Clostridioides Difficile (C. difficile) Dysbiosis and How to Relieve It

Clostridioides Difficile (C. difficile) Dysbiosis and How to Relieve It

Clostridioides Difficile (C. difficile) Dysbiosis and How to Relieve It

Cases of Clostridioides difficile (C. difficile) infection are increasing throughout the United States causing a current healthcare crisis. An extensive, nationwide health insurance database analysis by the University of Pennsylvania determined that the annual incidence of acute C. difficile infections increased by almost two hundred percent from 2001 to 2012. “C. difficile causes over 500,000 infections per year in the United States alone, resulting in an estimated 29,000 deaths and an estimated cost of $1–3 billion.” There are many different contributing factors to why there is such an alarming increase in C. difficile infections. Overuse of antibiotics which weaken our normal probiotic flora that keeps the bacteria in check and proximity to multitudes of people within hospitals, mixing our microbiomes are significant causes of the increase in infection rate. Remember our probiotic microbiome produce many different bactericides and stimulate our immune system to reduce or eliminate the pathogens that we come in contact with in our everyday lives. C. difficile is being discussed as a potential pathogen that can be acquired as a foodborne illness as well since it can infect pigs and cattle that we ingest and can be found in commercially tested meat. The bacteria have also been found in improperly treated drinking water and raw sewage. C. difficile dysbiosis can be difficult to remedy; many people spend weeks or months in the hospital trying to recover from an infection. So what is causing the increase in C. difficile dysbiosis and what can be done to keep people from getting it as often? In addition, what protocol’s can someone follow to relieve C. difficile dysbiosis?1 2 3 4

All About Clostridioides difficile

Clostridioides difficile is an opportunistic Gram-positive bacteria that is found generally in the microbiome of at least two to five percent of the adult population. The bacteria was first named Bacillus difficilis by Ivan C. Hall and Elizabeth O’Toole in 1935. The bacteria was named difficilis because it was difficult to isolate and grew very slowly within the culture medium. André Romain Prévot eventually transferred it to the genus Clostridium, where it became commonly known as Clostridium difficile. It has recently been changed again to Clostridiodes difficile after being transferred to the new genus Clostridioides. Clostridioides are anaerobic (does not like oxygen), motile bacteria, ubiquitous in nature. C. diff forms unique endospores that are rod-shaped, produce biofilm, produce toxins, and is found in soil.5 6 7 8 9

C. diff produces two toxins when they are vegetative cells and not encapsulated in endospores that can cause significant health issues, including Clostridioides difficile toxin A and Clostridioides difficile toxin B. TcdA gene encodes C. diff toxin A and TcdB gene encodes C. diff toxin B. The toxins also are capable of reducing or eliminating some organisms within our native flora as well. Both toxins bind to specific host cell receptors in the digestive tract, which the toxins then enter the cell and induce cytopathic and cytotoxic effects. Since both toxins increase cellular oxidative stress and trigger premature cell death, they can cause inflammation (increase in immune function and cytokine production in response to the toxins) and cellular destruction in the colon leading to colitis and in the small intestine leading to ileitis for example which is sometimes severe. Finally, if the toxins enter into the bloodstream from someone having “leaky gut” they can cause toxemia, heart, kidney, and brain inflammation and damage.10 11

Endospores (not a true spore) are dormant Gram-positive bacteria generally from the Firmicutes phylum. The endospores are tough encapsulations that protect spore-forming bacteria from your immune system, antibiotics, antibacterials, and your microbiome. Spore-forming bacteria can lay dormant in endospore form until their environment becomes favorable for faster reproduction and survival. Spore-forming bacteria form endospores when there is a lack of nutrients and can survive a very long time till they get the nutrients they need to survive (the amino acids l-alanine, l-valine, l-asparagine, glycine, and fructose are some of those nutrients), they will germinate and multiply. Clostridioides difficile are resistant to stomach acid, but interestingly stomach acid reducing medications including H2 antagonists and proton pump inhibitors have been linked to increasing the risk C. difficile dysbiosis. Researchers believe it is because they interfere with normal gastrointestinal microbial diversity and people on these medications long term seem to suffer from dysbiosis which allows C. difficile to thrive because of a lack of a probiotic microbiome. Endospores are likely to germinate in the colon from repeated exposure (if enough colony forming units are ingested) or supplementation. The bacteria may also share in a commensal relationship with probiotic bacteria for a time and continue to replicate when nutrients are available. Bacterial endospores are resistant to ultraviolet radiation, desiccation, many antibiotics, boiling, extreme freezing, and most chemical disinfectants. For example, bacteria in the Clostridia class are spore-forming; it becomes difficult to eliminate them if they become opportunistic and return to their spore form.12 13 14 15

Clostridioides difficile germinates when it is exposed to bile (unlike other endospore bacteria that are a part of the Bacillus genus for example that perish when exposed to bile) or glycine within the small intestine. Once C. diff germinates, it attempts to colonize the large intestine (a perfect anaerobic environment for it). Usually, our immune system and our microbiome keeps C. diff in check so that it does not have the opportunity to become opportunistic and our digestive tract eliminates it through our stool. However, if our immune system is hindered or our gut flora is severely disrupted (taking antibiotics for example), C. diff either colonizes or if it is already native flora germinates and causes dysbiosis and infection.”Because C. difficile is an obligate anaerobic pathogen, the vegetative cells are unable to survive outside of a host in the aerobic environment. When C. difficile cells meet certain environmental stimuli (e.g., nutrient deprivation, quorum sensing, and other unidentified stress factors), they will initiate a sporulation pathway to produce sufficient dormant spores to survive in extreme situations. C. difficile pathogenesis relies on the formation of aerotolerant dormant spores which allows C. difficile to persist within the host and to disseminate through patient-to-patient contact/environmental contamination. In the host GI tract, the dormant spores must germinate from dormancy to form the actively growing vegetative cells which produce the toxins that cause the primary symptoms of the disease. Under suitable conditions, when germinant receptors sense the presence of small molecules (germinants), spore germination will be induced.16

Though C. diff dysbiosis is generally found in the large intestine, it can be found in the small intestine as well there are many reported cases of it being able to colonize the ileum. It is unknown how far in the upper gut C. diff is able to colonize but it looks like in most cases it goes no farther than the small intestine (the rest of the intestinal tract is exposed to a lot more oxygen). One of the functions of the appendix is to be a “house” for probiotic flora to colonize after a foodborne illness. In a study conducted in 2011, when C. difficile were introduced into the gut, the appendix housed cells that increased the antibody response of the body to eliminate it. The B cells of the appendix stimulate the production of toxin A-specific IgA and IgG antibodies, leading to an increased probability of probiotic flora surviving and overcoming C. difficile. Finally, here is a conclusion from a study discussing C. diff small intestine colonization: “Small intestinal Cl. difficile seems to be increasing in incidence. The spectrum of CDI has definitely expanded with small bowel involvement. Heightened public awareness and initiation of prompt preventive measures are the keystones to control of this infection. This disease is no longer limited to the colon and physicians should be educated to think beyond the colon in patients with CDI.17 18 19

How to Properly Diagnose and the Symptoms of Clostridioides difficile Dysbiosis and Infection

Symptoms of a acute Clostridioides difficile infection and dysbiosis include severe diarrhea (makes up 20% of cases of antibiotic-resistant diarrhea), abdominal pain, fever, nausea, vomiting, colitis, ileitis, malabsorption, bloating, abdominal distension, weight loss, small intestinal bacterial overgrowth, colonic overgrowth, and a distinctive foul stool odor. If you have these symptoms and have had recent antibiotic therapy (clindamycin (highest known risk of all antibiotics), fluoroquinolones, cephalosporins, aztreonam, carbapenems, macrolides, sulfonamides/trimethoprim, and penicillins all have increased risks of causing C. difficile dysbiosis), use of acid reducing medication including H2 antagonists and proton pump inhibitors, compromised immune system, recent abdominal surgery, prior appendectomy, or recent hospitalization then it is likely you have a C. difficile infection. Finally, many gastroenterologists are unaware that C. difficile in cases of chronic dysbiois and severe infection can actually cause constipation instead of diarrhea, sometimes quite severe.20 21 22 23 24

Clostridioides difficile in certain cases can cause a “reconstruction“, swelling, and extreme inflammation of the colon, a medical condition known as pseudomembranous colitis. Exogenous “mucous membranes” (very intricate biofilm colonies) are produced by C. difficile further protecting it from your immune system, probiotic flora, and antimicrobial agents and causing severe colitis. If your C. difficile infection is severe it can cause a condition known as toxic megacolon, a life-threatening medical condition where the colon greatly swells and hemorrhages causing blood loss and perforations (holes in the intestinal tract where organisms can enter the blood stream and surrounding organs) causing sepsis.25 26

Clostridioides difficile is generally diagnosed through symptomology, medical history, ELISA tests for C. difficile toxins A and B (make sure both are tested), culture and biopsy during colonoscopies or endoscopies, and diagnostic scanning including abdominal X-ray or computed tomography (CT) scan with contrast (I would recommend supplementing with iodine if possible before the CT scan with contrast and afterwards if they use Iodine-131 to protect your thyroid) to determine the health of your digestive tract and the extent of the infection. Remember, if you test positive for the C. difficile toxins, have elevated Clostridium in stool testing, and have many of the above symptoms, then C. difficile dysbiosis might be the cause of your digestive issues, even if you are suffering from chronic constipation.27 28

Clostridioides difficile is resistant to many antibiotics, creates biofilms, and can form endospores to survive treatment which makes it very difficult to recover and has a recurrence rate of around twenty percent. C. difficile infections are severe and in most cases are treated at a hospital. There are supplements and lifestyle changes that may help prevent the infection from occurring when you are hospitalized. If you are hospitalized or are on strong antibiotics for a long period, supplementation of the probiotic supplement Gutpro (taken separately during the day from the antibiotics) should be considered to help prevent opportunistic C. difficile infection. One or two servings daily of fermented food ingestion or kombucha, when ingested away from your antibiotic, may help as well. You can also supplement with thirty milligrams of exposure, and doing your best to maintain proper sleep hygiene can help as well. Excessive dietary or supplementation of calcium can also stimulate C. difficile’s germination. I would also refrain from ingesting any foods that are high in glycine like protein powders or collagen, large amounts of fructose, or trehalose (a sugar that is found in honey) because they can improve C. difficile’s chances of colonization of virulence. Proper hand washing as well (I do not recommend conventional antibacterial soap) can help reduce your chances of contracting C. difficile’s. Hand sanitizer can work against germinated C. difficile’s but does nothing to eliminate C. difficile’s spores; proper hand washing is always superior. Finally, I would avoid iron-fortified foods and carrageenan which are known to cause gut inflammation and try to follow the Perfect Health Diet if possible.29 30 31 32 33 34 35 36 37

Finally, I generally do not recommend fecal microbiome transplantation because I have read a multitude of studies and anecdotal evidence and coached many people that have had it done with minimal positive results especially in people with chronic dysbiosis. However, since Clostridioides difficile primarily colonizes the colon (where fecal microbiome transplantation appears to work best) and fecal microbiome transplantation for C. difficile is backed by research from many studies and reports of anecdotal evidence, it appears that the correct use of fecal microbiome transplantation maybe high effective in people suffering from C. difficile dysbiosis and infection. Fecal microbiome transplantation for C. difficile should be considered when all other options have failed to relieve the issue.38 39

Clostridioides difficile Dysbiosis Protocol

The Following Are My Medication Recommendations:

  • If your C. difficile dysbiosis is in the small intestine I recommend the use of the antibiotic rifaximin – take as directed (push for the use of rifaximin if possible, it has been shown through multiple studies that it can help eliminate C. difficile with fewer side effects then metronidazole (Flagyl) or vancomycin).40
  • Fidaxomicin (Dificid) – a fermentation product obtained from the actinomycete Dactylosporangium aurantiacum subspecies hamdenesis, that is a narrow spectrum macrocyclic antibiotic. Fidaxomicin seems to be poorly absorbed into systemic circulation (ninety-two percent is eliminated directly through deification) like rifaximin and seems to have little effect on some of our Gram-negative colonic probiotic flora. “Fidaxomicin has poor activity against aerobic and facultative gram-negative bacilli, Bacteroides species (MIC90 of >1,024 μg/ml), and other gram-negative anaerobes, a feature that might result in a reduced ecologic impact.” Fidaxomicin is effective against Gram-positive bacteria (remember some probiotic bacteria are Gram-positive including Lactobacillus and Bifidobacteria) especially C. difficile infection and dysbiosis. Fidaxomicin binds to and prevents movement of the “switch regions” of bacterial RNA polymerase (similar to rifamycins), trapping the RNA polymerase “clamp” in the open conformation, not allowing it to close and hold onto DNA killing the bacteria. Fidaxomicin has only been approved for use by the FDA since 2011, so more studies need to be done to prove its safety, that being said I recommend fidaxomicin over other antibiotics (other than rifaximin) that are used for the treatment of C. difficile.41 42 43
  • Nitazoxanide (Alinia)– an antibacterial, antiarchaeal, antiparasitical, antiviral medication that works well against C. difficile. Nitazoxanide has average antimicrobial side effects associated with its use including stomach pain, headache, upset stomach, vomiting, discolored urine, excessive urinating, skin rashes, itching, fever, Herxheimer reactions, and rare systemic allergic reactions. Since it binds with plasma proteins, it can increase drug toxicity for other drugs that have high plasma bonding affinity including warfarin. Finally, nitazoxanide does not appear to affect the CYP450 system. Therefore nitazoxanide should not interfere with most medications that require CYP450 proteins for metabolism unless they have high plasma bonding affinity.44
  • Chenodeoxycholic acid – a bile acid that is effective in inhibiting C. difficile germination. Side effects include allergic reactions, dark urine, constipation, diarrhea, heartburn, reflux, upset stomach, gastritis, bloating, fatigue, loss of appetite, nausea, vomiting, and jaundice. Rarely it can cause liver damage so have your liver enzymes monitored during use and try to use the lowest therapeutic dose possible. Do not use if you have gallstones in your bile duct.45 46 47 48
  • If you cannot use rifaximin (Xifaxan), fidaxomicin, or nitazoxanide (Alinia) then I would recommend the use of metronidazole (Flagyl) instead of vancomycin (bacteriostatic, inhibits the growth of C. difficile it does not outright kill it fidaxomicin) if at all possible. Vancomycin, in my opinion, should always be used as a last resort because of the risk of side effects associated with it.49

Anti-Biofilm and Anti-Endospore Protocol

  • InterFase plus (use if you do not have any mercury amalgams or are mercury burdened, if you are use InterFase instead) – two capsules in between breakfast and lunch and two capsules between lunch and dinner. If need two capsules one hour before bedtime and must be taken on an empty stomach.
  • Lactoferrin – 1,000 to 3,000 milligrams daily in divided doses with meals.50

Improve C. difficile Toxin Elimination

Protocol Recommendations and Supplements

If symptoms have not improved on a antibiotic or if you decided to tackle C. difficile dysbiosis naturally the following are antimicrobial agents that are effective against C. difficile. I recommend that you talk to your healthcare professional about choosing two or three antimicrobial agents and rotating them with new antimicrobial agents every few weeks until you recover:

  • Nature’s Way enteric-coated peppermint oil – thirty to sixty minutes before meals, twice daily. Recommended if you are suffering from diarrhea only.51
  • Thorne Research berberine – take five hundred milligrams, twice daily with meals. You can take up to three thousand milligrams daily with meals but if berberine causes hypoglycemia or gastritis, discontinue.52
  • Allicin – one capsule with breakfast and one with dinner. Use with caution if you are suffering from hydrogen sulfide dysbiosis or have CBS polymorphisms.53
  • Thorne Meriva curcumin – take one to four capsules total daily in divided doses with meals, also reduces intestinal inflammation.54
  • Ceylon cinnamon oil – works well in combination with other agents since it is bacteriostatic and hinders the growth of C. difficile but does not kill it. It also does not broadly affect the probiotic microbiome, especially probiotic Gram-negative bacteria. Mix one or two drops in with 1/2 teaspoon of extra virgin coconut oil and taken with breakfast and dinner.55

I generally do not recommend the use of the following antimicrobials unless C. difficile dysbiosis is severe since they can strongly impact the probiotic microbiome:

  • Colloidal silver (Mesosilver) – the harshest antimicrobial on the microbiome. Take one and a half teaspoons with breakfast and one and a half teaspoons with dinner.56
  • Zane Hellas oil of oregano – potent, broad spectrum, systemic antimicrobial agent. One to two soft gels with breakfast and one to two soft gels with dinner.57

Lifestyle changes and supplements that may help you recover from C. difficile dysbiosis

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