Clostridium difficile and Clostridium perfringens: Clostridial Enteropathy

Clostridial enteropathy is typically associated with stressors or situations that induce intestinal dysbiosis, allowing opportunistic overgrowth. Clostridial enterop­athy occurs sporadically in the mouse due to infection with toxigenic C.

Epizootiology and Pathogenesis

Clostridium difficile causes enteropathy in many species, including the laboratory mouse. Toxigenic C. difficile produces two exotoxins known as C. difficile Toxin A (TcdA) and Toxin B (TcdB). Clostridium perfringens may produce one or more major exotoxins that are associated with disease in many species. Exotoxins define C. per­fringens into 5 major types (A through E). Type A is most often associated with production of enterotoxin, but any type can produce enterotoxin. Natural disease in labora­tory mice has been associated with C. perfringens nontype A, type A, type B, and type D. Anecdotal observations have associated outbreaks with high carbo­hydrate diets, inadequate normal microbial flora in barrier-maintained pathogen-free colonies, reduced fre­quency of cage changing, and peak lactation.

Pathology

Enteropathy due to C. difficile has been common in mice from one commercial vendor. Lesions are similar to enteropathy associated with C. perfringens (below), and involve the small and/or large intestine. Clostrial enter­opathy due to C. perfringens has been reported in mice ranging from 2 to 52 days of age and female mice of breeding age. Clinically affected mice have distended abdomens, soft feces, and sudden death. Both the small and large intestine may be dilated with gas and fluid, with mucosal hyperemia, petechiae, ulceration, and fibrinous pseudomembrane formation. Intestinal rup­ture and peritonitis may occur. In addition to inflamma­tory and hyperplastic changes in the mucosa of the small and/or large intestine (Fig. 1.53), multiple focal atypia were described in the duodenal mucosa of monoconta­minated BALB/c mice, as well as atrial thrombosis and pulmonary inflammation.

FIG. 1.53. Large intestine of a mouse naturally infected with Clostridium difficile. There is moderate hyperplasia of crypts with marked edema and leukocytic infiltration of the mucosa and submucosa.

FIG. 1.54. Postparturient lactating mouse with markedly dilated intestine filled with fluid and gas. The mouse has been skinned, and the intestine is visible through the unincised abdominal wall. This syndrome may be Clostridial in origin. (Source: Feinstein et al. 2008. Reproduced with permission from American Association for Laboratory Animal Science.)

A spontaneous disease, which has been termed “paralysis of peristalsis in lactating mice,” occurs in lactating dams of various genetic backgrounds, with mortality up to 40%. The syndrome is manifest as sud­den death, usually during the second week of their first lactation. There may be fecal staining in the perineal region with distention of the abdomen. The stomach is usually slightly dilated and filled with watery fluid. The proximal small intestine is distended with fluid con­tents. Firm, conical fecal plugs may be present in the ileum and the tip of the cecum. Histological findings have been reported to be unremarkable, and pathogenic organisms were not recovered from the intestine or other tissues. More recently, similar syndromes have been described in which affected mice had segmental disten­tion of the small intestine with fluid and gas (Fig.

Diagnosis

A presumptive diagnosis can be based upon clinical history and intestinal lesions containing overgrowth of Gram-positive rods. Culture does not necessarily incriminate the bacterium, since they are often present without disease and may not be toxigenic. Although detection of exotoxins in the intestinal con­tent is desirable, assays are generally not available, expensive, or insensitive due to lability of toxins. PCR can be used to speciate organisms and determine presence of toxin genes. Differential diagnoses include Tyzzer's disease and (in the recovery phase) causes of hyperplastic enteritides (Citrobacter, Helicobacter, E. coli, etc.).