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Proc Natl Acad Sci U S A. 2006 Jun 13; 103(24): 8913–8914.
Published online 2006 Jun 5. doi:  10.1073/pnas.0603508103
PMCID: PMC1482538

Inducing endogenous antimicrobial peptides to battle infections

If asked how we currently treat a bacterial infection such as Shigella dysentery, most informed individuals would offer that we administer antibiotics. Our informed individual would add that we must also restore the losses of water and salts leaving the body as diarrhea, most likely with an appropriately designed “oral rehydration” solution. But to halt the infection itself, surely we must either treat shigellosis with antibiotics or let the infection run its course. By “run its course,” we mean simply that if we can hold off giving antibiotics long enough, the adaptive immune system will eventually assemble the macrophages, lymphocytes, and antibodies capable of fighting off this organism. Unfortunately, many children die waiting for the “sluggish” adaptive immune system to do its thing. Furthermore, overuse of antibiotics has resulted in the emergence of drug-resistant strains of Shigella in countries besieged with dysentery (1).

In this issue of PNAS, Raqib et al. (2) offer a radical and revolutionary alternative to our conventional way of thinking about the treatment of acute infectious diseases. They suggest that a disease such as shigellosis can be treated by stimulating the epithelial lining of the colon and rectum to produce an endogenous antimicrobial peptide (AMP) that kills Shigella. The “therapeutic”-inducing substance is sodium butyrate, the salt of a short-chain fatty acid normally produced in the colon, itself hardly antibacterial, and a substance that appears to be effective when administered by mouth.

To understand the logic behind the approach taken by Raqib et al. (2), we must review what is known about the role of endogenous AMPs in the defense of the intestine. AMPs are produced by all multicellular organisms, in both circulating defensive cells and on epithelial surfaces (3). By rapidly killing a broad spectrum of microbes, AMPs play a “frontline” role in the defense of epithelial barriers. Many thick, multilayered epithelial surfaces, such as epidermis and the oral mucosa, tolerate the attachment of microbes on the dead superficial layers of epithelium (which are continuously being sloughed), bacteria, and cells together. The single-celled epithelial layers that comprise the intestine, in contrast, attempt to prevent microbes from attachment by secreting AMPs onto their luminal surface.

In mammals, including humans, defensins and cathelicidins are the major classes of AMPs (35). In humans, defensins and cathelicidins are expressed by both circulating white blood cells and epithelial surfaces. Certain epithelial defensins are constitutively expressed, whereas others are induced after tissue injury or microbial exposure. In the intestine, two “systems” of AMP defense are recognized—those of the Paneth cells, which lie at the base of the small bowel crypts, and those of the “enterocyte,” which line the gut wall. Paneth cells secrete “α-defensins,” which are believed to help constrain the numbers and species of microbe in the small intestine, and protect crypt stem cells from microbial assault. The enterocytes of the small and large intestine synthesize several “β-defensins,” and the large intestine produces the cathelicidin LL-37 as well. These enterocyte-derived AMPs are secreted into a thin film overlying the luminal surface of the intestine, forming a thin antimicrobial barrier that discourages the successful attachment and growth of microbes within the lumen. Mucus covers the antimicrobial-rich film, creating a physical coat that helps limit diffusion of the secreted AMPs and itself further limits direct access by microbes to the delicate epithelial layer.

The microbial sensors that are used by the epithelium to detect the presence of microbes or tissue damage are the subject of considerable current investigation. Chronic inflammatory bowel diseases, such as Crohn’s disease, appear to, in part, result from a defect in the microbe-sensing circuitry used by certain intestinal cells, including Paneth cells, leading to inadequate production of certain AMPs (6, 7), a breakdown of the functional barrier protecting the intestinal epithelium, and a secondary, compensatory, inflammatory response.

In 2001, Islam et al. (8) published a study that suggested that Shigella caused human intestinal infection in part because it suppressed the expression of LL-37 by the enterocytes of the rectal colon. No longer subject to killing by LL-37, Shigella could home in on the enterocyte, cause barrier disruption, and eventually invade. Synthesis of LL-37 was blocked as long as clinical symptoms of shigellosis persisted. As patients began to recover, expression of LL-37 was restored (Fig. 1A). (The precise mechanism responsible for Shigella’s ability to block LL-37 remains unclear, although free bacterial or phage DNA appears to be the mediator.)

Fig. 1.
Inducing rectal epithelial antimicrobial genes to battle Shigella. The rectal colon is depicted in the setting of a Shigella infection (A) and after the resolution of the infection by oral administration of sodium butyrate (B). (A) Shigella infection. ...

In 2003, Schauber et al. (9) reported that butyric acid could induce expression of LL-37 in colonic epithelial cells in culture. Butyric acid is produced by resident colonic flora and represents a major source of the colonic enterocyte’s energy needs. It had been reported that butyric acid was required for the progressive maturation of the enterocyte (10) and that only the mature enterocyte expressed LL-37. Schauber et al. (9) convincingly demonstrated that the butyrate was inducing LL-37 expression via a mechanism independent of its effects on cell maturation. Furthermore, butyrate stimulation required engagement of the mitogen-activated protein kinase pathway and likely did not function simply as an inhibitor of histone deacetylase. Much of the intracellular pathway stimulated by butyrate, including the receptor that recognizes it, remains unknown.

In this issue of PNAS, Raqib et al. (2) evaluate the use of sodium butyrate in the treatment of shigellosis in an experimental infection in rabbits. Rabbits were administered a bacterial suspension, and almost all developed dysentery within 24 h. Once diarrhea was noted, the animals received a saline solution of sodium butyrate (0.14 mmol/kg) by mouth twice daily for 3 days (controls received saline alone). Significant benefit was observed from butyrate administration, including improvement of clinical symptoms, less blood in stool, and reduction in stool output. Within 24 h after butyrate administration, Shigella titers in stools of treated animals had fallen by 100-fold compared with controls, and by 48 h, >1,000-fold compared with those receiving saline. Examination of the rectal tissue of butyrate-treated rabbits demonstrated recovery of epithelial LL-37, in contrast to the severe suppression observed in controls. Conventional antibiotics were not administered (Fig. 1B).

Raqib et al. (2) hypothesize that butyrate improves the outcome in shigellosis as a direct consequence of its ability to restore the production of an AMP, which in turn rids the epithelium of Shigella.

The study (2) provokes several questions that we might need to answer before advancing butyrate therapy into human trials. How does orally administered sodium butyrate actually reach the rectal epithelium? We presume that butyrate would be absorbed from the proximal intestine before coming into direct contact with the distal colon. Must certain blood levels of butyrate be reached? In this experiment, animals were killed several days after treatment. Would continued administration of sodium butyrate actually effect a cure? Would oral butyrate have increased the resistance of the rabbit to the initial Shigella inoculation, thereby providing prophylaxis against disease? Would a diet rich in complex starches, natural substrates used by colonic bacteria to produce butyrate, “protect” humans and other animals from certain intestinal infections? Vitamin D has been shown recently to stimulate expression of LL-37 in human white cells and epithelial tissues, and very possibly, as a consequence, facilitate our ability to fight Mycobacterium tuberculosis (11). Would vitamin D be of benefit in shigellosis, alone or in combination with a short-chain fatty acid? What other infectious diseases, acute and chronic, might be effectively treated by administration of “nutrients” that stimulate expression of endogenous AMPs?

Conflict of interest statement: No conflicts declared.

See companion article on page 9178.


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