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Probiotics, the Gut, and Muscle Mass -- Part 2

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Par Deus

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Bacteria

Bifidobacteria and Lactobacillus are by far the most common and well-known probiotic bacteria.  They are commercially available and quite affordable. We can also readily manipulate levels of the good bacteria that are not commercially available such as Bacteroides species, Roseburia species, Akkermansia muciniphilia, and Facealbacterium prausnitzii via diet and supplementation of ingredients that ARE available. More on that later.

Bifidobacteria

Bifidobacteria are significantly lower in type-II diabetics and have been consistently shown to combat the cycle of LPS inflammation, leaky gut, and insulin resistance (49, 50, 51).  They are reinforcing on intestinal epithelial cells and mucosa, improving the physical barrier of the intestine, preventing translocation of pathogenic bacteria and LPS from intestine to body tissue (52, 53).  They limit pro-inflammatory signals and increase tight junction proteins supporting mucosal recovery, ultimately restoring normal intestinal permeability and preserving gut barrier function in the face of inflammation (54, 55).

Bifidobacteria administration quells general colonic inflammation, particularly from LPS and its downstream signal, TNF-alpha (56, 57, 58).  In reducing LPS levels, inflammation induced insulin resistance is reversed in the face of a high-fat diet (59, 60, 61).  They shift the composition of the microbiota toward that of a lean phenotype, reducing inflammatory activity and insulin resistance while lowering body fat (62, 63).

Bifidobacteria are also extremely important for cross-feeding. This is where one bacterial strain produces metabolites that other species and strains can use for fuel (64, 65).  This is particularly important for the bacteria that are not commercially available, which we will discuss in detail in a bit.  Bifidobacteria produce acetate and oligosaccharides which are then consumed by these acetate utilizing, butyrate and propionate producing bacteria (66).

Faecalibacterium prausnitzii is almost fully dependent on acetate.  It converts it to butyrate with 85% efficiency, and its growth is enhanced by co-culture with Bifidobacteria (67, 68).  Roseburia is also an acetate user, and it is generally required for its growth (69, 70).  Combined with bifidobacteria, Roseburia was able to grow in pure complex carbohydrate cultures, which it cannot metabolize on its own, owing to cross-feeding (71). Cross-feeding with Bifidobacterium also modulates the positive effects of prebiotic oligosaccharides on growth of Roseburia and F. prausnitzii by making acetate available (72).  And, butyrate production increases mucins, which are fed on by Bacteroides and Akkermansia, two more great, but commercially unavailable bacteria.

 

Lactobacillus

Lactobacillus consistently increases tight junction protein formation and improves intestinal barrier function, ultimately inhibiting systemic inflammation from LPS and its downstream pathways (73, 74, 75, 76, 77, 78). They also increase the levels of butyrate and the other short-chain fatty acids (79, 80).  Lactobacillus raises levels of Bacteroides, a propionate producer, and another one of the types of great bacteria that we cannot get commercially (81).  They promote favorable intestine morphology, improving parameters such as villus height, crypt depth, mucin expression, and the quantity of goblet cells, all things favoring digestive function and efficiency (82).

Lactobacillus decrease LPS, systemically, as well as downstream inflammatory markers including TNF-alpha , IL-6, and COX-2, (83, 84, 85, 86). Relatedly, they also reduce expression of TLR-4, which is basically the “LPS receptor” (87, 88).  They have also shown improvements of inflammatory colitis, which is essentially an extreme version of a “leaky gut” (89, 90).  The reduction in inflammatory responses downstream of the LPS signaling pathway is a consistent finding in studies with Lactobacillus, including decreased adipose tissue inflammation, further evidence of preventing LPS actions outside of the gut (91, 92, 93, 94).

In combating these inflammatory pathways, Lactobacillus lower oxidative stress levels, ultimately improving insulin sensitivity (95, 96, 97). They also increase the insulin sensitizing peptide adiponectin (98, 99, 100).  Finally, they specifically improve insulin sensitivity against Western-style, obesity promoting diets (101, 102, 103).

In even more direct findings on probiotics and body composition improvements, Lactobacillus have been found to protect the testes from oxidative stress, increasing testosterone levels (104, 105). In fact, testosterone levels were 4-8 times higher in aging mice (a model of chronic, low-level inflammation), given Lactobacillus (106).

They have been found to increases growth hormone levels and reduce the expression of atrophy inducing genes (107, 108). They increased weight with the same body fat, meaning more lean mass (109).  Lactobacillus dose-dependently increased grip strength, muscle fiber number, and endurance swimming while decreasing muscle tissue breakdown (110). They inhibited increased levels of cortisol in response to stress (111). Finally, Lactobacillus feeding stimulates IGF-1 and decreases myostatin (112, 113, 114).

Bacillus, another genus of commercial probiotic, increased goblet cell number, villus length, and mucin synthesis in the intestine (115). This would be expected to improve intestinal mucosal cell proliferation and, ultimately, efficiency of nutrient digestion and absorption (116). And, indeed, improved growth performance and enhanced protein utilization has been found with Bacillus (117).

 

Probiotic Combinations

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.

First of all, microbial diversity seems to be good, in and of, itself. Essentially, a diverse gut is a healthy gut (118). Obesity has been associated with a lack of microbial diversity and, as you might expect, lean subjects have greater microbial diversity in the gut (119, 120, 121). Insulin sensitivity is also improved along with diversity increases (122).  Finally, in the interesting but not terribly shocking category, exercise increases microbial diversity (123, 124).

Combinations also work to specifically create an environment where probiotic bacteria can thrive, thus enhancing their ultimate performance (125). Compared to individual strains alone, combinations greatly increase adhesion to intestinal mucus, which is necessary for most survival, growth, and activity (126, 127).  Conversely, they inhibit adhesion and growth of pathogenic bacteria better when in combination (128, 129).

However, you do not want to just throw every single commercially available species and strain into a product as so many companies do. They need to be rationally combined. If not, they can interfere with each other’s actions and compete for space and resources (130, 131, 132).

But, perhaps the most interesting benefit of probiotic combinations is through the afore-mentioned cross-feeding of the commercially unavailable bacteria we are about to discuss, right now.

 

The Best Probiotics 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. Several groups are working on these, 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.  So, let’s take a look at these novel wonder-bacteria.

 

Bacteroides Species

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 (133, 134, 135, 136). Levels in Type-2 diabetics were only half that of subjects with normal glucose tolerance (137).

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 (138).  B. fragilis releases a symbiotic immunomodulatory anti-inflammatory factor called Polysacharride A – kind of an anti-LPS (139, 140). This has been shown not just to prevent but to cure experimental colitis, an extreme version of a leaky, inflammatory gut (141). 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 (142).

 

 

Faecalibacterium prausnitzii

Faecalibacterium prausnitzii are butyrate producing and considered a physiological sensor and marker of human health (143). It does not get much more important than that. It is lower in the obese and type-2 diabetics (144, 145, 146). Conversely, it is higher in normal glucose tolerance vs. pre-diabetic subjects (147).

Faecalibacterium prausnitzii is also negatively correlated with inflammatory markers and sharply decreased in inflammatory bowel diseases (148, 149). It is greatly reduced in ulcerative colitis and less abundant in Crohn’s disease (150, 151). As would be expected from the above, it improves intestinal barrier function (152).

 

Akkermansia muciniphilia

Akkermansia muciniphilia is mucin degrading, meaning it feeds on mucins (153). It is also decreased in obesity and type-2 diabetes. Its administration reduced fat mass, adipose tissue inflammation, and enhances insulin sensitivity. Along with this, improved gut barrier function and increased intestinal endocannabinoid levels were seen (154).

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 (155). Along with enhanced glucose tolerance, it reduced adipose tissue inflammation (156). Akkermansia levels are higher in normal glucose tolerance vs. pre-diabetic subjects (157). It decreases inflammatory cytokine production and protected intestinal barrier function in experimental colitis (158). Finally, its levels are reduced in ulcerative colitis (159).

 

Roseburia Species

Roseburia species are butyrate producing (160). An increase in this species is associated with decreased body weight, fat mass, insulin sensitivity, and triglycerides -- independent of calorie intake (161). Increased Roseburia correlated with reduced body weight, improved profile of lipid and obesity related gene expression, along with a normalized inflammatory status (162). It is also lower in type-2 diabetes (163). Levels are increased by a Mediterranean diet, as is insulin sensitivity (164). Finally, its levels display an inverse correlation with disease activity in ulcerative colitis (165).

High protein/low carbohydrate diets, which are so effective and popular, reduce Roseburia and SCFA levels, making pro- and prebiotics particularly useful with these (166, 167).

 

 

Prebiotics

Prebiotics are the food for our probiotic bacteria, and they are also the substrates that get transformed into super beneficial short-chain fatty acids like butyrate, so we will look at some data on those as well. 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. Let’s briefly look at some data on the positive effects various prebiotics.

 

Increased Good Bacteria and SCFAs

Prebiotics, by definition, increase beneficial bacteria, with data being most focused on Lactobacillus and Bifidobacterium, as they were the earliest studied and most common. Bifidogenic potential was the primary measurement for prebiotic activity until about 10 years ago.

Lactobacilli are promoted by a wide range of fibers and oligosaccharides (168, 169, 170). They can also ferment sugars, such a sucrose, fructose, and glucose (171). They are stimulated even by flour (172). So, one doesn’t have to put that much effort into getting them to grow. As you would expect from their growth being how prebiotics were defined, Bifidobacteria also grow quite well on a wide range of commercial prebiotics, with 5-10 fold increases in some subjects being noted (173, 174, 175, 176).

The much more interesting prebiotic data is the increases found in levels of the aforementioned commercially unavailable butyrate and propionate producing bacteria via the aforementioned cross-feeding. As we have mentioned, and as you will really see later, butyrate production is probably the single most important way that probiotics and prebiotics ultimately work their magic.

And, indeed, prebiotics have been found to not only raise Bifidobacterium counts, but do so concomitant with increased Akkermansia and F. prausnitzii (177, 178, 179).  They also promote increases in Bacteroides  (180, 181, 182, 183).  Other studies have found elevated Roseburia, F. prausnitzii, and Bacteroides together with greater butyrate levels, with total SCFA increases as high as 2-3 fold (184, 185, 186, 187).  Other prebiotic studies have shown increased propionate production along with Roseburia levels (188, 189).  They have also been found to increase butyrate and propionate to go along  with raised bifidobacteria and acetate levels  – again, suggestive of cross-feeding to butyrate and propionate producing bacteria (190, 191, 192, 193).

 

Mucins

Prebiotics administration has shown 2-4 fold mucin elevations, which would create a positive environment for mucin feeders such as Akkermansia, Roseburia, and Bacteroides (194). Another found prebiotic augmentation of mucin production of 6-fold, leading to large elevations in Akkermansia, Roseburia, and propionate (195).  Akkermansia is the most well characterized mucin consumer (196, 197). Verrucomicrobia, of which Akkermansia is the primary genus, was increased from .03% to 5.25% by mucin (198). That is a 175-fold increase, if you are counting.  Multiple species of Bacteroides are also mucin degrading specialist, as well (198, 199, 200, 201, 202).  A species of Roseburia, R. intestinalis also colonizes the mucosal layer and feeds on mucins (203).

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, so they are especially important and effective.

 

Gut Permeability and Inflammation

Prebiotics augment intestinal protein junction assembly, decreasing intestinal permeability and preventing loss of gut barrier function (204).  Oligosaccharides also directly displayed a microbiota independent increase in tight junction assembly and improved barrier function (205).  Prebiotics decrease LPS and increase epithelial cell proliferation (206, 207).  They decrease downstream inflammatory markers triggered by LPS (208, 209). Increases in tight junction proteins and improved barrier function inhibited systemic inflammation in adipose tissue (210). Finally, prebiotics protect against stress induced LPS inflammation and activity (211, 212).  

 

Insulin Sensitivity and Protein Sparing

Along with decreased LPS and inflammation, prebiotics reduced plasma glucose (213). They improved glucose tolerance by reducing oxidative stress and low-grade inflammation (214). Prebiotic inhibition of LPS target Toll-like Receptor 4 (TLR4), and downstream inflammatory affecter TNF-alpha, improved insulin sensitivity (215, 216). They also improve post-prandial blood glucose and insulin levels as well as improving glucose uptake in insulin resistant cells (217, 218, 219).

In addition, by supplying SCFAs, the preferred fuel of the enterocyte, prebiotics reduce protein fermentation in the gut (220, 221, 222). This spares amino acids for more useful purposes like building muscle as well as preventing formation of toxic breakdown products (223). We will talk a good bit more about protein sparing, later.

 

 

Polyphenols as Prebiotics

Less well known than with typical prebiotics, polyphenols are also fermented by the gut microbiota. Polyphenols are generally prebiotic for good bacteria (Bifidobacterium, Akkermansia, Bacteroides, and Roseburia), and antibacterial for less favorable and pathogenic ones (224, 225, 226). Fruit/berry based polyphenols seem to be particularly favorable toward Bacteroides and Akkermansia growth compared to other polyphenol sources (227, 228, 229). Lactobacillus lack glycan degrading enzymes, thus do not grow on them particularly well compared to the others, so they are especially targeted to butyrate producers (230).

Fermentation of herbs and such containing polyphenols also transforms them, resulting in much higher concentrations of active compounds compared to unfermented (231). 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 (232, 233). As an example, a fermented herb preparation inhibited LPS mediated inflammatory damage, while the unfermented one was ineffective (234, 235). The same was true for insulin sensitivity (236, 237). So, not only do polyphenols increase good bacteria, but the good bacteria make the polyphenols work better. The prebiotic effect plus the transformation into more active compounds is why polyphenols so consistently show a myriad of great benefits despite supposedly being so poorly bioavailable.

 

Mechanisms of Action

With the background information and general overview out of the way, we will now get deeper into the mechanisms of how this affects muscle mass. There are a lot of interacting pathways and systems here, though much of it comes down to inflammation and butyrate, both inside of the gut and outside. First, we will talk about fixing the gut, itself, both the inflammatory signaling (LPS et al) as well as the intestinal barrier that prevents them from escaping.  Within the gut, we will also discuss protein sparing and absorption/utilization improvements from a healthy microbiota and gut. Then, we will talk about anabolic and anti-catabolic pathways outside the gut.

 

Part 3 on Thursday, June 21st

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