines and protects the intestinal barrier (235, 235b).
SupraBiotic™ contains an industry-best Mulberry Extract, standardized to over 5% 1-Deoxynojirimycin (1-DNJ) and containing relevant amounts of d-Fagomine, as well. Like all berries, it also has high polyphenol content, the benefits of which we have already talked about.
1-DNJ is a naturally occurring carbohydrate mimic. Its use significantly lowered body weight, blood glucose, and serum insulin levels, and it conversely improved glucose tolerance and insulin sensitivity (236). It increased the insulin and leptin sensitizing peptide adiponectin (which activates AMPK), reduced visceral adipose tissue, adipose mass, triglycerides, lipid accumulation, and increased fatty acid oxidation (237).
It is remarkably potent, elevating adiponectin, GLUT4, and AMPK at just .5uM (238). This is 1000 times as potent as metformin. Along with increasing AMPK, it improved mitochondrial function and lipid metabolism (239). Finally, it is a more potent alpha-glucosidase inhibitor than acarbose, which futher helps with glucose and insulin (240).
D-fagomine is also a naturally occurring sugar mimic. It reduced weight gain, plasma triglycerides, glucose, and enhanced leptin and insulin sensitivity (241). It attentuated fat gain on high-fat diet (242). D-fagomine was also found to inhibit intestinal sucrase, lowering post-prandial glucose levels (with either sucrose or starch), as well as modulating bacterial adhesion, inhibiting pathogenic ones without effecting Bifidobacterium or Lactobacillus (243).
Selenium increases microbial diversity, and it is synergistic with probiotics for this gut bacteria modulation (244, 245). It works by enhancing the fermentation activity of gut bacteria resulting in better bacteria growth as well as output of SCFAs (246).
Queen’s Bee Acid (10-hydroxy-2-decenoic acid)
QBA is a medium chain fatty acid from Royal Jelly. It is a very potent AMPK agonist, being effective at just 20uM. This is 25 times as potent as research standard AICAR and the pharmaceutical metformin. (247)
We have mentioned it over and over, but it bears repeating more about the machinations that result in the vicious cycle of gut dysbiosis. Inflammation in the gut, followed by low-level but constant systemic inflammation, PRECEDES obesity and insulin/leptin resistance. It is what gets them started. If you are not either quite lean, or have been on a diet long enough that fat loss has basically stopped, insulin and leptin resistance are already at work, particularly in the brain/adipostat (248). This is bad news for appetite control, metabolism, and body weight regulation.
LPS levels of just 2 to 3-fold above normal, which occur during a Western-style/high-fat diet, initiate the low level inflammatory response that leads to reduced insulin and leptin senstivity, and ultimately type-2 diabetes and Metabolic Syndrome. And, again, this happens before the weight gain starts (249). It sets you up for it to begin in earnest.
AMPK is one of the primary brakes on this ride. It inhibits the LPS induced inflammatory response, as well as the leaky gut. Super potent AMPK agonist, like 1-DNJ and QBA, are basically airbrakes on a runaway train.
QBA inhibits LPS induced cytokine production (250). It increases GLUT4, glucose uptake, and insulin signaling (247). It enhances intestinal barrier function and tight junction assembly in an AMPK dependent manner (251-253). AMPK activation also improves LPS induced blood-brain-barrier disruption much as it does with the intestinal barrier (254). This improves central insulin and leptin signaling, keeping your adipostat functioning properly.
PEA is a naturally occurring cannabinoid-like lipid, from a class called acylethanolamides. It is a competitive FAAH inhibitor (this is the enzyme that breaks down endocannabinoids). Decreased levels of endocannabinoids lead to upregulation of cannabinoid receptors, which leads to the increased activity at CB1 via LPS that gets the increased fat storage and over-eating part of the vicious cycle really going into overdrive.
Endocannabinoid activation of CB2, along with PEA/acylethanolamide activation of PPAR-alpha, normally keeps this inflammatory response balanced and in check, but when it gets out of whack, LPS à CB1 reigns supreme.
Let’s take a closer look at all of this and what PEA does to fix it.
Intake of dietary fat stimulates production of PEA, and the other acylethanolamides (255, 256). They increase satiety, and reduce food intake and body weight (257, 258). It creates satiety via activation of PPAR-alpha in the intestine followed by direct vagal signal to brain -- i.e. immediate, no gene transcription needed (259, 260). This is one of the steps in which fast transit times in the proximal small intestine become problematic. You get less PEA, thus less satiety signaling to the brain.
In addition, PEA specifically decreases this intestinal transit rate, so it is double plus good on appetite and satiety signaling (261). It both directly makes you feel full and prolongs its own duration of activity in doing so. PEA does, in fact, ultimately reach the brain, where it is active in nM concentrations through gene transcription (258). But, you would have already finished eating too much at that sitting, and each of your other meals, before it did anything, centrally.
In addition to the appetite side of things, PEA decreases intestinal inflammation and permeability. It does so through CB2 and PPAR-alpha as this is blocked by antagonists of either one (262, 263). It is also anti-inflammatory in the intestine via selective targeting of TLR-4 (263).
All sounds great, right? Well, the problem is that with a Western-style or chronic high-fat diet, the PEA release trigger becomes desensitized, ultimately resulting in reduced levels (256, 259, 265). This disrupts normal functioning of the whole system, leading to LPS induction of CB1 becoming dominant. And, this is on top of losing its direct beneficial effects on satiety and food intake.
An increase in inflammation happens in parallel with decreases in PEA, endocannabinoids, and FAAH – and, an upregulation of the cannabinoid receptors (266). It all happens together, at the same time, because they are all connected. And, FAAH inhibitors restore levels of all of these and suppress this inflammation (266). FAAH inhibitors also decrease intestinal motility, as we would expect (267). They do so by restoring PEA and the endocannabinoids, thus normalizing the system.
The final bit of evidence on how this operates is that chronic administration of tetrahydrocannabinol (THC), the main active ingredient in marijuana, reduces weight gain, fat mass gain, and energy intake in obese but not lean mice, despite an initial increase in food consumption (268). This is because it is both a CB1 and CB2 agonist. So, you have anti-inflammatory CB2 activation by THC snuffing out the inflammatory LPS pathway, as well as it down-regulating and competing for CB1, such that LPS cannot act on it to wreak its havoc, unchallenged.
This THC administration even improved select gut microbiota profiles. It increased Akkermansia by 4-fold, and improved the Firmicutes:Bacteroides ratio by 6-fold (268). It did not have these same effects in lean subjects because these pathways were not messed up to begin with for them.
So, you can see that PEA helps correct the system at basically all levels that we have been talking about.
One more thing of note is that, as we mentioned with high protein diets negatively altering the bacterial make-up of the microbiota if one does not make a point to get plenty of fiber/prebiotics, the high-fat side of such diets will negatively affect PEA levels, long-term, thus the entire system will be functioning sub-optimally.
Again, I am not bashing these diets at all, they are quite effective. Consuming an excess of glucose and/or fructose is the worst thing you can do to your body as far as inflammation and insulin and everything we have been talking about, just to be clear. But, we want to be optimal, and we can be, quite easily with supplementation.
Ginger Extract (20% Gingerols)
Ginger is well known as a digestive aid. The extract is an all-around nice ingredient, aiding through several pathways, and it is particularly effective as an anti-inflammatory and protector of barrier function. The primary component of the extract is 6-gingerol, though 8-, and 10-gingerol, as well as 6-, 8, and 10-shogaol are present in significant, pharmacologically relevant numbers. They all pretty much do the same thing, just at different potencies.
Mechanistically, it is primarily an anti-inflammatory and antioxidant. It decreases basically all inflammatory cytokines (269, 275, 276). It inhibits LPS induced inflammation as well as TNF-alpha (270). It reduced interleukins 3-fold at just 50uM, and its COX inhibition is comparable to aspirin (271-273). It also displays extremely potent anti-oxidant activity, being effective against various radicals at just 1-25uM (274).
Gingerols activate PPAR-alpha, as well as AMPK, with 5 times the potency of metformin and AICAR in suppression of inflammatory cytokines (275, 276). They increase tight junction proteins and integrity via protection against inflammatory assault (277, 278). They suppress colitis via anti-inflammatory and anti-oxidant activity (279). Gingerols enhanced the survival and proliferation of intestinal epithelial cells via reductions in pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β), while also elevating anti-inflammatory cytokines (IL-10 and IL-22) in colitis models (280). They also reduce spasms of smooth muscle in the digestive tract (281).
In addition, gingerols displayed some modest inhibitory activity on α-glucosidase and α-amylase, being about 1/6 as potent as acarbose (282). Finally, it increased uptake of Calcium (100+%) and Glutamic acid (60%), both of which we will talk in detail about in the Primer™ write-up (283).
As you can see, SupraBiotic™ takes the concept of probiotic far beyond where anyone has previously taken it before. It starts with bacterial species carefully and purposefully selected to protect against dysfunction of the gut and microbiota to promote better health, better appetite control, better metabolism, and better fat loss. On top of this, SupraBiotic™ addresses and supports novel probiotic bacterial species that you cannot attain, anywhere. And, it does so in a way that no other product is even close to doing. Finally, its supporting ingredients crush inflammation and repair your leaky gut, leaving your body functioning in the optimal way it is intended to.
SupraBiotic™ is a one of a kind product that fits in perfectly with and enhances any diet and exercise program, any supplement regimine, any lifestyle.
See "Full Science Write-up" here http://neobium.org/product-line/suprabiotic/ for references.