Protein Malnutrition Impairs Intestinal Epithelial Cell Turnover, a Potential Mechanism of Increased Cryptosporidiosis in a Murine Model

Abstract

Malnutrition and cryptosporidiosis form a vicious cycle and lead to acute and long-term growth impairment in children from developing countries. Insights into mechanisms underlying the vicious cycle will help to design rational therapies to mitigate this infection. We tested the effect of short-term protein malnutrition on Cryptosporidium parvum infection in a murine model by examining stool shedding, tissue burden, and histologic change and explored the mechanism underlying the interaction between malnutrition and cryptosporidiosis through immunostaining and immunoblotting. Protein malnutrition increased stool shedding and the number of intestine-associated C. parvum organisms, accompanied by significant suppression of C. parvum-induced caspase 3 activity and expression of PCNA and Ki67, but activation of the Akt survival pathway in intestinal epithelial cells. We find that even very brief periods of protein malnutrition may enhance (or intensify) cryptosporidiosis by suppressing C. parvum-induced cell turnover and caspase-dependent apoptosis of intestinal epithelial cells. This implicates a potential strategy to attenuate C. parvum's effects by modulating apoptosis and promoting regeneration in the intestinal epithelium.

Campylobacter jejuni and associated immune mechanisms: short-term effects and long-term implications for infants in low-income countries

“…If malnutrition leads to villous blunting and thus poor absorption, does the resultant malabsorption then foster further malnutrition, or is there a limit to the dysfunction one can accrue? Recently, Liu et al [39] demonstrated that even short-term protein malnutrition can lead to decreased weight gain, increased pathogen burdens and stifled epithelial cell proliferation in a murine model of Cryptosporidium parvum infection. Although C. parvum and C. jejuni infections differ greatly in their pathogenesis and rates of occurrence per location, the conclusion of this study is that diet plays a major role in the body’s ability to initiate repair mechanisms even after abbreviated periods of protein malnutrition.…”

The Burden of Enteropathy and “Subclinical” Infections

“…68,69 Cryptosporidial infection in the setting of protein deficiency also caused impaired turnover of infected epithelial cells. 70 Similar synergies with protein or zinc deficiency were seen with EAEC infections. 71–73 Conversely, murine rotavirus infections were less severe in undernourished conditions, 74 which may be because the intestinal villi were blunted and less efficiently provided the lactase needed to “uncoat” the virus as part of pathogenesis.…”

“…Furthermore, field and lab model studies can identify hypotheses to be tested in other study designs and raise potential interventions worthy of testing. For example, the impairment of cell turnover with protein deficiency that greatly increases the intensity and severity of cryptosporidial infection noted above 70 raises the possibility that intestinal repair nutrients like glutamine or citrulline might reduce the impaired growth and development seen with this infection in clinical studies.…”

“…Such protection could range from improved innate or acquired immunity to epithelial cell turnover, an important component of host defense. 70 Equally, very limited, carefully targeted, single-dose antimicrobials might enable catch-up growth responses to nutrition therapy to set a child’s growth onto a new trajectory. Finally, an alert and healthy child will engage more parental and caregiver interactions to support the critical impact of cognitive stimulation on child development.…”

Deprivation of dietary fiber enhances susceptibility of mice to cryptosporidiosis

“…Various Cryptosporidium species are recognized weeks [17,18]. A protective role of the gut microbiota against cryptosporidiosis was also observed in neonatal mice [19,20] A protein-deficient diet was also found to increase susceptibility of mice to C. parvum [21]. This phenotype was attributed to a reduced epithelial cell turnover.…”