Phenylbutyrate Counteracts Shigella Mediated Downregulation of Cathelicidin in Rabbit Lung and Intestinal Epithelia: A Potential Therapeutic Strategy

Sarker, Protim; Ahmed, Sultan; Tiash, Snigdha; Rekha, Rokeya Sultana; Strömberg, Roger; Andersson, Jan; Bergman, Peter; Guðmundsson, Guðmundur H.; Agerberth, Birgitta; Raqib, Rubhana

doi:10.1371/journal.pone.0020637

Cited by 79 publications

(70 citation statements)

References 32 publications

(52 reference statements)

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“…Given the broad spectrum of beneficial effects attributed to PBA (21), it is not too surprising that the specific mode of action may vary depending on the disease models employed. Nevertheless, our study agrees with those of (12,16), although different mechanisms appear to contribute to this effect.…”

Section: Discussionsupporting

confidence: 91%

“…These advantageous outcomes are consistent with previous studies that illustrated the beneficial effects of PBA treatment during infection with either Shigella or M. tuberculosis (16,17), as well as during DSS colitis (12). However, the mechanism by which PBA administration is beneficial during S. Typhimurium infection appears to be different than what has been described in these earlier studies.…”

Section: Discussionsupporting

confidence: 89%

“…Both diet and dietary supplements can shape the composition of the intestinal microbiota, which in turn modulates the immune system and determines resistance or susceptibility to infection (reviewed in reference 41). As supplementation with PBA was shown to provide benefit to the host during intestinal infection with Shigella flexneri (16) and in a dextran sodium sulfate (DSS) colitis model (12), we first set out to investigate whether PBA supplementation alters the composition of the intestinal microbiota.…”

Section: Resultsmentioning

confidence: 99%

“…It was first shown that, in a rabbit model of Shigella infection, PBA counteracted the Shigella-mediated downregulation of antimicrobial protein CAP-18 (also known as cathelicidin-related antimicrobial peptide [CRAMP]), thereby leading to reduced clinical illness in the rabbit lung and gut epithelium (15,16). In a subsequent study, the authors demonstrated that administration of PBA in combination with vitamin D 3 induced cathelicidin (called LL-37 in humans) in macrophages and lymphocytes, leading to effective intracellular killing of Mycobacterium tuberculosis by macrophages (17).…”

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confidence: 99%

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Beneficial Effects of Sodium Phenylbutyrate Administration during Infection with Salmonella enterica Serovar Typhimurium

et al. 2016

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c Sodium phenylbutyrate (PBA) is a derivative of the short-chain fatty acid butyrate and is approved for treatment of urea cycle disorders and progressive familial intrahepatic cholestasis type 2. Previously known functions include histone deacetylase inhibitor, endoplasmic reticulum stress inhibitor, ammonia sink, and chemical chaperone. Here, we show that PBA has a previously undiscovered protective role in host mucosal defense during infection. Administration of PBA to Taconic mice resulted in the increase of intestinal Lactobacillales and segmented filamentous bacteria (SFB), as well as an increase of interleukin 17 (IL-17) production by intestinal cells. This effect was not observed in Jackson Laboratory mice, which are not colonized with SFB. Because previous studies showed that IL-17 plays a protective role during infection with mucosal pathogens, we hypothesized that Taconic mice treated with PBA would be more resistant to infection with Salmonella enterica serovar Typhimurium (S. Typhimurium). By using the streptomycin-treated mouse model, we found that Taconic mice treated with PBA exhibited significantly lower S. Typhimurium intestinal colonization and dissemination to the reticuloendothelial system, as well as lower levels of inflammation. The lower levels of S. Typhimurium gut colonization and intestinal inflammation were not observed in Jackson Laboratory mice. Although PBA had no direct effect on bacterial replication, its administration reduced S. Typhimurium epithelial cell invasion and lowered the induction of the proinflammatory cytokine IL-23 in macrophage-like cells. These effects likely contributed to the better outcome of infection in PBA-treated mice. Overall, our results suggest that PBA induces changes in the microbiota and in the mucosal immune response that can be beneficial to the host during infection with S. Typhimurium and possibly other enteric pathogens. S odium 4-phenylbutyrate (phenylbutyric acid [PBA]) is related to the short-chain fatty acid (SCFA) butyrate, differing by the presence of a phenyl group at the 4 position. PBA is an orphan drug, originally approved for urea cycle disorders (1) and subsequently approved for progressive familial intrahepatic cholestasis type 2 (2). The compound has been used in preclinical and clinical studies as a treatment for a variety of diseases, including other urea cycle disorders (3), spinal muscular atrophy (4), homozygous ␤-thalassemia (5), and cancer (6). Additionally, PBA was shown to be effective in the treatment of neurodegenerative diseases, including Parkinson's disease (7).Recent studies have revealed that PBA also plays a role in the reduction of endoplasmic reticulum (ER) stress caused by the unfolded protein response (UPR), thereby suppressing oxidative stress in several animal models (8-11), including in a mouse colitis model (12). In vitro studies further demonstrated that PBA can suppress the activity of nuclear factor B (NF-B), suggesting anti-inflammatory properties for the compound (13). Moreover, administration of PBA w...

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Beneficial Effects of Sodium Phenylbutyrate Administration during Infection with Salmonella enterica Serovar Typhimurium

et al. 2016

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“…Studies in animals have shown that gut microbiota composition regulates immunity in the lung mucosa through inflammasome activation 7 and that intestinal Shigella infection influences respiratory epithelial antimicrobial peptide expression. 8 Clinical and epidemiological studies looking at interactions between diarrhea and pneumonia are limited, and risk factors have not been well described. Furthermore, no studies have examined the contributions of specific enteric pathogens and the risk of concurrent pneumonia.…”

Section: Introductionmentioning

confidence: 99%

Concurrent Pneumonia in Children Under 5 Years of Age Presenting to a Diarrheal Hospital in Dhaka, Bangladesh

Leung

Das

Malek

et al. 2015

The American Journal of Tropical Medicine and Hygiene

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Abstract. Respiratory and gastrointestinal infections are the top killers of children worldwide, and their co-occurrence is reported but not well understood. Our aim was to determine the risk factors for concurrent presentation of diarrhea and pneumonia (DP) in a resource-limited setting in Bangladesh. We used data from the Diarrheal Disease Surveillance System of the icddr,b Dhaka Hospital to identify children < 60 months of age with diarrhea and concurrent pneumonia, defined as a history of cough, an abnormal lung examination, and tachypnea. For the years 1996-2007, out of total 14,628 diarrheal patients surveyed, there were 607 (4%) patients who satisfied criteria for pneumonia. Those with DP had a higher mortality rate (4% versus 0.05%, odds ratio [OR] = 86, 95% confidence interval [CI] = 26-286) and a longer hospital stay (mean 84 versus 26 hours, difference 58 hours, 95% CI = 52-64 hours) than those with diarrhea (D) only. In multivariable logistic regression comparing cases (N = 607) with controls matched for month and year of admission at a ratio of 1:3 (N = 1,808), we found that DP was associated with younger age, male gender, severe acute malnutrition (SAM), less maternal education, lower family income, and lack of current breast-feeding history.

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Unique features of human cathelicidin LL‐37

et al. 2015

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Cathelicidins are antimicrobial peptides produced by humans and animals in response to various pathogenic microbes. This review intends to provide a brief overview of the expression, structure, properties and function of human cathelicidin LL-37 which may be a therapeutic agent against a variety of bacterial and viral diseases, cancers, and hard-to-heal wounds. Cathelicidins act as a primary defense against bacteria and other pathogens in the case of inflammation. They are able to kill bacteria and fungi, inhibit and destroy bacterial biofilms, and possess antiviral and antiparasitics properties. They can also play a role in angiogenesis, wound healing, and the regulation of apoptosis. The host defense peptide LL-37 has emerged as a novel modulator of tumor growth and metastasis in carcinogenesis of various types of cancers. LL-37 is an antimicrobial peptide able of inducing various effects. It acts as an anti- and pro- inflammatory factor. Cathelicidins are able to directly and selectively destroy membranes of various microbes and cancer cells, but they do not attack normal cells. The role of cathelicidins in cancer is double-sided. They play an important role in killing cancer cells and may provide a new possibility for the development of cancer therapeutics. However, they also can participate in carcinogenesis. Due to its activity spectrum LL-37 could be applied in pharmacotherapy. Cathelicidin peptides could serve as a template for the development of modern anti-microbial and anti-viral drugs. LL-37 is an excellent candidate to develop into therapeutics for infected wounds.

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Phenylbutyrate Counteracts Shigella Mediated Downregulation of Cathelicidin in Rabbit Lung and Intestinal Epithelia: A Potential Therapeutic Strategy

Cited by 79 publications

References 32 publications

Beneficial Effects of Sodium Phenylbutyrate Administration during Infection with Salmonella enterica Serovar Typhimurium

Beneficial Effects of Sodium Phenylbutyrate Administration during Infection with Salmonella enterica Serovar Typhimurium

Concurrent Pneumonia in Children Under 5 Years of Age Presenting to a Diarrheal Hospital in Dhaka, Bangladesh

Unique features of human cathelicidin LL‐37

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