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Clostridium Difficile - C-Diff You Say ?

Updated: Sep 27, 2023

Increasingly common has been discussion around C. Difficile both in the ME/CFS community and in the Long Haul community. A rash of clients with gut issues appeared, and so have their 4 Cresol and HPHPA results:). This article covers tools to understand and monitor c. Difficile, and a vast array of dietary, herbs, phages, and pro biotics based on published research that can tilt the odds in your favor against both gastro intestinal pathogenic strains (the most discussed) and the neurotoxic strains less discussed. 4 Cresol is linked to clostridium Difficile levels.


Clostridia Difficile infections are estimated at around 500,000 cases in the USA each year costing an estimated economic impact of around $1B, and is on the CDC's 'urgent threat' list. As many as 35% of those infected fall into cycles of infection recurrence. [59]


Exposure to C. Difficile is common in hospitals, nursing homes, and health care settings. No causal relationship is being proposed here - be it a visit to a hospital, being a nurse, or working in a hospital, or how this can "run in families" - given the very contagious nature of C. Difficile. And you can draw your own conclusions.


You may want to read this article if you are interested in :

  1. Simple, consumer direct ways to test for c. Difficile (Urine)

  2. Research that illuminates the different virulent strains of c. difficile in different parts of the world, and why testing for just 1 strain may be sub optimal

  3. Research that indicates what types of foods have been shown to trigger c. difficile to re occur

  4. Research that indicates what types of supplements and substances feed c. difficile

  5. Research that indicates which pro biotic strains have action against c. difficile

  6. Pre biotics that have been shown to inhibit c. Difficile

  7. Research that indicates which herbs have anti microbial and anti biofilm action against c. difficile

  8. Phage therapy and the specific ones that inhibit c. Difficile

  9. How depression and anti depressants effect c. Difficile susceptibility

  10. Notes on tea and how it effects both c. difficile susceptibility and can inhibit c. difficile once you have it.


I will not comment on anti biotics, nor FMT, given they are well documented, have a host of particulars i do not intend to address. My simple assessment, is they have their risks.


1. Clostridium Difficile - Testing Considerations

There are different strains of Clostridium Difficile, and there are many associated with gastro intestinal distress and infections, while others 'only' produce neurotoxins. Hugh. So, when folks say, "the hospital tested me for C. Difficile, and they said i dont have it!"..........you have to be clear what they were tested for, specifically which strain. And as you can see from the below section, there are many virulent strains, and they vary by geographic location in their prevalence. Oh crap. So, perhaps as a first step, figure out if you have too much 4 Cresol , not strain specific, and as an add on do a stool test that looks for Toxin A and Toxin B produced by some strains of Clostridium Difficile (my favorite is Vibrant America's Gut Zoomer, practitioner only ordered). You can can order organic acids tests consumer direct from one of my favorite start up businesses of all time, MyLabsForLife.com. You can also order the GI MAP and Doctors Data stool tests here, although i prefer Vibrant's offering.


From William Shaw, at Mosaic Labs, "However, the prevalent testing for Clostridium difficile toxins A and B are focused on strains that cause gastrointestinal damage. Strains that produce 4-cresol but not toxins A or B may still cause significant psychiatric disease, so performing these toxin tests may muddy the interpretation of the clinical situation if these tests are negative. I think that it is easier to treat based on the 4-cresol results and then do follow-up testing of the 4-cresol on the organic acid test 30 days after completion of treatment.". Further, William Shaw has made many public videos on the prevalence of elevated 4 Cresol in Autism cases, as well as other cases with Bipolar and other psychiatric issues. [27]


WHICH STRAIN(S) WERE YOU TESTED FOR ?

Clostridium difficile can be characterized according to its ribotyping which is performed using the polymerase chain reaction. Several different ribotypes have been associated with CDI. The ribotypes 001, 002, 014, 046, 078, 126, and 140 have been found to be prevalent in the Middle East. In Asia, ribotypes 001, 002, 014, 017, and 018 are more prevalent. The predominant strains in Europe and North America include ribotypes 001, 014, 020, 027, and 078. The ribotype 027 (also referred to as NAP1/B1/027) has emerged in the last decade. Studies have underlined antimicrobial resistance as one of the causes of its epidemic outbreaks. Capillary electrophoresis (CE) ribotyping is used as the standard for characterization of C. diff isolates. This method relies on the intergeneric region variability between 16S and 23S ribosomal deoxyribonucleic acid (DNA). Ribotype 027 was found to have reduced susceptibility to metronidazole, rifampicin, moxifloxacin, clindamycin, imipenem, and chloramphenicol. It is clinically and financially concerning as it leads to severe disease presentation, as well as antimicrobial resistance with high morbidity and mortality rates as compared to other strains. Strains, such as ribotype 027 (especially its spores), spread more easily within the hospital because they can resist the hospital environment, cleaning, and disinfectants. An observational study conducted on patients admitted with diarrhea in a Veteran Affairs Medical Center showed that around 22% of the patients were positive for the NAP1/B1/027 strain out of all the people who tested positive for CDI. Further, a reduction in the rate of diarrhea caused by the NAP1/B1/027 strain was observed with a prevalence of 16.9% in 2016, down from 26.2% in 2013. An increase in the level of awareness and education was thought to be the reason for this decline. The prevalence of this strain in North America is reportedly around 22% - 36%. Ribotype 027 was identified as the most prevalent strain causing CDI with recent outbreaks in North America. The prevalence of this strain was shown to be 48% in hospitals in Poland with an outbreak of CDI during September 2011 to August 2013. [50]


The gastrointestinal damage caused by C. difficile is thought to be due to exposure to two toxins produced by C. difficile, toxin A and toxin B, with toxin B considered to be more toxic [32]. The toxins can be tested by immunoassay of stool samples which is a fairly rapid test. Toxigenic stool culture, which requires growing the bacteria in a culture and detecting the presence of the toxins, is the most sensitive test for C. difficile, and it is still considered to be the gold standard [32]. However, it can take 2 to 3 days for results. Polymerase chain reaction (PCR) evaluation of the C. difficile toxins is also becoming more available. Virtually all of the research on C. difficile is related to the effects of this species of bacteria on the intestinal tract. Toxin-negative C. difficile strains are considered nonpathogenic for the infection of the intestine [32] but cresol producing strains that don’t produce toxins A and B may be pathogenic due to their effects on brain metabolism and for the inherent toxicity of 4-cresol itself. [32]


TESTING - WHY NOT TEST FOR ALL THE STRAINS TO START (4 CRESOL, HPHPA) ?

Fecal testing for C-Difficile is problematic, and often is characterized as black and white, you either have it or you don't. This black and white thinking could not be more effective at mis-understanding the situation. Most every body has some level of C. Difficile bacteria in their GI tract, that isn't the question - the question is - is the amount you have producing too much of a toxin load (be it Toxin A, Toxin B, or a Neuro toxin). Further, the time and preservation of a fecal sample for C. Difficile testing is very controversial, and time sensitive. I won't go into those particulars, but rather simply state that the simple to measure urine metabolites, 4 Cresol, lets you measure the level of C. Difficile indirectly, effectively, simply, and inexpensively. Organic Acids Testing (Vibrant America, Genova, Great Plains Labs - all measure this metabolite). I have never seen a test with zero 4 Cresol:). They range from $238-$400, and all are urine, and can be ordered consumer direct in some cases. Oh, that's interesting. This also lets you measure the levels over time relatively easily so you can see your progress in reducing the C. Difficile you do have, if its a problem. Oh, that's interesting. Is what I am doing working ? Who would want to know that ? Please keep in mind that the markers for being high vary test to test, and that Great Plains Lab has the biggest database - their high marker for 4 Cresol is around 39 mmol / mol creatinine for middle aged men - which is pegged at 2 standard deviations from the mean:).


William Shaw, at Great Plains Lab, has written extensively on the detection and treatment of C. Difficile. He, states, "Sometimes total Clostridia are tested using culture methods or PCR (polymerase chain reaction) technology. In one case, a parent showed me the stool test results of their child with autism. They had done a stool test with a laboratory using PCR technology to determine both C. difficile and total Clostridia. The total Clostridia was reported as extremely low and the C. difficile negative, but The Great Plains Laboratory organic acid test found high levels of the HPHPA marker. If the parent had relied on the stool test alone, their child might have missed an important therapeutic intervention that can restore normal neurotransmitter balance. The advantage of The Great Plains Laboratory organic acid test is that it is not necessary to determine particular species of Clostridia because it is the HPHPA and/or 4-cresol that are neurotoxic." [27]


He goes on. "4-cresol is predominantly produced by C. difficile, a pathogenic bacteria, that is one of the most common pathogens spread in hospitals. Toxin-producing strains of C. difficile can cause illness ranging from mild or moderate diarrhea to pseudomembranous colitis, which can lead to toxic dilatation of the colon (megacolon), sepsis, and death. 4-cresol (para-cresol) has been used as a specific marker for Clostridium difficile. 4-Cresol, a phenolic compound, is classified as a type-B toxic agent and can cause rapid circulatory collapse and death in humans. Yokoyama et al. have recently proposed that intestinal production of 4-cresol may be responsible for a growth-depressing effect on animals. Signs of acute toxicity in animals typically include hypoactivity, salivation, tremors and convulsions. High amounts of 4-cresol have been found in autism; the amount of 4- cresol in the urine has been found elevated in baseline samples and in replica samples of autistic children. Higher values of 4-cresol are found in girls with autism compared to boys with autism and higher values are associated with greater clinical severity of autistic symptoms and history of behavioral regression. 4-cresol is apparently produced by Clostridia difficile as an antimicrobial compound that kills other species of bacteria in the gastrointestinal tract, allowing the Clostridia difficile to proliferate and predominate."[27]


It appears, at least 85% of the problem is defining and identifying the problem. Are we willing to look and be curious ? It appears the easiest, simplest, most cost effective way to 'look' is to examine 4 Cresol and HPHPA first, and then move from there.


HPHPA ( 3-(3-hydroxyphenyl)-3-hydroxypropionic acid)

The primary Clostridia species which produce HPHPA include C. botulinum, C. sporogenes, and C. caloritolerans. C. botulinum is a Gram-positive, rodshaped, anaerobic, spore-forming, motile bacterium with the ability to produce the neurotoxin botulinum. Symptoms of botulism include weakness, impaired vision, fatigue, and difficulty with speech. These may then be followed by weakness of the arms, chest muscles and legs. In food borne botulism, symptoms generally begin 18 to 36 hours after eating a contaminated food, but they can occur as early as 6 hours or as late as 10 days. C. sporogenes is virtually identical to C. botulinum except it is lacking the gene for the botulinum neurotoxin. Like C. botulinum, it is an anaerobic Gram-positive, rod-shaped bacterium that produces oval, subterminal endospores and is commonly found in soil. C. caloritolerans is named after the fact that it is extremely heat (calor) resistant (tolerans). It can survive at the water temperature boiling point for 8 hours; its extreme resistance to heat may allow transmission even in well-cooked food. [57]


4-Hydroxyphenylacetic Acid

High 4-hydroxyphenylacetic acid may be associated with small intestinal bacteria overgrowth (SIBO) due to its production by C. difficile, C. stricklandii, C. lituseburense, C. subterminale, C. putrefaciens, and C. propionicum. C. difficile can be distinguished from the other species by its production of 4-cresol. No other Clostridia species produce 4-cresol. Elevated values of 4-hydroxyphenylacetic acid are common in celiac disease and cystic fibrosis and have been reported as elevated in jejuna web, transient lactose intolerance, Giardia infection, ileal resection, ileo-colic intersusseception, septicemia, and projectile vomiting. Elevations of 4-hydroxyphenylacetic acid in celiac disease and cystic fibrosis are common enough to suggest that these Clostridia bacteria may play a role in these illnesses. [57]


3-Indoleacetic Acid

High 3- indoleacetic acid in urine is a tryptophan byproduct of C. stricklandii, C. lituseburense, C. subterminale, and C. putrefaciens. No information is available on the pathogenicity of these species producing indoleacetic acid. However, very high amounts of this metabolite derived from tryptophan might indicate a depletion of tryptophan needed for other physiological functions. [57]


4-Cresol

4-Cresol is predominantly produced by C. difficile, a pathogenic bacteria, that is one of the most common pathogens spread in hospitals and nursing homes. Toxin-producing strains of C. difficile can cause illness ranging from mild or moderate diarrhea to pseudomembranous colitis, which can lead to toxic dilatation of the colon (megacolon), sepsis, and death. 4-cresol (para-cresol) has been used as a specific marker for C. difficile. It is classified as a toxic agent and can cause rapid circulatory collapse and death in humans. Intestinal production of 4-cresol may be responsible for growth suppressing effect in animals. Signs of acute toxicity in animals typically include hypoactivity, salivation, tremors and convulsions. High amounts of 4-cresol have been found in the urine of patients with Autism. [57]


How Clostridia Metabolites Inhibit Key Neurotransmitters in the Brain and Peripheral Nervous System

The combined metabolic pathway for production of human neurotransmitters in the brain, adrenal gland, and sympathetic nervous system is outlined in Figure 1 on the back page, along with the production of Clostridia bacterial substances that alter the this pathway. The key starting material for both human and Clostridia pathways is the amino acid phenylalanine. In humans, phenylalanine and/or tyrosine from dietary proteins or amino acid supplements are absorbed into blood from the intestinal tract where these amino acids cross the blood-brain barrier and enter the brain. Phenylalanine in the brain is converted to tyrosine by phenylalanine hydroxylase. The ring of tyrosine is then hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase. DOPA is then converted to dopamine by DOPA decarboxylase which requires a vitamin B6 cofactor. The fate of further dopamine metabolism depends on the neuron type. In dopamine-secreting neurons, dopamine is the final product. In these neurons, dopamine is metabolized into homovanillic acid which can be measured in the urine organic acid test. In norepinephrine-containing brain neurons, neurons in the peripheral central nervous system, and in the adrenal gland, dopamine is converted to norepinephrine by dopamine-beta-hydroxylase. Dopamine-beta-hydroxylase requires ascorbic acid and copper as cofactors. In the adrenal gland, norepinephrine is further converted to epinephrine. Both epinephrine and norepinephrine may then be metabolized into vanillylmandelic acid (VMA). In the species of Clostridia bacteria mentioned at the beginning of the article, phenylalanine is converted to HPHPA by a pathway that requires both human and bacterial enzymes. If Clostridia difficile is present, tyrosine is largely converted to 4-cresol. These byproducts are then absorbed into the body through the intestinal tract where they have the ability to inhibit dopamine-beta-hydroxylase. These byproducts covalently bind to the enzyme active site, irreversibly inhibiting conversion of dopamine to norepinephrine. [57]


Interaction Between Clostridia Markers and Neurotransmitters

The Organic Acids Test is very sensitive and can differentiate between harmful and beneficial bacteria, which is is unique among tests for Clostridia. It is also the only organic acids test available that measures HPHPA, one of the primary toxic metabolites of Clostridia. In the sample results below, the patient has a high level of HPHPA, but a low level of 4-Cresol, the main marker for C. difficile. Other tests that only measure 4-Cresol, and not HPHPA, would have missed this harmful bacterial overgrowth. [57]


Another benefit to The Organic Acids Test is that it evaluates Clostridia metabolites that can inhibit metabolism of important neurotransmitters. The test measures Homovanillic Acid (HVA), a metabolite of dopamine, as well as vanillylmandelic acid (VMA), a metabolite of norepinephrine and epinephrine. Clostridia bacteria can produce toxins that may inhibit the conversion of dopamine to norepinephrine. This can lead to a buildup of dopamine and a disruption in the dopamine to norepinephrine ratios. By assessing these metabolites, the Organic Acids Test is able to better determine the possible underlying cause of many different conditions. [57]


2. DIETARY CONSIDERATIONS (Avoid Calcium and Muciliginous Fiber)

It appears our good friend calcium is in play here based on a variety of research [1,2,3, 4, 5]. In fact so much so, some nursing homes have stopped giving and offering calcium supplements because C. Difficile is so common and easily spread in those environments, and the research so compelling that Calcium intake lays the groundwork for a C. Difficile problem to erupt. Hmmm. I have had multiple clients who had C. Difficile, and one in particular had C. Difficile re occur directly after taking calcium based supplements.


Another consideration in the dietary realm is muciliginous fiber - avoid this like the plague if you can [10,11,12,13,16, 17, 21, 22]. It is found in:

  • Flaxseeds, Chia seeds, Psyllium, Aloe vera, Kelp, Okra, Figs

  • Agar agar (algae), Cactus pads (AKA nopales)

  • Fenugreek, Marshmallow root, Slippery elm, Licorice root

  • Plantain, Cassava, Celery

Uh, oh. Some of those are commonly recommended for GI issues, as binders, as heart and brain healthy super foods, and as anti microbials. Hmmm.


Also avoid direct supplementation of the following supplements which directly feed clostridia difficile [49], and where you can foods that are naturally high in these amino's:

  • Glycine (collagen powder, bone broth, cartlidge, ice cream)

  • Leucine (cheese, dairy, animal protein)

  • Pro-line (collagen powder)

  • Alinine (workout supplements)

  • Succinate (Vitamin E Succinate)

Additionally, primary bile acids can set the stage for C. Difficile germination like taurocholate. One competitive inhibitor of taurocholate mediated germination is CamSa, a bile salt analog [61]. On the other hand secondary bile acids, like lithocholate and deoxycholate inhibit C. Difficile germination. Anti biotic treatment can kill bacteria that are necessary to convert primary bile acids into secondary bile acids, setting the stage for C. Difficile germination and expansion. [59]. Clostridia cluster xvia, and cluster XI both convert primary bile acids to secondary bile acids. TUDCA is a secondary bile acid. The gene cyp7a1 converts primary bile acids to secondary bile acids. Often mutated in clients with gut issues and high cholesterol:). It is stimulated by berberine, hawthorne, and modified citrus pectin.


Foods high in succinic acid may be wise to limit as well such as broccoli, rhubarb, sugar beets, cheese, sauerkraut, and wine.


A final note on diet. It is rare that folks who test high in 4Cresol or HPHPA don't have other significant gut dysbiosis. With this context, diets may want to be constructed in such a way to also not make these others issues worse.


5 Bacteria that compete for common food sources, like mucous derived sugars, with C. Difficile are: akkermansia muciniphila Muc, and ruthenibacterium lactatiformans 585-1, Alistipes timonensis JC136, Muribacululm intestinale YL27, Bacteroides FP24. [60]




3. PRO BIOTICS THAT HAVE DIRECT ACTION AGAINST C. DIFFICILE

[L. RETUERRI, L. PLANTARUM, L. ACIDOPHOLOUS, L. Rhamnosus GG, B. BREVE, B. LONGUM, B. LACTIS, B. pseudocatenulatum, BACILLUS CLAUSII, bacillus subtillus].


I have various and conflicting reports related to using Saccharomyces Boulardii at fairly high doses with success in containing and reducing C. Difficile, while other cases where it has caused issues. There appears to be conflicting research too. Upon further review, sacchromyces boulardii binds to one of the toxins produced by certain strains of c. Difficile, toxin A, so it is helpful in some portion of cases [70].


SOME STUDIES SUGGEST THE USE OF PROBIOTICS REVEAL NO MAGICAL STRAINS

Studies on the use of probiotics in the prevention and treatment of C. difficile infections have been promising with many well‐respected institutions incorporating them into protocol, particularly for patients with reoccurring C. difficile infections. A meta‐analysis was recently conducted that reviewed several randomized controlled trials investigating the use of probiotics against C. difficile in human subjects. The results demonstrated a reduction in the reoccurrence of infection in patients with reoccurring C. difficile infection when probiotic strains of Lactobacillus or Saccharomyces boulardii were used in combination with antibiotic treatment (PMID 19324296). A separate study indicated that S. boulardi inhibits toxins associated with C. difficile and mitigates the inflammation associated with infection (PMID: 9864230). Restoration of the intestinal microbial balance is thought to be an important aspect to preventing reoccurring infections (PMID 18199029). Patients receiving treatment with vancomycin have better outcomes when the treatment is combined with probiotic supplementation (PMID 11049785). Here probiotics can potentially prevent reoccurring infection associated with Clostridia species and reduce inflammation associated with the toxins produced by Clostridia. Here again, these are used in conjunction with antibiotic therapy, not alone to fight infection. [39]


BUT WAIT - THE DEVIL IS IN THE DETAILS.....AGAIN

Bacillus clausii and Lactobacillus reuteri secrete compounds that directly inhibit C. difficile

Certain bacteria produce antibacterial compounds, that could prevent or treat CDI. This can include molecules such as the bacteriocin produced by Bacillus thuringiensis DPC 6431. Other bacteria produce non-protein antimicrobial compounds. Lactobacillus reuteri ferments glycerol to produce reuterin, an antibacterial substance with activity against numerous enteric pathogens, including C. difficile. A recent study by Spinler and colleagues utilized L. reuteri strain 17938, which displays high-level resistance to vancomycin, metronidazole, and fidaxomicin, making it an attractive option in patients receiving concomitant anti-CDI therapy.[27] These investigators utilized a mini-bioreactor system that contained a human-derived microbial community to compare the ability of L. reuteri 17938 with or without the addition of glycerol to inhibit C. difficile growth in bioreactors pretreated with clindamycin. The combination of L. reuteri and glycerol resulted in a 5-log reduction in the growth of C. difficile in these bioreactors (P =.008). [40]


Integration of antibiotic and probiotic therapy has the potential to lessen the public health burden of antimicrobial-associated diseases. Clostridium difficile infection (CDI) represents an important example where the rational design of next-generation probiotics is being actively pursued to prevent disease recurrence. Because intrinsic resistance to clinically relevant antibiotics used to treat CDI (vancomycin, metronidazole, and fidaxomicin) is a desired trait in such probiotic species, we screened several bacteria and identified Lactobacillus reuteri to be a promising candidate for adjunct therapy. Human-derived L. reuteri bacteria convert glycerol to the broad-spectrum antimicrobial compound reuterin. When supplemented with glycerol, strains carrying the pocR gene locus were potent reuterin producers, with L. reuteri 17938 inhibiting C. difficile growth at a level on par with the level of growth inhibition by vancomycin. Targeted pocR mutations and complementation studies identified reuterin to be the precursor-induced antimicrobial agent. Pathophysiological relevance was demonstrated when the codelivery of L. reuteri with glycerol was effective against C. difficile colonization in complex human fecal microbial communities, whereas treatment with either glycerol or L. reuteri alone was ineffective. A global unbiased microbiome and metabolomics analysis independently confirmed that glycerol precursor delivery with L. reuteri elicited changes in the composition and function of the human microbial community that preferentially targets C. difficile outgrowth and toxicity, a finding consistent with glycerol fermentation and reuterin production. Antimicrobial resistance has thus been successfully exploited in the natural design of human microbiome evasion of C. difficile, and this method may provide a prototypic precursor-directed probiotic approach. Antibiotic resistance and substrate bioavailability may therefore represent critical new determinants of probiotic efficacy in clinical trials. [101]


When L. reuteri is ingested, the protective effects are reported to be due to different metabolic mechanisms. First, certain strains of L. reuteri produce an anti-inflammatory compound that lowers the expression of the proinflammatory cytokine tumor necrosis factor alpha (TNF-α) in cultured activated macrophages by more than 90% [15,16]. Second, L. reuteri produces reuterin, an antibacterial molecule that is bactericidal against a wide range of species, including enterohemorrhagic Escherichia coli strains [17]. Reuterin, also known as 3-hydroxypropionaldehyde [3-HPA], is an intermediate in the metabolism of glycerol to 1,3-propanediol, guaranteeing that the cell replenishes NAD+ during glucose metabolism [18]. This review provides an overview of data that support the role of probiotic properties, and the antimicrobial and immunomodulatory effects of L. reuteri strains in relation to their metabolism on the amelioration of many diseases and disorders (Figure 1).


Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia and insulin insensitivity associated with a diminished incretin response, subclinical inflammatory processes, and impaired glucose tolerance [32]. The insulin resistance and the postprandial glucose response can be regulated by the modulation of the gut microbiota in animal models [33]. Furthermore, the enhanced intestinal barrier function is linked to the lowering of portal lipopolysaccharide (LPS) endotoxin concentrations and of systemic and hepatic inflammation [34]. Simon et al. [32] demonstrated that daily treatment of L. reuteri SD5865 increased glucose-stimulated GLP-1 and GLP-2, improved insulin sensitivity, and elevated insulin secretion through increasing incretin release. The blood glucose-lowering action of GLP-1 is terminated due to its enzymatic degradation by dipeptidyl-peptidase-IV (DPP-IV) [35]. Another study showed that oral gavage of L. reuteri GMNL-263 (Lr263) decreased serum glucose, insulin resistance, leptin, C-peptide, and GLP-1. Moreover, when Lr263 was given, the level of HbA1c, a key indicator of glucose metabolism, was reduced [36]. The consumption of Lr263 dramatically decreased the load of Clostridia and Bacteroidetes while boosting the number of bifidobacteria and lactobacilli. These findings suggested that Lr263 treatment may have a therapeutic effect on diabetes, particularly by increasing Bifidobacterium spp. [36,37]. However, Mobini et al. [38] did not find any improvement in HbA1c in people with T2DM on insulin therapy after 12 weeks of L. reuteri DMS intake. A subset group of patients benefited from the treatment, which may be due to the diversity in their gut microbiota.


The reduction in pro-inflammatory cytokines, enhanced bile salt hydrolase (BSH) activity, and alterations in intestinal microbiota composition are all probable explanations for the positive effects of L. reuteri consumption on T2DM treatment [36]. It has been suggested that taking probiotics can increase the integrity of the intestinal epithelium and limit the TLR 4 pathway, thus lowering pro-inflammatory signals and improving insulin sensitivity [39,40]. Microbial BSH activity has been demonstrated to increase the level of unconjugated bile acids and activate G protein-coupled receptor 5 (TGR5) to improve insulin sensitivity [41].


A few strains of L. reuteri may convert the amino acid L-histidine, which is found in many foods, to the biogenic amine histamine [60]. Thomas et al. [74] reported that histamine produced from L. reuteri 6475 reduced the production of tumor necrosis factor (TNF). The activation of the histamine H2 receptor, which increased intracellular cAMP and protein kinase A, and the inhibition of MEK/ERK signaling were all required for this suppression [74]. The findings of this research point to the possible use of L. reuteri in the treatment of people with GI abnormalities. Similarly, osteoporosis that is predominant in Type 1 diabetes, which is mediated by TNF-α and suppression of Wnt10b expression, was prevented in animal model by L. reuteri [75].


Bacillus subtillus also has research that suggests it inhibits clostridium difficile [71]. Megasporebiotic, and Just Thrive have bacillus subtillus and bacillus clausii.


Yun et al., in an experimental study, revealed that L. acidophilus has a bactericidal effect on C. difficile in addition to mRNA downregulation of C. difficile virulence genes. L. acidophilus also inhibits C. difficile growth in the Clostridium difficile infected (CDI) mouse model, which may be due to a lower pH caused by organic acids produced by the probiotic bacterium.[41]


Bifidobacterium breve 46, Bifidobacterium lactis 8:8 and Bifidobacterium longum 6:18 and three reference strains B. breve CCUG 24611, B. lactis JCM 10602, and Bifidobacterium pseudocatenulatum JCM 1200 were examined for acid and bile tolerance, prebiotic utilization and antimicrobial activity against four Clostridium difficile (CD) strains including the hypervirulent strain, PCR ribotype NAP1/027. B. lactis 8:8 and B. lactis JCM 10602 exhibited a high tolerance in MRSC broth with pH 2.5 for 30 min. B. breve 46 and B. lactis 8:8 remained 100% viable in MRSC broth with 5% porcine bile after 4 h. All six strains showed a high prebiotic degrading ability (prebiotic score) with galactooligosaccharides (GOS), isomaltooligosaccharides (IMOS) and lactulose as carbon sources and moderate degradation of fructooligosaccharides (FOS). Xylooligosaccharides (XOS) was metabolized to a greater extent by B. lactis 8:8, B. lactis JCM 10602, B. pseudocatenulatum JCM 1200 and B. longum 6:18 (prebiotic score >50%). All strains exhibited extracellular antimicrobial activity (AMA) against four CD strains including the CD NAP1/027. AMA of B. breve 46, B. lactis 8:8 and B. lactis JCM 10602 strains was mainly ascribed to a combined action of organic acids and heat stable, protease sensitive antimicrobial peptides when cells were grown in MRSC broth with glucose and by acids when grown with five different prebiotic-non-digestible oligosaccharides (NDOs). None of C. difficile strains degraded five prebiotic-NDOs. [43]


Bifidobacterium longum JDM301, can inhibit c. difficile growth can degrade TcdA and TcdB, and the author further proved that the exertion of inhibition of B. Longum is that it depends on an acidic pH [Wei et. al, 2018]. Hmmm. Perhaps some betaine?


The combination of xylitol with L. plantarum Inducia suppresses the germination of spores and outgrowth into vegetative toxin producing cells of C. difficile and reduces the colonization of gut with the pathogen. [44]


Given folks with homozygous FUT2 mutations often have little to no bifido bacteria in their gut, you can see how this may be a risk factor for being more vulnerable to C. Difficile.


Pace et al. reached the same conclusion, finding that Lactobacilli, mainly L. rhamnosus GG, were not only very effective in treating recurrent C. difficile infections and other types of diarrhea but also that probiotics could be used as preventive medicine in healthy individuals. [58]


Further, a consortium of five lactobacillus and two bifidobacterium strains reduced c. Difficile numbers primarily by lowering the production of primary bile acids and increasing the production of secondary bile acids [Li, et. Al.2019].


4. SOME PREBIOTICS INHIBIT C. DIFFICLE [XOS, FOS, MANNOSE]

The xylooligosaccharides (XOS) are made up of xylose units linked by β-(1→4) ... to be effective in the treatment of recurrent C. difficile infection. [42].

Furthermore, among the carbohydrates examined, only fructooligosaccharides and mannose were found to significantly decrease adhesion (p < 0.001) of C. difficile strains. Alternatively, using a biofilm assay, we observed, via confocal laser scanning microscopy, that sub-inhibitory concentrations (1%) of fructooligosaccharides and mannose functioned to increase biofilm formation by C. difficile. [45].


5. HERBS WITH ANTI MICROBIAL EFFECTS AGAINST C. DIFFICILE

[MYRRH, B. CUMMIN SEED, POMEGRANATE, ANGELICA, VCO, CURCUMIN, THYME, OREGANO, MINT, WORMWOOD, HOPS, GARLIC, PEPPERMINT, CLOVE, NUTMEG, GINGER, CINNAMON]; [BIO FILMS - BERBERINE CHLORIDE, MANUKA HONEY]


There is quite a bit of literature on the herb Myrrh and its effect on C. Difficile, but also literature on Virgin Coconut Oil (aka Monolaurin), Black Seed Oil, Pomegranate, and Angelica (Black Pepper) [25]. Even Curcumin enters the picture [47].


Curcuminoids, the major phytoconstituents of turmeric including curcumin, demethoxycurcumin, and bisdemethoxycurcumin inhibit growth of C. difficile at concentrations ranging from 4 to 32 μg/ml. Additionally, curcuminoids showed no negative effect on major populating species of the human gut. Curcumin was more effective than fidaxomicin in inhibiting C. difficile toxin production, but less so in inhibiting spore formation. [47]


Essential oils of wild oregano, black pepper and garlic are candidates for adjunctive therapeutics in the treatment of CDI. Oregano oil should certainly be preferred due to the lack of selectivity of action in relation to the ribotype, the strength of the produced biofilm and/or antibiotic-susceptibility patterns. These natural preparations inhibited C. difficile growth in similar active concentrations (2%). Antimicrobial activity of purified hop (Humulus lupulus L.) constituents humulone, lupulone and xanthohumol against toxigenic and clinically relevant gut anaerobic bacteria B. fragilis, C. perfringens and C. difficile was demonstrated, and the strongest activity was observed for xanthohumol (15–107 μg/mL), which is close to the active concentrations of conventional antibiotics in the strains with increased antibiotic resistance [23]. Efficacy of numerous natural raw and processed products against C. difficile was demonstrated in the study of Roshan et al. [24], with the highest activity of garlic juice, peppermint oil and the four pure plant-derived compounds trans-cinnamaldehyde, allicin, menthol and zingerone. [55]


Essential oils as potential agents for control of CDI and C. difficile biofilms have been poorly studied. In previous work of Justin & Antony, antibacterial activity of the clove, nutmeg and ginger essential oils against 40 isolates of C. difficile (20 toxigenic and 20 non toxigenic) were investigated in vitro, and the results signaled for the first time essential oils as a new therapeutic option for C. difficile [25]. Antibacterial and antibiofilm activity of plant-derived compounds, e.g. asiatic acid [26], Manuka honey [27,28] and berberine chloride [29] were investigated in the recently published studies. Asiatic acid displayed an inhibitory effect on 19 C. difficile isolates collected from different sources, but did not interfere with biofilm formation [26]. Manuka honey could inhibit biofilm formation in vitro in clinically significant strains of C. difficile, especially those belonging to PCR RT (ribotype) 027 [27,28]. Berberine chloride decreased the MIC of vancomycin against the planktonic C. difficile growth, but decrease in biofilm formation has been observed for only one strain treated with a sub-inhibitory concentration of berberine chloride-vancomycin. In contrast to this, some C. difficile strains demonstrated promoted biofilm formation when sub-MIC of berberine chloride in combination with vancomycin was applied [55].


We found that thyme, ajenjo (common wormwood), and mint were the most effective against the isolates. [56]


6. PHAGE THERAPY

Recent Research indicates bacteriophages may have effective action against C. Difficile [6, 7, 8]. There are certain phage cocktails that have been studied with impressive results, namely PreforPro, found in products like Body Bio Gut Plus. It has a patented combination of LHO1 (Myoviridae); T4D (Myoviridae); LL5 (Siphoviridae); LL12 (Myoviridae), along with research that supports overall growth of healthy bacteria. [54]. Another product that contains this phage blend is Dr Tobias, PreBiotics, PreforPro Ultimate PreBiotic, available in a capsule so you can empty to a partial capsule to start.


7. TEA YOU SAY ?

Based on some preliminary research it looks like tea may be a good addition to the fight against an existing C. Difficile [9], but also pre dispose you to c. Difficile because of its broad anti microbial properties.


“Since we discovered that tea inhibits the growth of the hospital ‘superbug’, for the last two years we have been collaborating with the National Botanic Garden of Wales to try to discover what components in tea are responsible for its antibacterial activity against clostridium difficile and to understand its mechanisms of action.

“Armed with this knowledge, we will try to modify the growth conditions of a small plantation of Camellia sinensis plants this summer to produce a ‘super tea’ rich in polyphenols and high in antibacterial activity.

“The ultimate aim is to successfully produce a naturally enhanced tea that will be clinically effective against clostridium difficile infection. The idea is to find out if we can we grow a tea that has high levels of antibacterial compounds.

“We obtained 33 single plantation teas from different regions around the world and they were tested against 79 clinical strains of C.diff that arose between 2000 and 2011. We were able to test a cohort of strains to see if our tea had a broad spectrum activity against them all and they did.”

It was found that green teas were more active than black teas and that the best green tea was still potent at 3% volume in liquid form."


BUT WAIT THERE IS MORE - Tea

Interestingly enough, tea is also the only food based on statistical regression analysis to predict the recurrence of C. Difficile [26]. As always, the devil us usually in the details:). Just like with anti biotic use being a leading cause of C. Difficile, perhaps continued persistent use of herbs that kill bacteria in our gut, we can become susceptible to C. Difficile infection with tea drinking. The nuances of life:).


8. LETS NOT FORGET ABOUT BUTYRATE

Antibiotic-induced dysbiosis is a key factor predisposing intestinal infection by Clostridium difficile. Here, we show that interventions that restore butyrate intestinal levels mitigate clinical and pathological features of C. difficile-induced colitis. Butyrate has no effect on C. difficile colonization or toxin production. However, it attenuates intestinal inflammation and improves intestinal barrier function in infected mice, as shown by reduced intestinal epithelial permeability and bacterial translocation, effects associated with the increased expression of components of intestinal epithelial cell tight junctions. Activation of the transcription factor HIF-1 in intestinal epithelial cells exerts a protective effect in C. difficile-induced colitis, and it is required for butyrate effects. We conclude that butyrate protects intestinal epithelial cells from damage caused by C. difficile toxins via the stabilization of HIF-1, mitigating local inflammatory response and systemic consequences of the infection. [46]


9. DEPRESSION AND ANTI DEPRESSANTS

The population-based rate of CDI in older Americans was 282.9/100,000 person-years (95% confidence interval (CI)) 226.3 to 339.5) for individuals with depression and 197.1/100,000 person-years for those without depression (95% CI 168.0 to 226.1). The odds of CDI were 36% greater in persons with major depression (95% CI 1.06 to 1.74), 35% greater in individuals with depressive disorders (95% CI 1.05 to 1.73), 54% greater in those who were widowed (95% CI 1.21 to 1.95), and 25% lower in adults who did not live alone (95% CI 0.62 to 0.92). Self-reports of feeling sad or having emotional, nervous or psychiatric problems at baseline were also associated with the later development of CDI. Use of certain antidepressant medications during hospitalization was associated with altered risk of CDI. Adults with depression and who take specific anti-depressants seem to be more likely to develop CDI. Older adults who are widowed or who live alone are also at greater risk of CDI. [28]


Favorite Probiotic / Phage Products From Clients

  1. Body Bio - Gut Plus

  2. Dr. Tobias PreBiotics PreformPro

  3. Lifted Naturals - Super Mood Strains (L. Rhamnosus, B. Breve, B. Longum, B. Lactis); 30B

  4. Lifted Naturals - Mood Boosting Probiotic; (L. Plantarum, L. Acidopholous, L. Rhamnosus, B. Breve, B. Longum, B. Brevis) 30B

  5. Seeking Health - Histamin X (L. Plantarum, B. Breve, B. Lactis, B. Longum); 10 B

  6. Just Thrive (Bacillus Subtillus, Clausii)

  7. Restora Flora (Bacillus Subtillus, Bacillus Clausii, Sacchromyces Boullardi)

  8. Bio K + (80B formula; L. Acidopholous, L. Casei)

  9. Swanson L. Retuerri Plus (L. Acidopholous, L. Reteurri) and NOW Vegetable Glycerine

  10. Jarrow Ideal Bowel Support (L. Plantarum 299V); 10B

  11. Ecosh - Bacillus Subtilis (6B)

  12. Renew Life Ultimate Flora, Ultimate Care Probiotic, 150B, 40 Strains

  13. MicroBiome Labs Mega Genesis (L. Reuterri)

  14. Ancient Nutrition SBO Probiotics Ultimate - 50B (Sachromyces Bouldardii, Bacillus Caugulans, Bacillus Subtilis, Bacilus Clausii); 350mg (Black Pepper Fruit, Fermented Tumeric Root, Fermentd Ginger Root)

Favorite Herbals From Clients:

  1. Myrrh - Natures Way

  2. Oregano - Biotics Research

  3. Angelica - Swanson

  4. Cinnamon - Natures Way

  5. Clove - Kroger Herbs

  6. Monolaurin


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