Clostridium difficile
*This article is not medical advice. Before starting on any health related regimen, seek the advice of your Primary Care Physician or an M.D.
C. difficile Overview
Discussion around C. difficile has become increasingly common, particularly in the ME/CFS and Long Haul communities. Many clients with gut issues are now seeing elevated 4-Cresol and HPHPA levels, both of which are linked to C. difficile. This article explores tools to monitor and understand C. difficile, as well as a variety of dietary approaches, herbal treatments, phage therapy, and probiotics—based on published research—that can help manage both the more commonly discussed gastrointestinal pathogenic strains and the less frequently mentioned neurotoxic strains. It's important to note that 4-Cresol is specifically associated with Clostridium difficile levels.
C. difficile infections affect around 500,000 people in the U.S. each year, with an estimated economic impact of $1 billion. The CDC lists it as an 'urgent threat,' with approximately 35% of infected individuals experiencing recurring infections [59].
Exposure to C. difficile is common in hospitals, nursing homes, and other healthcare settings. While this article does not suggest direct causality—whether from hospital visits, working in healthcare, or familial transmission—the highly contagious nature of C. difficile speaks for itself.
Infections: Around 500,000 cases are reported annually in the USA, with an economic impact of $1 billion. Up to 35% of those infected experience recurring infections.
Urgent Threat: C. difficile is on the CDC's "urgent threat" list.
Common Exposure: C. difficile exposure often occurs in hospitals, nursing homes, and healthcare settings.
Why Read This Article?
You may find this article valuable if you're interested in:
Testing for C. difficile: Simple, consumer-direct methods (e.g., urine testing for 4-Cresol).
Strains and Locations: Research shows varying virulent strains in different parts of the world, indicating that testing for only one strain may be insufficient.
Triggers and Supplements: Foods and supplements that either trigger or inhibit C. difficile recurrence.
Probiotics & Prebiotics: Probiotic strains and prebiotics that can act against C. difficile.
Herbal Remedies: Herbs with antimicrobial and anti-biofilm action against C. difficile.
Phage Therapy: Specific phages that inhibit C. difficile.
Mental Health: How depression and antidepressants impact susceptibility to C. difficile.
Tea: Insights on tea’s dual role in both susceptibility and inhibition of C. difficile.
Note: Antibiotics and fecal microbiota transplants (FMT) are not covered in this article as they are well-documented elsewhere.
Testing Considerations
Understanding Strains and Testing
There are various strains of Clostridium difficile. Some are associated with gastrointestinal distress and infections, while others produce neurotoxins without causing gut-related symptoms. This distinction is critical when testing for C. difficile. For instance, when someone says, "The hospital tested me for C. difficile, and I don’t have it," it's important to know exactly which strain they were tested for. Many virulent strains exist, and their prevalence varies by geographic location.
As a first step, consider testing for 4-Cresol levels, which is not strain-specific but provides insight into toxin production. You can also perform a stool test for Toxins A and B, which are produced by some strains. My preferred testing option is Vibrant America's Gut Zoomer (practitioner-ordered). For consumer-direct options, you can order organic acids tests through MyLabsForLife.com. Other stool test options include GI MAP and Doctors Data tests, though I personally favor Vibrant.
According to William Shaw at Mosaic Labs, prevalent tests for C. difficile focus on Toxins A and B, which are associated with gastrointestinal damage. However, strains that produce 4-Cresol but not these toxins can still cause significant psychiatric disease. Relying solely on Toxin A and B tests may obscure the clinical picture if these results come back negative. Shaw recommends treating based on 4-Cresol results and following up with organic acid testing 30 days after completing treatment. He has also discussed the link between elevated 4-Cresol levels and conditions like Autism and Bipolar Disorder [27].
Which Strain Were You Tested For?
Clostridium difficile can be classified by its ribotypes, which are identified using polymerase chain reaction (PCR). Different ribotypes are prevalent in various regions:
Middle East: Ribotypes 001, 002, 014, 046, 078, 126, 140
Asia: Ribotypes 001, 002, 014, 017, 018
Europe and North America: Ribotypes 001, 014, 020, 027, 078
The 027 ribotype (NAP1/B1/027) has gained prominence in recent years due to its antimicrobial resistance. This ribotype has a higher morbidity and mortality rate compared to other strains and is particularly concerning in hospitals, where it can resist cleaning and disinfectants. Studies show that 22%–36% of C. difficile cases in North America involve this strain, with higher rates reported during outbreaks [50].
Toxins and Testing
The gastrointestinal damage from C. difficile is primarily caused by Toxins A and B, with Toxin B being more toxic. Testing for these toxins is often done via immunoassay or toxigenic stool culture. The latter remains the gold standard, although results take 2–3 days. PCR testing for C. difficile toxins is also becoming more common.
While toxin-negative C. difficile strains are typically considered nonpathogenic, those that produce 4-Cresol can still be harmful due to its neurotoxic effects on brain metabolism [32].
Testing for All Strains: A More Comprehensive Approach
Fecal testing for C. difficile is often viewed in black-and-white terms—either you have it, or you don’t. However, this binary thinking oversimplifies the situation. Most people carry some level of C. difficile in their gastrointestinal tract. The real question is whether your levels are producing a high toxin load, be it Toxin A, Toxin B, or a neurotoxin. Fecal testing is also time-sensitive and can be controversial due to sample preservation issues.
A more effective and simpler method is to measure urine metabolites like 4-Cresol. This test indirectly reflects C. difficile levels and is available through Organic Acids Testing at labs such as Vibrant America, Genova, and Great Plains Labs. These tests range from $238–$400 and are easy to order, even for consumers. Monitoring 4-Cresol over time can help track your progress in reducing C. difficile levels.
William Shaw from Great Plains Lab has written extensively on C. difficile detection and treatment. He points out that traditional stool tests may not catch neurotoxic strains, whereas organic acids tests can detect markers like HPHPA and 4-Cresol, which are neurotoxic.
Neurotoxins and Their Impact
4-Cresol is produced predominantly by C. difficile, a common hospital pathogen. Toxin-producing strains can cause illnesses ranging from mild diarrhea to severe colitis, megacolon, sepsis, and even death. 4-Cresol is a toxic compound that has been linked to acute toxicity in animals and elevated levels in individuals with autism.
Shaw notes that 4-Cresol production allows C. difficile to outcompete other gut bacteria, promoting its proliferation. This makes testing for 4-Cresol a valuable tool in understanding and treating C. difficile.
The Role of HPHPA
HPHPA (3-hydroxyphenyl-3-hydroxypropionic acid) is another toxic metabolite produced by Clostridium species such as C. botulinum, C. sporogenes, and C. caloritolerans. While C. botulinum produces neurotoxin botulinum, other species like C. sporogenes do not but are still pathogenic. Elevated levels of HPHPA can contribute to various neurotoxic effects, and testing for this marker can help detect harmful overgrowths of Clostridium [57].
Final Thoughts on Testing and Treatment
A comprehensive approach to Clostridia and C. difficile testing should include both fecal and urine metabolite tests, focusing on markers like 4-Cresol and HPHPA. By doing so, you can assess the full range of potential toxins and address the neurotoxic effects that may not show up in standard stool tests. Additionally, this approach allows for continuous monitoring of your progress during treatment.
By exploring both the gastrointestinal and neurotoxic impacts of C. difficile, you can make informed decisions about your health and treatment options.
Dietary Considerations: Avoid Calcium and Mucilaginous Fiber
Avoid Calcium and Mucilaginous Fiber: Calcium supplements may promote C. difficile, as seen in some nursing home settings. Avoid mucilaginous fibers like flaxseeds, psyllium, and okra, which can exacerbate issues.
Supplementation Risks: Direct supplementation of glycine, leucine, proline, and succinate should be avoided, as they feed C. difficile.
Bile Acids: Primary bile acids can aid C. difficile germination, while secondary bile acids like lithocholate inhibit it.
Research has highlighted the role of calcium in Clostridium difficile infections [1, 2, 3, 4, 5]. Some nursing homes have even stopped providing calcium supplements due to the prevalence of C. difficile in these environments and the compelling evidence that calcium intake can create favorable conditions for a C. difficile infection. I've observed multiple clients with C. difficile, and in one case, the infection recurred after taking calcium-based supplements.
Another key dietary consideration is mucilaginous fiber. It is advisable to avoid mucilaginous fiber, which can exacerbate C. difficile issues [10, 11, 12, 13, 16, 17, 21, 22]. These fibers are found in:
Flaxseeds, Chia seeds, Psyllium, Aloe vera, Kelp, Okra, Figs
Agar agar (algae), Cactus pads (Nopales)
Fenugreek, Marshmallow root, Slippery elm, Licorice root
Plantain, Cassava, Celery
Many of these fibers are commonly recommended for gastrointestinal issues, heart health, or as antimicrobials, but in the context of C. difficile, they may worsen the situation.
Supplements to Avoid
Direct supplementation of certain amino acids can also feed C. difficile [49]. It's best to avoid or limit foods and supplements high in the following:
Glycine: Found in collagen powder, bone broth, cartilage, and ice cream.
Leucine: Common in cheese, dairy, and animal protein.
Proline: Found in collagen powder.
Alanine: Present in many workout supplements.
Succinate: Found in Vitamin E succinate.
Bile Acids and C. difficile
Primary bile acids, such as taurocholate, can promote C. difficile germination. However, secondary bile acids like lithocholate and deoxycholate inhibit its growth. Antibiotic treatments may disrupt the conversion of primary bile acids to secondary bile acids, further encouraging C. difficile growth [61]. The conversion of primary to secondary bile acids is facilitated by Clostridia cluster XIVa and cluster XI. TUDCA is an example of a secondary bile acid, and the cyp7a1 gene (which may be mutated in individuals with gut issues or high cholesterol) also plays a role in this conversion [59]. This gene can be stimulated by compounds such as berberine, hawthorn, and modified citrus pectin.
Foods High in Succinic Acid
It may also be wise to limit foods high in succinic acid, such as:
Broccoli, Rhubarb, Sugar beets, Cheese, Sauerkraut, and Wine
Final Note on Diet
Individuals who test high for 4-Cresol or HPHPA often have other forms of gut dysbiosis. Therefore, it is important to structure diets in a way that addresses these broader issues without worsening the existing condition.
Bacteria That Compete with C. difficile
Several beneficial bacteria compete for common food sources (such as mucous-derived sugars) with C. difficile, including:
Akkermansia muciniphila Muc
Ruthenibacterium lactatiformans 585-1
Alistipes timonensis JC136
Muribacululm intestinale YL27
Bacteroides FP24
These bacteria can help maintain balance in the gut and reduce the chances of C. difficile overgrowth [60].
Probiotics with Direct Action Against C. difficile
Certain probiotic strains have shown effectiveness in combating C. difficile. These include:
L. reuteri,
L. plantarum,
L. acidophilus,
L. rhamnosus GG,
B. breve, B. longum,
B. lactis,
B. pseudocatenulatum,
Bacillus clausii, and
Bacillus subtilis
There have been mixed reports regarding the use of Saccharomyces boulardii at high doses. Some studies show it helps contain and reduce C. difficile, while others have reported complications. Saccharomyces boulardii binds to toxin A produced by certain C. difficile strains, which may explain its effectiveness in some cases [70].
Probiotics in Research:
Studies have shown that probiotics can be beneficial in preventing and treating C. difficile infections, especially when used alongside antibiotics. A meta-analysis of clinical trials found that probiotics like Lactobacillus and Saccharomyces boulardii reduced infection recurrence [39]. Another study highlighted that S. boulardii inhibits C. difficile toxins and reduces inflammation [PMID 9864230]. Probiotic supplementation, particularly with vancomycin treatment, improves patient outcomes by helping restore microbial balance and reducing inflammation [PMID 11049785].
The Details Matter:
Bacillus clausii and Lactobacillus reuteri secrete compounds that inhibit C. difficile. L. reuteri ferments glycerol to produce reuterin, an antimicrobial that fights various pathogens, including C. difficile. In one study, combining L. reuteri and glycerol reduced C. difficile growth significantly [40].
This approach highlights the potential of integrating probiotics and antibiotics to lessen the burden of C. difficile infections. Strains like L. reuteri have been identified as promising candidates due to their intrinsic resistance to antibiotics commonly used to treat C. difficile. When supplemented with glycerol, L. reuteri produced reuterin, which inhibited C. difficile growth as effectively as vancomycin [101].
In addition to reuterin, L. reuteri also produces an anti-inflammatory compound that lowers TNF-α, a key pro-inflammatory cytokine [15,16]. This and other mechanisms make L. reuteri a powerful tool in managing gastrointestinal and systemic inflammatory issues.
Research also suggests that Bacillus subtilis can inhibit C. difficile growth, making it another useful strain in this fight. Products like Megasporebiotic and Just Thrive contain Bacillus subtilis and Bacillus clausii [71].
Additional Studies on Probiotic Strains:
Lactobacillus acidophilus was shown to inhibit C. difficile growth and downregulate virulence genes in an experimental mouse model [41]. Similarly, a consortium of Lactobacillus and Bifidobacterium strains reduced C. difficile numbers by altering bile acid production, lowering primary bile acids while increasing secondary bile acids [Li et al., 2019].
Probiotics offer promising potential in reducing C. difficile infection rates, especially when combined with other treatments. Strains like L. reuteri, L. acidophilus, and Bifidobacterium have demonstrated significant antimicrobial activity and may be effective adjuncts in managing C. difficile infections.
Prebiotics That Inhibit C. difficile
Xylooligosaccharides (XOS), Fructooligosaccharides (FOS), and Mannose: These prebiotics have been found to reduce adhesion and inhibit C. difficile.
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].
Herbal Remedies Against C. difficile
Key Herbs: Myrrh, black cumin seed, pomegranate, curcumin, thyme, oregano, mint, garlic, cinnamon, and berberine chloride have shown antimicrobial action against C. difficile.
Biofilm Disruptors: Manuka honey and berberine chloride can help break down C. difficile biofilms.
Herbs with Antimicrobial Effects Against C. difficile
Several herbs and natural compounds have demonstrated antimicrobial activity against Clostridium difficile. These include:
Myrrh, Black Cumin Seed, Pomegranate, Angelica, Virgin Coconut Oil (Monolaurin), Curcumin, Thyme, Oregano, Mint, Wormwood, Hops, Garlic, Peppermint, Clove, Nutmeg, Ginger, and Cinnamon.
Additionally, compounds like Berberine Chloride and Manuka Honey show promise in breaking down biofilms that protect C. difficile.
Key Herbs and Essential Oils
Myrrh and Virgin Coconut Oil (Monolaurin) have been studied for their antimicrobial effects against C. difficile, along with Black Seed Oil, Pomegranate, and Angelica (Black Pepper). Curcumin, a major component of turmeric, is also notable. Curcuminoids, including curcumin, demethoxycurcumin, and bisdemethoxycurcumin, inhibit the growth of C. difficile at concentrations of 4 to 32 μg/ml. Importantly, curcuminoids do not negatively affect the major beneficial species in the human gut. While curcumin is more effective than fidaxomicin in inhibiting C. difficile toxin production, it is less effective in inhibiting spore formation.
Essential oils from wild oregano, black pepper, and garlic also show potential as adjunctive treatments for C. difficile infections (CDI). Oregano oil, in particular, is promising due to its broad-spectrum activity, including inhibition of C. difficile biofilms. Similarly, hop constituents (humulone, lupulone, xanthohumol) demonstrated strong antimicrobial effects, with xanthohumol showing activity at levels close to conventional antibiotics against antibiotic-resistant strains.
A study by Roshan et al. found that garlic juice, peppermint oil, and four pure plant compounds—trans-cinnamaldehyde, allicin, menthol, and zingerone—were highly effective against C. difficile.
Essential Oils and Biofilm Disruption
Research into essential oils as agents to control C. difficile biofilms is limited, but early studies are promising. Clove, nutmeg, and ginger essential oils demonstrated antibacterial activity against C. difficile isolates in vitro, marking them as potential therapeutic options.
Other plant-derived compounds, such as asiatic acid, Manuka honey, and berberine chloride, have been studied for their ability to inhibit C. difficile biofilms. Asiatic acid showed inhibitory effects on 19 different C. difficile isolates, though it did not disrupt biofilm formation. Manuka honey, on the other hand, was able to inhibit biofilm formation in C. difficile strains, particularly the virulent PCR ribotype 027. While berberine chloride reduced the minimum inhibitory concentration (MIC) of vancomycin against C. difficile, it was only effective at decreasing biofilm formation in certain strains. Interestingly, some C. difficile strains showed increased biofilm formation when treated with sub-inhibitory concentrations of berberine chloride combined with vancomycin.
Most Effective Herbs Against C. Difficile
Studies have identified thyme, wormwood (ajenjo), and mint as some of the most effective herbs against isolates.
Phage Therapy
Phage Cocktails: Research indicates that PreforPro phage cocktails, found in products like BodyBio Gut Plus, may inhibit C. difficile effectively.
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.
Tea as a Potential Ally and Risk Factor
Tea's Dual Role: While tea has antibacterial properties that can inhibit C. difficile, research suggests it may also predispose individuals to infection with long-term use.
Preliminary research suggests that tea may play a dual role in the fight against Clostridium difficile [9]. On one hand, its broad antimicrobial properties could help combat an existing C. difficile infection. On the other hand, frequent consumption of tea may predispose individuals to C. difficile infections due to these same properties.
A study conducted in collaboration with the National Botanic Garden of Wales explored the antibacterial activity of tea against C. difficile. Researchers aimed to identify the specific components in tea responsible for this activity and understand their mechanisms of action.
“Since we discovered that tea inhibits the growth of the hospital ‘superbug,’ we’ve been working to uncover which components in tea provide this antibacterial effect. This summer, we plan to modify the growth conditions of Camellia sinensis to produce a ‘super tea’ rich in polyphenols and antibacterial compounds,” said one researcher [26].
The team tested 33 single plantation teas from different regions against 79 clinical strains of C. difficile. The results revealed that tea had broad-spectrum antibacterial activity against all strains. Green tea was particularly effective, maintaining its potency even at a 3% volume in liquid form.
The Flip Side: Tea and C. difficile Recurrence
Interestingly, tea is the only food that, based on statistical regression analysis, can predict the recurrence of C. difficile infections [26]. This is reminiscent of the effect of antibiotics, which, while fighting infections, also increase the risk of C. difficile recurrence due to their disruption of gut bacteria. Similarly, persistent tea consumption, with its bacteria-killing properties, could potentially lead to a higher susceptibility to C. difficile infection.
As with many aspects of health, the details and nuances are crucial. While tea can be a valuable tool, its effects on gut health should be considered carefully.
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]
Depression and Anti-Depressants
Increased Risk: Depression and the use of specific antidepressants are associated with a higher risk of developing C. difficile infections, especially in older adults.
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]
Understanding and managing C. difficile involves more than just treating infections. Through targeted testing, dietary changes, probiotics, herbs, and even phage therapy, you can support your body in reducing the risk of C. difficile while enhancing overall gut health.
Food for Thought,
Mike
Favorite Probiotic / Phage Products From Clients
Body Bio - Gut Plus
Dr. Tobias PreBiotics PreformPro
Lifted Naturals - Super Mood Strains (L. Rhamnosus, B. Breve, B. Longum, B. Lactis); 30B
Lifted Naturals - Mood Boosting Probiotic; (L. Plantarum, L. Acidopholous, L. Rhamnosus, B. Breve, B. Longum, B. Brevis) 30B
Seeking Health - Histamin X (L. Plantarum, B. Breve, B. Lactis, B. Longum); 10 B
Just Thrive (Bacillus Subtillus, Clausii)
Restora Flora (Bacillus Subtillus, Bacillus Clausii, Sacchromyces Boullardi)
Bio K + (80B formula; L. Acidopholous, L. Casei)
Swanson L. Retuerri Plus (L. Acidopholous, L. Reteurri) and NOW Vegetable Glycerine
Jarrow Ideal Bowel Support (L. Plantarum 299V); 10B
Ecosh - Bacillus Subtilis (6B)
Renew Life Ultimate Flora, Ultimate Care Probiotic, 150B, 40 Strains
MicroBiome Labs Mega Genesis (L. Reuterri)
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:
Myrrh - Nature’s Way
Oregano - Biotics Research
Angelica - Swanson
Cinnamon - Natures Way
Clove - Kroger Herbs
Monolaurin
References:
[1] Study: Calcium Levels Could Be Key to Contracting —and Stopping — C. Diff U-M and FDA scientists show the key role of excess gut calcium in awakening Clostridium difficile spores. July 13, 2017. 2:00 PM
[2] Intestinal calcium and bile salts facilitate germination of Clostridium difficile spores Travis J. Kochan, Madeline J. Somers et. al. University of Michigan Medical School, Department of Microbiology and Immunology. Ann Arbor, Michigan,United States of America, 2 Center for Biologics Evaluation and Research, US Food and Drug Administration. Silver Spring, Maryland, United States of America. pchanna@umich.edu
[3] The Journal Of Immunology RESEARCH ARTICLE , NOVEMBER 15 1999. Roles of Intracellular Calcium and NF-κB in the Clostirum Dificile.....Kimberly K. Jefferson; ... et. al. J Immunol (1999) 163 (10): 5183–5191. https://doi.org/10.4049/jimmunol.163.10.5183
[4] Medical News Today, Calcium could be the answer to C.difficile infection. By Maria Cohut, Ph.D. on July 14, 2017. Scientists have found that a dangerous bacteriumcapable of causing serious gut infections is triggered byexcess calcium in its environment, but the triggeringfactor might also provide the solution
[5] HCP Live, Calcium Could Usher In Next Breakthrough in C. difficile Treatment. Aug 11, 2017. Rachel Lutz
[6] Bacteriophage Combinations Significantly Reduce Clostridium difficile Growth In Vitro and Proliferation In Vivo. Janet Y Nale 1, Janice Spencer 2, et. al. PMID: 26643348. PMCID: PMC4750681. DOI: 10.1128/AAC.01774-15
[7] NIH: Efficacy of an Optimised Bacteriophage Cocktail to Clear Clostridium difficile in a Batch Fermentation Model. Janet Y. Nale,1 Tamsin A. Redgwell, et al. Antibiotics (Basel). 2018 Mar; 7(1): 13. Published online 2018 Feb 13. doi: 10.3390/antibiotics7010013. PMCID: PMC5872124 PMID: 29438355
[8] Front Microbiol. Battling Enteropathogenic Clostridia: Phage Therapy for Clostridioides difficile and Clostridium perfringens Jennifer Venhorst, 1 , * Jos M. B. M. van der Vossen, 2 and Valeria Agamennone2022; 13: 891790. Published online 2022 Jun 13. doi: 10.3389/fmicb.2022.891790. PMCID: PMC9234517. PMID: 35770172
[9] Cardiff University: Tea - the drink that could cure a hospital infection. A joint project between the National Botanic Garden of Wales and the School of Pharmacy and Pharmaceutical Sciences at Cardiff University has collected tea samples from across the globe and is testing its ability to kill the hospital bug. By Rachael Misstear. 00:01, 14 JUL 2012. UPDATED 22:01, 26 MAR 2013
[10] Anderson E & Fireman M. “The mucilage from psyllium seed, plantago psyllium, L.” J. Biol. Chem. 1935;109:437-442.
[11] Anderson E. & Lowe HJ. “The composition of flaxseed mucilage.” J. Biol. Chem. 1947;168:289-297.
[12]Bacic A, et al. “Structural Analysis of Secreted Root Slime from Maize (Zea mays L.).” Plant Physiol. 1986 Mar;80(3):771-7.
[13] Clifford SC, et al. “Mucilages and polysaccharides in Ziziphus species (Rhamnaceae): localization, composition and physiological roles during drought-stress.” J Exp Bot. 2002 Jan;53(366):131-8.
[14] Dumitriu S. “Polymeric Biomaterials, Revised and Expanded.” 2nd ed. 2001: CRC Press. Page 485.
[15] “E. coli (Escherichia coli).” Centers for Disease Control and Prevention. Accessed January 24, 2016.
[16] Enzi G, et al. “Effect of a hydrophilic mucilage in the treatment of obese patients.” Pharmatherapeutica. 1980;2(7):421-8.
[17] Frati Munari AC, et al. “Lowering glycemic index of food by acarbose and Plantago psyllium mucilage.” Arch Med Res. 1998 Summer;29(2):137-41.
[18] Garrity G, et al., eds. “Bergey’s Manual of Systematic Bacteriology: Volume 2: The Proteobacteria.” 2nd ed. 2005: Springer.
[19] Guevara-Arauza JC, et al. “Prebiotic effect of mucilage and pectic-derived oligosaccharides from nopal (Opuntia ficus-indica).” Food Science and Biotechnology. 2012 Aug;21(4):997-1003.
[20] Innami S, et al. “Jew’s mellow leaves (Corchorus olitorius) suppress elevation of postprandial blood glucose levels in rats and humans.” Int J Vitam Nutr Res. 2005 Jan;75(1):39-46.
[21] Jang CM, et al. “Effect of mucilage from yam on activation of lymphocytic immune cells.” Nutrition Research and Practice. 2007;1(2):94-99.
[22] Köpke M, et al. “Clostridium difficile is an autotrophic bacterial pathogen.” PLoS One. 2013 Apr 23;8(4):e62157.
[23] Sannasiddappa TH, et al. “The influence of Staphylococcus aureus on gut microbial ecology in an in vitro continuous culture human colonic model system.” PLoS One. 2011;6(8):e23227.
[24] Xu Q, et al. “Levan (beta-2, 6-fructan), a major fraction of fermented soybean mucilage, displays immunostimulating properties via Toll-like receptor 4 signalling: induction of interleukin-12 production and suppression of T-helper type 2 response and immunoglobulin E production.” Clin Exp Allergy. 2006 Jan;36(1):94-101.
[25] Conventional and alternative treatment approaches for Clostridium difficile infection. Khalid M. Aljarallah. Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah, KSA. Address for correspondence: Dr. Khalid M. Aljarallah,
Department of Medical Laboratory Sciences, College of Applied Medical Sciences,
Majmaah University, Majmaah, KSA. E-mail: K.aljarallah@mu.edu.sa . WEBSITE: ijhs.org.sa ISSN: 1658-3639. PUBLISHER: Qassim University
[26] NIH: Tea and Recurrent Clostridium difficile Infection. Martin Oman Evans II, 1 , * Brad Starley,Gastroenterol Res Pract. 2016; 2016: 4514687. Published online 2016 Aug 29. Doi: 10.1155/2016/4514687. PMCID: PMC5019912. PMID: 27651790
[27] Clostridia Detection And Comparison Of Organic Acid Detection Versus Stool Testing. William Shaw, PhD | March 26, 2023. www.mosaicdiagnostics.com
[28] BMC Medicine, Research article Depression, antidepressant medications, and risk of Clostridium difficile infection. Mary AM Rogers, M Todd Greene, et. al. Open Access Published: 07 May 2013 BMC Medicine volume 11, Article number: 121 (2013)
[29] Beatty, H. Botulism. In: Harrison’s Principles of Internal Medicine, 10th edition, ed. R. Petersdorf, et al. McGraw Hill. New York. 1983. Pages 1009-1013.
[30] Meyer, K.F. and Lang, O.W. A highly heat-resistant sporulating anaerobic bacterium: Clostridium caloritolerans, N. SP. The Journal of Infectious Diseases Vol. 39, No. 4 (Oct., 1926), pp. 321-327
[31] Chalmers, R.A., Valman. H.B., and Liberman, M.M., Measurement of 4-hydroxyphenylacetic aciduria as a screening test for small-bowel disease. Clin Chem 25:1791, 1979
[32] Carrico, R.M. Association for Professionals in Infection Control and Epidemiology (APIC) Implementation Guide to Preventing Clostridium difficile Infections http://apic.org/Resource_/EliminationGuideForm/59397fc6-3f90-43d1-9325-e8be75d86888/File/2013CDiffFinal.pdf (accessed Oct 30,2014)
[33] Sivsammye, G. and Sims, H.V. Presumptive identification of Clostridium difficile by detection of p-cresol (4-cresol) in prepared peptone yeast glucose broth supplemented with p-hydroxyphenylacetic acid. J Clin Microbiol. Aug 1990; 28(8): 1851–1853.
[34] Phua, T.J., Rogers, T.R., and Pallett, A.P. Prospective study of Clostridium difficile colonization and paracresol detection in the stools of babies on a special care unit. J. Hyg., Camb. (1984). 93. 17-25 17
[35] Yokoyama, M. T., Tabori, C., Miller, E. R. and Hogberg, M. G. (1982). The effects of antibiotics in the weanling pig diet on growth and the excretion of volatile phenolic and aromatic bacterial metabolites. The American Journal of Clinical Nutrition 35, 1417-1424.
[36] Persico, A.M. and Napolioni, V. Urinary p-cresol (4-cresol) in autism spectrum disorder. Neurotoxicology and Teratology 36 (2012) 82–90
[37] Wells, J.M. and Allison, C. Molecular genetics of intestinal anaerobes. In: Human Colonic Bacteria. Role in Nutrition, Physiology, and Pathology. Gibson and MacFarlane, ed. CRC Press. Ann Arbor. 1995. Page28
[38] Conway, P. Microbial ecology of the human large intestine. In: Human Colonic Bacteria. Role in Nutrition, Physiology, and Pathology. Gibson and MacFarlane, ed. CRC Press. Ann Arbor. 1995. Pages 1-24.
[39] Mosaic Diagnostics, The Role of Probiotics in Candida and Clostridia Treatment: What Does the Evidence Say?. Jessica Bonovich, RN, BSN | January 3, 2023
[40] Probiotics for Prevention of Clostridium difficile Infection John P Mills,a Krishna Rao,a and Vincent B Younga,b,*. Curr Opin Gastroenterol. Author manuscript; available in PMC 2019 Jan 16. Published in final edited form as: Curr Opin Gastroenterol. 2018 Jan; 34(1): 3–10. doi: 0.1097/MOG.0000000000000410. PMCID: PMC6335148 NIHMSID: NIHMS1000968 PMID: 29189354
[41] Yun B, Oh S, Griffiths MW: Lactobacillus acidophilus modulates the virulence of Clostridium difficile. J Dairy Sci. 2014, 97:4745-58. 10.3168/jds.2014-7921
[42] Science Direct, Abdullah Safar Althubiani, ... Hesham A. Malak, in New Look to Phytomedicine, 2019. 4.4.4.5 Xylooligosaccharides
[43] Prebiotic-non-digestible oligosaccharides preference of probiotic bifidobacteria and antimicrobial activity against Clostridium difficile. Kanthi Kiran Kondepudi 1, Padma Ambalam et al. PMID: 22940065. DOI: 10.1016/j.anaerobe.2012.08.005
[44] A combination of the probiotic and prebiotic product can prevent the germination of Clostridium difficile spores and infection. M Rätsep 1, S Kõljalg 2, et al. PMID: 28465256. DOI: 10.1016/j.anaerobe.2017.03.019
[45] Fructooligosaccharides and mannose affect Clostridium difficile adhesion and biofilm formation in a concentration-dependent manner
Michał Piotrowski, Dorota Wultańska Eur J Clin Microbiol Infect Dis. 2019; 38(10): 1975–1984. Published online 2019 Jul 30. doi: 10.1007/s10096-019-03635-7. PMCID: PMC6778530. PMID: 31363870
[46] Cell Press, Butyrate Protects Mice from Clostridium difficile-Induced Colitis through an HIF-1-Dependent Mechanism. Jose´ Luı´s Fachi,1 Jaqueline de Souza Felipe, et al. *Correspondence: mvinolo@unicamp.br https://doi.org/10.1016/j.celrep.2019.03.054
[47] NIH: Curcumin: A natural derivative with antibacterial activity against Clostridium difficile Deepansh Mody, 1 Ahmad I. M. Athamneh, J Glob Antimicrob Resist. Author manuscript; available in PMC 2021 Jun 1. Published in final edited form as: J Glob Antimicrob Resist. 2020 Jun; 21: 154–161. Published online 2019 Oct 14. doi: 10.1016/j.jgar.2019.10.005. PMCID: PMC7153983 NIHMSID: NIHMS1544776. PMID: 31622683
[50] Cureus. The Hypervirulent Strain of Clostridium Difficile: NAP1/B1/027 - A Brief Overview
Monitoring Editor: Alexander Muacevic and John R Adler Rawish Fatima1 and Muhammad Aziz2. 2019 Jan; 11(1): e3977. Published online 2019 Jan 29. doi: 10.7759/cureus.3977. PMCID: PMC6440555 PMID: 30967977
[54] PHAGE Study: Effects of Supplemental Bacteriophage Intake on Inflammation and Gut Microbiota in Healthy Adults. by Hallie P. Febvre, 1,Sangeeta Rao, 2,Melinda Gindin et. al. Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO 80523, USA Department of Clinical Sciences, Colorado State University, Fort Collins, CO 80523, USA. Nutrients 2019, 11(3), 666; https://doi.org/10.3390/nu11030666
Received: 21 January 2019 / Revised: 8 March 2019 / Accepted: 14 March 2019 / Published: 20 March 2019
[55] In vitro anti-clostridial action and potential of the spice herbs essential oils to prevent biofilm formation of hypervirulent Clostridioides difficile strains isolated from hospitalized patients with CDI. https://doi.org/10.1016/j.anaerobe.2022.102604
[56] In Vitro Analysis of Extracts of Plant Used in Mexican Traditional Medicine, Which Are Useful to Combat Clostridioides difficile Infection
Jacqueline E. Martínez-Alva,1 Emilio Espinoza-SimónPathogens. 2022 Jul; 11(7): 774. Published online 2022 Jul 7. doi: 10.3390/pathogens11070774 PMCID: PMC9316953. PMID: 35890019
[57] The Great Plains Laboratory, now known as Mosaic Labs, "Clostridia Detection by Organic Acids Test Why the GPL Organic Acids Test is Superior to Stool Tests for Detecting Clostridia"
[58] Probiotics and Clostridium Difficile: A Review of Dysbiosis and the Rehabilitation of Gut Microbiota, Monitoring Editor: Alexander Muacevic and John R Adler, Ashish S Kalakuntla. Cureus. 2019 Jul; 11(7): e5063. Published online 2019 Jul 2. doi: 10.7759/cureus.5063. PMCID: PMC6721914. PMID: 31516774
[59] Targeting The Metabolic Basis of C. difficile's Life Cycle, American Society for Microbiology, March 4, 2021. Madelaine Barron, Ph.D.
[60] Rational design of a microbial consortium of mucosal sugar utilizers reduces Clostridiodes diffcile colonization, Nature Communications, Pereira, Wasmund, et al, Nature Communcations 11, Article, 5104, 2020. Published October 9, 2020.
[61] A New Strategy for the Prevention of Clostridum Difficile Infection, Howertron, Patra, el al. The Journal of Infectious Diseases, Volume 207, Issue 10, May 15, 2013, pages 1498-1504. https://doi.org/10.1093/infdis/jit068
[62] Beatty, H. Botulism. In: Harrison's Principles of Internal Medicine, 10th edition, ed. R. Petersdorf, et al. McGraw Hill. New York. 1983. Pages 1009-1013.
[63] Meyer, K.F. and Lang, O.W. A highly heat-resistant sporulating anaerobic bacterium: Clostridium caloritolerans, N. SP. The Journal of Infectious Diseases Vol. 39, No. 4 (Oct., 1926), pp. 321-327
[64] Chalmers, R.A., Valman. H.B., and Liberman, M.M., Measurement of 4-hydroxyphenylacetic aciduria as a screening test for small-bowel disease. Clin Chem 25:1791, 1979
[65] Carrico, R.M. Association for Professionals in Infection Control and Epidemiology (APIC) Implementation Guide to Preventing Clostridium difficile Infections http://apic.org/Resource_/EliminationGuideForm/59397fc6-3f90-43d1-9325-e8be75d86888/File/2013CDiffFinal.pdf (accessed Oct 30,2014)
[66] Sivsammye, G. and Sims, H.V. Presumptive identification of Clostridium difficile by detection of p-cresol (4-cresol) in prepared peptone yeast glucose broth supplemented with p-hydroxyphenylacetic acid. J Clin Microbiol. Aug 1990; 28(8): 1851–1853.
[67] Phua, T.J., Rogers, T.R., and Pallett, A.P. Prospective study of Clostridium difficile colonization and paracresol detection in the stools of babies on a special care unit. J. Hyg., Camb. (1984). 93. 17-25 17
[68] Yokoyama, M. T., Tabori, C., Miller, E. R. and Hogberg, M. G. (1982). The effects of antibiotics in the weanling pig diet on growth and the excretion of volatile phenolic and aromatic bacterial metabolites. The American Journal of Clinical Nutrition 35, 1417-1424.
[69] Persico, A.M. and Napolioni, V. Urinary p-cresol (4-cresol) in autism spectrum disorder. Neurotoxicology and Teratology 36 (2012) 82–90
Wells, J.M. and Allison, C. Molecular genetics of intestinal anaerobes. In: Human Colonic Bacteria. Role in Nutrition, Physiology, and Pathology. Gibson and MacFarlane, ed. CRC Press. Ann Arbor. 1995. Page28
[70] Conway, P. Microbial ecology of the human large intestine. In: Human Colonic Bacteria. Role in Nutrition, Physiology, and Pathology. Gibson and MacFarlane, ed. CRC Press. Ann Arbor. 1995. Pages 1-24
[71] Recent advances in the understanding of antibiotic resistance in Clostridium difficile infection. Spigaglia P. Ther Adv Infect Dis. 2016;3:23–42. [PMC free article] [PubMed] [Google Scholar]
[72] Clostridium difficile infection: new developments in epidemiology and pathogenesis. Rupnik M, Wilcox MH, Gerding DN. Nat Rev Microbiol. 2009;7:526–536. [PubMed] [Google Scholar]
[73] Disease associated with Clostridium difficile infection. Gerding DN. Ann Intern Med. 1989;110:255–257. [PubMed] [Google Scholar]
[74] Clostridium difficile colitis. Kelly CP, Pothoulakis C, LaMont JT. N Engl J Med. 1994;330:257–262. [PubMed] [Google Scholar]
[75] Clostridium difficile: a cause of diarrhea in children. Moreno MA, Furtner F, Rivara FP. JAMA Pediatr. 2013;167:592. [PubMed] [Google Scholar]
[76] Antibiotic associated diarrhoea: infectious causes. Ayyagari A, Agarwal J, Garg A. http://www.ijmm.org/text.asp?2003/21/1/6/8307 Indian J Med Microbiol. 2013;21:6–11. [PubMed] [Google Scholar]
[77] Epidemiology of clostridium difficile infection. DePestel DD, Aronoff DM. J Pharm Pract. 2013;26:464–475. [PMC free article] [PubMed] [Google Scholar]
[78] Probiotics as adjunctive therapy for preventing Clostridium difficile infection - what are we waiting for? Spinler JK, Ross CL, Savidge TC. Anaerobe. 2016;41:51–57. [PMC free article] [PubMed] [Google Scholar]
[79] Emergence and global spread of epidemic healthcare-associated Clostridium difficile. He M, Miyajima F, Roberts P, et al. Nat Genet. 2013;45:109–113. [PMC free article] [PubMed] [Google Scholar]
[80] Emergence and global spread of epidemic healthcare-associated Clostridium difficile. Anne-Sophie B, Benoit G. Swiss Med Wkly. 2017;147:0. [Google Scholar]
[81] Guidelines for the Evaluation of Probiotics in Food . [Jul;2018 ];http://www.who.int/foodsafety/fs_management/en/probiotic_guidelines.pdf 2002
[82] Microbiota-based therapies for Clostridium difficile and antibiotic-resistant enteric infections. Lewis BB, Pamer EG. Annu Rev Microbiol. 2017;71:157–178. [PubMed] [Google Scholar]
[83] Probiotics for prevention and treatment of Clostridium difficile infection. Valdés-Varela L, Gueimonde M, Ruas-Madiedo P. Adv Exp Med Biol. 2018;1050:161–176. [PubMed] [Google Scholar]
[84] Probiotics for gastrointestinal conditions: a summary of the evidence. Wilkins T, Sequoia J. http://www.aafp.org/afp/2017/0801/p170.html. Am Fam Physician. 2017;96:170–178. [PubMed] [Google Scholar]
[85] The Mexican consensus on probiotics in gastroenterology. Valdovinos MA, Montijo E, Abreu AT, et al. Rev Gastoenterol Mex. 2017;82:156–178. [PubMed] [Google Scholar]
[86] Probiotics for gastrointestinal disorders: proposed recommendations for children of the Asia-Pacific region. Cameron D, Hock QS, Kadim M, et al. World J Gastroenterol. 2017;23:7952–7964. [PMC free article] [PubMed] [Google Scholar]
[87] Timely use of probiotics in hospitalized adults prevents Clostridium difficile infection: a systematic review with meta-regression analysis. Shen NT, Maw A, Tmanova LL, et al. Gastroenterology. 2017;152:1889–1900. [PubMed] [Google Scholar]
[88] Review of the role of probiotics in gastrointestinal diseases in adults. Sebastián Domingo JJ. Gastroenterol Hepatol. 2017;40:417–429. [PubMed] [Google Scholar]
[89] Implementation of global strategies to prevent hospital-onset Clostridium difficile infection: targeting proton pump inhibitors and probiotics. Lewis PO, Lundberg TS, Tharp JL, Runnels CW. Ann Pharmacother. 2017;51:848–854. [PubMed] [Google Scholar]
[90] Probiotics for antibiotic-associated diarrhea: do we have a verdict. Issa I, Moucari R. World J Gastroenterol. 2014;20:17788–17795. [PMC free article] [PubMed] [Google Scholar]
[91] Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Goldenberg JZ, Yap C, Lytvyn L, Lo CK, Beardsley J, Mertz D, Johnston BC. Cochrane Database Syst Rev. 2017;12:0. [PMC free article] [PubMed] [Google Scholar]
[92] Probiotics for the prevention of antibiotic-associated diarrhea in children. Szajewska H, Canani RB, Guarino A, et al. J Pediatr Gastroenterol Nutr. 2016;62:495–506. [PubMed] [Google Scholar]
[93] Probiotics in digestive diseases: focus on Lactobacillus GG. Pace F, Pace M, Quartarone G. https://www.minervamedica.it/en/journals/gastroenterologica-dietologica/article.php?cod=R08Y2015N04A0273#. Minerva Gastroenterol Dietol. 2015;61:273–292. [PubMed] [Google Scholar]
[94] A randomized controlled trial of probiotics for Clostridium difficile infection in adults (PICO) Barker AK, Duster M, Valentine S, Hess T, Archbald-Pannone L, Guerrant R, Safdar N. J Antimicrob Chemother. 2017;72:3177–3180. [PMC free article] [PubMed] [Google Scholar]
[95] Next-generation probiotics targeting Clostridium difficile through precursor-directed antimicrobial biosynthesis. Spinler JK, Auchtung J, Brown A, et al. Infect Immun. 2017;85:0–17. [PMC free article] [PubMed] [Google Scholar]
[96] In vitro and in vivo antagonistic activity of new probiotic culture against Clostridium difficile and Clostridium perfringens. Golić N, Veljović K, Popović N, Djokić J, Strahinić Strahinić, Mrvaljević I, Terzić-Vldojević A. BMC Microbiol. 2017;17:108. [PMC free article] [PubMed] [Google Scholar]
[97] A combination of the probiotic and prebiotic product can prevent the germination of Clostridium difficile spores and infection. Rätsep M, Kõljalg S, Sepp E, et al. Anaerobe. 2017;47:94–103. [PubMed] [Google Scholar]
[98] A prospective control study of Saccharomyces boulardii in prevention of antibiotic-associated diarrhea in the older inpatients (Article in Chinese) Zhang DM, Xu BB, Yu L, Zheng LF, Cheng LP, Wang W. http://www.ncbi.nlm.nih.gov/pubmed/28592037. Zhonghua Nei Ke Za Zhi. 2017;56:398–401. [PubMed] [Google Scholar]
[99] Prospective randomized controlled study on the effects of Saccharomyces boulardii CNCM I-745 and amoxicillin-clavulanate or the combination on the gut microbiota of healthy volunteers. Kabbani TA, Pallav K, Dowd SE, et al. Gut Microbes. 2017;8:17–32. [PMC free article] [PubMed] [Google Scholar]
[100] Saccharomyces boulardii CNCM I-745 in different clinical conditions. Dinleyici EC, Kara A, Ozen M, Vandenplas Y. Expert Opin Biol Ther. 2014;14:1593–1609. [PubMed] [Google Scholar]
[101] Next-Generation Probiotics Targeting Clostridium difficile through Precursor-Directed Antimicrobial Biosynthesis Authors: Jennifer K. Spinler https://orcid.org/0000-0002-7830-7665, Jennifer Auchtung, et. al. DOI: https://doi.org/10.1128/iai.00303-17. SM Journals, Infection and Immunity, Vol. 85, No. 10