Antibiotic-Induced Clostridium Difficile Infection: Combating Bacteria with Bacteria

Ongoing research hopes to improve prevention, treatment

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By Gail Cresci, PhD, RD

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Over half of hospitalized patients receive an antibiotic for at least one day. While lifesaving, antibiotics can also put patients at risk for further infections, such as Clostridium difficile infection (CDI). The overall incidence of CDI is rising in hospitals, longterm care facilities and the community, with cases increasing in complication severity, deaths and higher healthcare-associated costs. Amongst the pediatric population, the rate of asymptomatic CD colonization is increasing. CDI is both costly and debilitating, and risk factors include exposure to antibiotic therapy, hospitalization, gastrointestinal procedures and surgery.

While antibiotic treatment is the major risk factor for CD colonization, treatment of CDI also involves antibiotic therapy. Although most patients respond to treatment, CDI recurrence rates are 15 to 30 percent, with patients highly likely to have second and third recurrences. In children, reported CD recurrence rates are 20 to 24 percent and more commonly classified as community-associated, with patients being younger (ages 3 to 10 years). To date, the best preventive measure for CDI is restricting inappropriate antibiotic usage.

In Cleveland Clinic’s Pediatric Research Center, ongoing research focuses on the gut microbiota, centering on clinical situations in which gut dysbiosis occurs, with investigations targeting alterations in metabolic byproducts of the gut microbiota. The long-term goal is to develop therapies for optimizing the gut microbiota and its metabolic byproducts to prevent or treat disease.

Gut microbiota, butyrate and intestinal health

The human intestine houses trillions of commensal bacteria (gut microbiota) dominated by nearly 800 different species. According to 16S rRNA gene analysis, Bacteroidetes and Firmicutes are the two most abundant bacterial phyla in humans after about 3 years of age; the Firmicutes contain lactic acid and butyrate-producing bacteria. A “healthy” gut microbiota supports epithelial cell health and nutrient metabolism and breakdown, and provides an indirect mucosal defense against pathogenic bacteria. The gut microbiota ferments nondigestible polysaccharides to yield short-chain fatty acids (SCFA); acetate, propionate and butyrate. Butyrate is the most dynamic SCFA and important for intestinal health. In addition to serving as the primary fuel source for colonocytes, butyrate maintains gut integrity and modulates inflammation and immune function. Without butyrate, intestinal tissue is vulnerable to apoptosis, inflammation, mucosal atrophy and colonic pathology.

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Pediatrics and gut microbiota

Initial intestinal colonization is influenced by various factors including infant mode of delivery and feeding method. Both formula-feeding and cesarean delivery are risk factors for carriage of CD, with the rate of CD colonization lower among breast-fed infants at six weeks (21 percent vs. 47 percent) and six months (19 percent vs. 39 percent).  Infants born by C-section compared with those vaginally delivered are twice as likely at the age of 4 weeks to be colonized with CD.

Inset Figure 1 Factors-Impacting-Gut-Microbiome

Antibiotics, butyrate and intestinal protection

Antibiotic therapy is one of many causes of gut dysbiosis (Figure 1), depleting commensal butyrate-producing bacteria, resulting in reduced luminal butyrate levels. Data from mouse models of broad-spectrum antibiotic therapy reveal butyrate delivery, in the form of the structured lipid tributyrin, provides intestinal protection of tight junction proteins and an anion exchanger (NEH3) (Figure 2).

Antibiotic-induced gut dysbiosis creates an environment supporting CD germination and growth. Commensal Clostridia play an important role in the metabolic welfare of colonocytes by releasing butyrate as a fermentation end-product. A recent study analyzed the gut microbiome of patients with CDI, categorizing the patients as responders or nonresponders to initial therapy. Butyrate-producing bacteria were identified in responders and absent from nonresponders.

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Counteracting pathogenic bacteria with probiotics, not antibiotics

Multiple probiotics have been tested as a possible means to prevent and/or treat CDI, with limited effectiveness likely due to an untargeted approach. A synbiotic is a physical combination of a probiotic and a prebiotic. A designer synbiotic aims to target a specific bacteria species and/or its metabolic byproducts. The group has investigated the role of a butyrate-yielding symbiotic in protecting mice during CDI. Preliminary in vivo data reveal that compared with saline, a butyrate-yielding synbiotic provided during three days of clindamycin exposure followed by a single CD spore challenge allows for early immune responses that are rapidly resolved (Figure 3A) as well as protection of gut integrity (Figure 3B).

Future directions        

Pediatric patients with recurrence tend to receive additional antibiotics for non-CDI indications during their course for the initial episode of CDI. Research findings collectively show the SCFA butyrate is important for maintaining intestinal health during a single exposure to antibiotics. As a large number of patients receive multiple antibiotics, often requiring several antibiotic courses, finding a preventive treatment for recurrent CDI during antibiotic therapy would eliminate much of the health and economic burden and improve patient quality of life. Future research will be focused on developing a pediatric recurrent mouse model that can be tested for future therapies against CDI.

Inset Figure 2

Figure 2. Tributyrin protects tight junction proteins and anion exchanger during antibiotic therapy. C57BL/6 mice exposed to broadspectrum antibiotics in water supply daily for seven days were orally gavaged daily with 5mM butyrate. (A) ZO-1 and occludin localization in proximal colon by IHC; (B) Localization of NHE3 in jejunum and ileum by IHC. Images representative of four to six mice per group.

Inset Figure 3

Figure 3. Butyrate-yielding synbiotic optimizes immune responses and gut integrity following antibiotic and C. difficile challenge. NSA mice exposed to clindamycin (IP, 15 mg/mL) for three days then oral spores of VA17 (104 CFU) four days later were cotreated with saline or synbiotic orally. Mice were allowed free access to water and chow food. Mice were euthanized one or five days after CD challenge. Proximal colon was dissected for histology. (A) mRNA expression of 1L12p40 and IFNg; (B) NHE3, claudin-3, ZO-1, occludin localization in proximal colon by IHC. Image representative of three to five mice per group.