Gut Microbes In Diabetics Produce Lactic Acid, Ammonia And Endotoxins

[Hans]

From this study: Gut Microbiota in Human Adults with Type 2 Diabetes Differs from Non-Diabetic Adults

"The proportions of phylum Firmicutes and class Clostridia were significantly reduced in the diabetic group compared to the control group (P = 0.03). Furthermore, the ratios of Bacteroidetes to Firmicutes as well as the ratios of Bacteroides-Prevotella group to C. coccoides-E. rectale group correlated positively and significantly with plasma glucose concentration (P = 0.04) but not with BMIs. Similarly, class Betaproteobacteria was highly enriched in diabetic compared to non-diabetic persons (P = 0.02) and positively correlated with plasma glucose (P = 0.04)."​

"levels of Bifidobacterium significantly and positively correlated with improved glucose-tolerance and low-grade inflammation in prebiotic treated-mice [1], [6]. Furthermore, the development of diabetes type 1 in rats was reported to be associated with higher amounts of Bacteroides ssp."​

Diabetics are low in these.

"The mean bacterial diversity, as estimated by Chao1 indices from the equalized data sets (Table 2), was not different between the diabetic subjects and the controls"​

"reduction in Bacteroides-Prevotella spp. related to a strong decrease of metabolic endotoxemia and inflammation in type 2 diabetes mice"​

Diabetics have elevated levels of these, so more endotoxin producing bacteria.

"The significantly higher levels of Bacilli and the Lactobacillus group in diabetic subjects compared to controls in the present study, have recently been reported in relation to type 2 diabetes in mice models [6] and to obesity in human adults [17], [18]. Genus Lactobacillus represents a heterogeneous group with well documented immunomodulating properties [19] and might potentially contribute to chronic inflammation in diabetic subjects."​

Lactic acid bacteria (LAB), which are gram-positive (G+) organisms, vary greatly in their capacity to induce interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-alpha), whereas gram negative (G-) organisms are consistently weak IL-12 and TNF-alpha inducers.
When weakly IL-12- and TNF-alpha-inducing LAB were mixed with G- bacteria, they synergistically induced IL-12 and TNF-alpha.
Lactic acid increases the permeability of G- bacteria and creates endotoxins more powerful than stomach acid, so a high level of LAB seen in diabetes, could significantly contribute to endotoxin formation.

"The intestinal microbiota across the subjects with type 2 diabetes was relatively enriched with Gram-negative bacteria, belonging to the phyla Bacteroidetes and Proteobacteria. The main compounds of outer membranes in gram-negative bacteria are lipopolysaccharides (LPS), known as potent stimulators of inflammation, which can exhibit endotoxaemia"​

These are known to produce ammonia from protein sources.

In conclusion, the gut microbe of diabetics produce lots of lactic acid, ammonia and endotoxins, which contributes to glucose intolerance, endotoxaemia, weight gain, ulcers, brain fog, fatigue, indigestion, liver overload, inflammation, organs damage, such as with the pancreas, kidneys, liver, brain, eyes, etc.

 

[Vinero]

I guess one way to stop the production of lactic acid, ammonia and endotoxin is to use an antibiotic like a tetracycline antibiotic or penicillin. Then after the gut has been somewhat sterilized, use foods and supplements that increase the growth of the more benign kind of bacteria with things like Cocoa, milk, and riboflavin. Any other foods and supplements that increase the right bacteria and decrease the damaging ones?

 

[Suikerbuik]

Hi @Salmonamb, thank you for all these studies. I like your emphasis on gut health, the gut is still a mystery box for most and undoubtedly of major importance for the health of every cell in our body, and even more so during low metabolism and dysfunction. I wonder if you have found something regarding phenol, p-cresol, skatole and indole?

And like Vinero, I wonder what durable strategic measurements would be to keep the terrain as cooperative as possible? I am sure Amazoniac must have some interesting views on this too.

 

[EIRE24]

I guess one way to stop the production of lactic acid, ammonia and endotoxin is to use an antibiotic like a tetracycline antibiotic or penicillin. Then after the gut has been somewhat sterilized, use foods and supplements that increase the growth of the more benign kind of bacteria with things like Cocoa, milk, and riboflavin. Any other foods and supplements that increase the right bacteria and decrease the damaging ones?

Thats all well and good in theory but it doesn't work like this. I know someone who had that same idea and when they took the antibiotic it made them worse and they got c diff and took them a long time to come around. The anti killed all the good guys and left the c diff take hold in his gut. Need to be very careful.

 

[Hans]

@Suikerbuik I have not read much about them, but here are a few studies. I hope I don't post some that you already know.
The production of urinary phenols by gut bacteria and their possible role in the causation of large bowel cancer. - PubMed - NCBI
Aerobic bacteria tended to produce phenol from tyrosine while anaerobic bacteria produce p-cresol. p-cresol is largely produced by the anaerobic flora of the left colon while phenol was produced in the ileum (when colonized) and cecum. In patients with familial polyposis the activity of the aerobic flora was apparently normal but there was greatly reduced amounts of p-cresol produced. The amounts of urinary volatile phenols in six patients with newly diagnosed large bowel cancer were not different from the normal values, indicating that cocarcinogenic phenols were unlikely to be a major cause of the disease.

Ability of intestinal lactic bacteria to bind or/and metabolise phenol and p-cresol
"Metabolites of protein fermentation in the colon, such as ammonia, H2S, indole, phenol, skatole are toxic."

"After interaction of lactobacilli with 10 μg/ml of phenol they displayed a lower genotoxicity"

"Lactobacillus strains tested did not lower the genotoxicity of p-cresol."

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2672.1996.tb04331.x
"With respect to phenolic compounds, phenylacetate and phenylpropionate producers predominated, while indoleacetate‐forming bacteria were the major tryptophan‐utilizing organisms."
"low pH and high carbohydrate availability markedly reduced dissimilatory aromatic amino acid metabolism in some organisms, but stimulated this process in others."

Nutritional Influences on Skatole Formation and Skatole Metabolism in the Pig
"Whereas many bacteria are able to metabolize tryptophan to indole and indole acetic acid (IAA), the key precursor of skatole, only a few specialized gut bacteria, mainly from the Clostridium and Bacteroides genera, can catalyze the steps from IAA to skatole"

Impact of the Gut Microbiota on Intestinal Immunity Mediated by Tryptophan Metabolism
"the microbiota influences the development of the immune system; and the immune in turn system shapes the composition of the gut microbiota"

"The gut microbiota can directly utilize Trp, which partially limits Trp availability for the host. Approximately 4–6% of Trp is metabolized to indole, indican, tryptamine, and skatole as well as indole acid derivatives by the gut microbiota "

"In GF animals, KP metabolism (kynurenine:Trp ratio) is decreased due to the microbiota deficiency (Clarke et al., 2013), and colonization by a normal microbiota in GF animals increases KP metabolism (kynurenine:Trp ratio) and reduces plasma Trp."

"Host Trp depletion resulting from IDO1 activation can reduce microbial proliferation"

"Trp has proven to exert anti-inflammatory effects in mammals, and Trp and its regulatory pathway act as important regulators of inflammatory responses (Marsland, 2016). Mice fed a low-Trp diet are more susceptible to chemically induced inflammation "

"A Trp-rich diet can increase AhR mRNA expression and activate AhR and subsequently increase colonic IL-22mRNA expression."

"Lactobacilli spp can metabolize Trp to produce AhR ligands, such as indole-3-aldehyde (IAld), which can active innate lymphoid cells (ILCs) (Zelante et al., 2013), after which mucosal resistance against the potential pathogen Candida albicans is increased."

"colonization by Bifidobacteria infantis in rodents increases Trp levels, circulating KA and the KA:kynurenine ratio and decreases the kynurenine:Trp ratio, suggesting reduced activity of IDO and Trp metabolism through KP, with no effect on kynurenine concentrations"

"Colonization by Lactobacillus johnsonii in rats also decreases ileum IDO mRNA levels and serum kynurenine concentrations"

"On the one hand, the NO produced by iNOS inhibits IDO activity by direct interaction or by stimulating IDO degradation. On the other hand, 3-hydroxyanthranilic acid, a kynurenine metabolite, inhibits the expression and catalytic activity of iNOS. Other kynurenine metabolites, quinolinic, and picolinic acids, can also enhance IFN-γ-dependent iNOS expression"

"iNOS acts as a microbicidal mediator, reducing microbial growth, and indirect antimicrobial effects are suggested to be caused by local arginine depletion after induction of iNOS or NO-dependent induction of IFN-γ"

"Serotonin plays a role in regulating the permeability of the intestine and mucosal inflammation."

"SCFAs promote TPH1 transcription and colonic serotonin production"

"lower IDO activity may result in decreased kynurenine and increased 5-HT concentrations."

"Activation of the alpha 7 nicotinic acetylcholine receptor (α7nAChr), an inflammasome activator in lipopolysaccharide (LPS) models (Kim et al., 2014), or melatonin (Galley et al., 2014) can reduce the incidence of sepsis by decreasing NLRP3 activation. Melatonin is a significant positive regulator of α7nAChr"

"Bacterial Trp metabolites, such as indole and indolic acid derivatives, are potent bioactive metabolites that affect intestinal barrier integrity and immune cells in mice by activating the pregnane X receptor (PXR) or aryl hydrocarbon receptor (AhR)...PXR-deficient mice exhibit a leaky gut and reduced expression of Muc2 in the small intestine"

"Bacterial species including E. coli, Proteus vulgaris, Paracolobactrum coliforme, Achromobacter liquefaciens, and Bacteroides spp are capable of producing indole"

"indole has been recognized as a signaling molecule that can regulate bacterial motility, biofilm formation, antibiotic resistance, persister cell formation, and virulence (Li and Young, 2013) and that plays a role in affecting host cell invasion by other non-indole-producing species, such as Salmonella enterica and P. aeruginosa and even the yeast C. albicans"

"For normal cells, indole exposure can strengthen the mucosal barrier and mucin production by inducing expression of associated genes, thereby increasing resistance to pathogen invasion; for inflammatory cells, indole exposure can suppress activation of NF-κB and proinflammatory chemokine production and simultaneously increase anti-inflammatory cytokine production, thus ameliorating inflammation and damage"

"skatole has been described as an inhibitory factor for CYP11A1, leading to decreased formation of pregnenolone...disorders of intestinal steroidogenesis have been associated with IBD."

"sugar concentrations in the intestine have a significant impact on decarboxylase activity and subsequently influence skatole production"

"pigs fed zinc bacitracin have reduced skatole concentrations"

"Tryptamine can also induce the release of serotonin (Takaki et al., 1985). Fluctuation in intestinal serotonin levels can modulate GI motility (Lundgren, 1998; Turvill et al., 2000) and is also involved in the pathology of IBD...The common gut Firmicutes C. sporogenes and Ruminococcus gnavus are capable of decarboxylating Trp to tryptamine"

"stress-induced cortisol increases IDO1 activity and gut permeability."

"Increases in the Firmicutes to Bacteroidetes ratio (Clarke et al., 2009) and the abundance of Streptococcus and Ruminococcus species are observed in IBS patients (Hong and Rhee, 2014), whereas Lactobacillus and Bifidobacteriumpopulations (Balsari et al., 1982) are decreased.

In addition, IBS is associated with increased Trp metabolism via KP (Jenkins et al., 2016). The kynurenine:Trp ratio is positively related to symptom severity in IBS (Fitzgerald et al., 2008), and IFN-γ activation and subsequent IDO1 oxidation of Trp may be a pathogenic mechanism of IBS (Fitzgerald et al., 2008). In addition, dysfunction of the serotonergic system is associated with the pathophysiology of IBS. Serotonergic modulation through acute Trp increase treatment in IBS patients induced more severe GI symptoms compared with acute Trp depletion treatment"

A few good ways to keep gut bacteria low is activated carcoal, methylene blue + iodine + red light, thyme oil, oregano oil, cinnamon, garlic, coconut oil, MCT oil, olive leaf, cocoa, glycine and a low tryptophan diet. Anti-serotonin substances will also be very useful such as cyprohetadine, ginger, etc.

 

[Suikerbuik]

@Salmonamb thank you, especially the pregnenolone connection stands out. Apparently not something that is linked to T2D, but I still think theses compounds could interfere with proper mitochondrial respiration and health. Although this one is not completely unrelated: p-Cresyl Sulfate Promotes Insulin Resistance Associated with CKD

 

[Hans]

@Salmonamb thank you, especially the pregnenolone connection stands out. Apparently not something that is linked to T2D, but I still think theses compounds could interfere with proper mitochondrial respiration and health. Although this one is not completely unrelated: p-Cresyl Sulfate Promotes Insulin Resistance Associated with CKD

This is an in vitro study, but still.
The deleterious metabolic and genotoxic effects of the bacterial metabolite p-cresol on colonic epithelial cells. - PubMed - NCBI
"At higher concentrations (0.8mM), p-cresol pretreatment uncouples cell respiration and ATP synthesis, increases DNA damage, and finally decreases the ATP cell content. Thus, we have identified p-cresol as a metabolic troublemaker and as a genotoxic agent toward colonocytes."

P-cresylsulphate, the main in vivo metabolite of p-cresol, activates leucocyte free radical production. - PubMed - NCBI
"p-cresylsulphate, the main in vivo metabolite of p-cresol, has a pro-inflammatory effect on unstimulated leucocytes. This effect could contribute to the propensity to vascular disease in the uraemic population."

Urinary p-cresol in autism spectrum disorder. - PubMed - NCBI
"Urinary p-cresol and its conjugated derivative p-cresylsulfate have been found elevated in an initial sample and recently in a replica sample of autistic children below 8 years of age"

Yeah I'm not finding much of a connection between it and T2D, but it seem pro-inflammatory and inhibits ATP production, so maybe it can contribute.

 

[jet9]

+1, my tolerance to fruits and potatoes greatly improves after single align capsule for about 3-4 days.
It's pretty expensive, so i use 1 capsule every 4 days.

 

[lvysaur]

So is there any literature on the good bacterial substances secreted in healthy people? Or is it, as most of us suspected, a simple "lack of bad stuff"?

 

[methylenewhite]

What is a safe dose of sodium benzoate to reduce ammonia? Should I just dilute pure sodium benzoate granules in water and drink?

 

[Makrosky]

+1, my tolerance to fruits and potatoes greatly improves after single align capsule for about 3-4 days.
It's pretty expensive, so i use 1 capsule every 4 days.

What is single align?