Clostridium difficile

Microbiome and Clostridium difficile infection

Clostridium difficile is a gram-positive spore forming rod-shaped bacterium. In both humans and animals C. difficile can be found in the intestinal tracts [1]. People with an adequate immune system can eradicate the micro-organism or will become asymptomatic carriers [2]. Nevertheless in some cases C. diff. can cause disease in people with an adequate immune system. 

The damaging disadvantage of antibiotic use
We know, that C. difficile can cause an infection with symptoms like (mild) diarrhea and abdominal cramp or it can cause even severe symptoms like a fulminant and sometimes deadly (pseudo-membranous) colitis or that in extreme cases a megatoxic colon[3]. But how does this microorganism cause disease? The main reason developing an infection of C. diff. is a disturbance of the normal intestinal flora. This disturbance is mostly caused by the use antibiotics, mainly after a pneumonia or urinary tract infection [3]. C. diff. is the most common pathogen which is associated with AAD (antibiotic associated diarrhea), it is responsible for ~10-20% of all AAD cases [ 1]. After an antibiotic therapy it takes >3 months for the intestinal flora to recover. As a result, patients remain susceptible to CDI (C. difficile infection) development long after they stopped their treatment [1]. 

The course of C. difficile
Although C. difficile can be a part of our intestinal flora [1], you can also digest it because of the feco-oral transmission route. Beside the fact that C. diff. can survive for months on for example utensils in hospitals [3], this pathogen will distribute itself easily. When C. diff. travels to the stomach, stomach acid kills the vegetative form. However the spores of this pathogen can pass the organ and germinate under the influence of bile acids [1,3,4,5]. Because the microbiota and its structure is altered in the intestine due to antibiotics, it also significantly alters the gut bacterial metabolism, specifically the metabolism of bile acid, carbohydrate and amino acid [4]. These shifts in metabolism generate an environment conducive to CDI [5]. 

Role of secondary bile acids
Mainly the alteration of the secondary bile acid production allows spore germination and outgrowth in the large intestine of C. diff. [5]. Bile acids are produced out of cholesterol by liver enzymes. The synthesized bile (primary bile acids like conjugated TCA and unconjugated CA) is stored in the gallbladder. From this place the primary bile acids travel through the small intestine, where 95% of the bile is absorbed in the terminal ilium and through the hepatic system. Only a small amount of bile remains behind and reaches the large intestine. Via deconjugation and dihydroxylation by the microbiota of the gut, primary bile acids are bio-transformed into secondary bile acids like deoxycholic- (DCA), lithocholic- (LCA) and ursodeozycholic acid (UDCA). These secondary bile acids are really important to counteract C. difficile colonisation and prevent CDI. The primary bile acids TCA (taurocholate) and CA (cholate) in the ileum provide the germination of clostridium spores into actively growing vegetative cells [4]. The secondary bile acids and competition of other members of the gut microbiota will counteract the outgrowth of these cells and are hereby able to inhibit C. difficile colonisation in the large intestine.

Smits, WK. Lyras, D. Lacy, B. Wilcox, M. Kuijper, E.J. Clostridium difficile infection. HHS Public Acces 2017 june 01. Available via: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453186/pdf/nihms857742.pdf 

As mentioned before, the use of antibiotics alters the structure and metabolism functions of the gut microbiota. The antibiotics mainly ensure a decrease in the bacteria of the gut microbiota which are able to deconjugate and dehydroxylate primary bile acids into secondary bile acids [4]. Furthermore, the use of an antibiotic also reduces the diversity of the microbiota which means less competition for C. difficile. This makes it even more possible for C. diff. to grow his cells, colonize, produce toxin and eventually cause disease. 

In conclusion, the use of antibiotics is the main reason for developing CDI. In addition to the change of the secondary bile acid production, there are even more changes in the gut microbiota and its metabolism as factors contributing to the development of CDI. These changes can be further read in the articles below. In conclusion, the host microbiota and its associated metabolites greatly influence the ability of Clostridium difficile to colonize the gut and sometimes even cause a severe infection [1]. 

                                                                                                                               Written by Mirre Verstegen
                                                                                                                                                         Posted on 10 okt 2018 

[1] Smits, WK. Lyras, D. Lacy, B. Wilcox, M. Kuijper, E.J. Clostridium difficile infection. HHS Public Acces 2017 june 01. Available via: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453186/pdf/nihms857742.pdf

[2] Leffler, A. Lamont, T. Clostridium difficile infection. In: The New England Journal of Medicine. N Engl J Med 2015; 372:1539-1548.

[3] Rijksinstituut voor Volksgezondheid en Milieu. Clostridium difficile - LCI richtlijn. Available via: https://lci.rivm.nl/richtlijnen/clostridium-difficile

[4] Theriot, C. Young, V. Interactions Between the Gastrointestinal Microbiome and Clostridium difficile. HHS public Acces 2016 June 03. Available via: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892173/

[5] Theriot, C. Bowman, A. Young, V. Antibiotic-Induced Alterations of the Gut Microbiota Alter Secondary Bile Acid Production and Allow for Clostridium