Harnessing the Vnn1 pantetheinase pathway boosts short chain fatty acids production and mucosal protection in colitis.

OBJECTIVE: In the management of patients with IBD, there is a need to identify prognostic markers and druggable biological pathways to improve mucosal repair and probe the efficacy of tumour necrosis factor alpha biologics. Vnn1 is a pantetheinase that degrades pantetheine to pantothenate (vitamin B5, a precursor of coenzyme A (CoA) biosynthesis) and cysteamine. Vnn1 is overexpressed by inflamed colonocytes. We investigated its contribution to the tolerance of the intestinal mucosa to colitis-induced injury. DESIGN: We performed an RNA sequencing study on colon biopsy samples from patients with IBD stratified according to clinical severity and modalities of treatment. We generated the VIVA mouse transgenic model, which specifically overexpresses Vnn1 on intestinal epithelial cells and explored its susceptibility to colitis. We developed a pharmacological mimicry of Vnn1 overexpression by administration of Vnn1 derivatives. RESULTS: VNN1 overexpression on colonocytes correlates with IBD severity. VIVA mice are resistant to experimentally induced colitis. The pantetheinase activity of Vnn1 is cytoprotective in colon: it enhances CoA regeneration and metabolic adaptation of colonocytes; it favours microbiota-dependent production of short chain fatty acids and mostly butyrate, shown to regulate mucosal energetics and to be reduced in patients with IBD. This prohealing phenotype is recapitulated by treating control mice with the substrate (pantethine) or the products of pantetheinase activity prior to induction of colitis. In severe IBD, the protection conferred by the high induction of VNN1 might be compromised because its enzymatic activity may be limited by lack of available substrates. In addition, we identify the elevation of indoxyl sulfate in urine as a biomarker of Vnn1 overexpression, also detected in patients with IBD. CONCLUSION: The induction of Vnn1/VNN1 during colitis in mouse and human is a compensatory mechanism to reinforce the mucosal barrier. Therefore, enhancement of vitamin B5-driven metabolism should improve mucosal healing and might increase the efficacy of anti-inflammatory therapy.

Effect of irrigation and large dams on the burden of malaria on a global and regional scale.

Human-made ecologic transformations have occurred at an unprecedented rate over the past 50 years. Prominent among them are water resource development projects. An estimated 40,000 large dams and 800,000 small dams have been built, and 272 million hectares of land are currently under irrigation worldwide. The establishment and operation of water projects has had a history of facilitating a change in the frequency and transmission dynamics of malaria, but analyses of these environmental risk factors are sparse. Here, we present a comprehensive review of studies that assessed the impact of irrigation and dam building on malaria prevalence or incidence, stratified by the World Health Organization's (WHO) sub-regions of the world, and link these studies with the latest statistics on disability adjusted life years, irrigated agriculture, and large dams. We also present estimates of the population at risk due to proximity to irrigation schemes and large dam reservoirs. In WHO sub-regions 1 and 2, which have 87.9% of the current global malaria burden, only 9.4 million people are estimated to live near large dams and irrigation schemes. In contrast, the remaining sub-regions concentrate an estimated 15.3 million people near large dams and up to 845 million near irrigation sites, while here only 12.1% of the global malaria burden is concentrated. Whether an individual water project triggers an increase in malaria transmission depends on the contextual determinants of malaria, including the epidemiologic setting, socioeconomic factors, vector management, and health seeking behavior. We conclude that in unstable malaria endemic areas, integrated malaria control measures, coupled with sound water management, are mandatory to mitigate the current burden of malaria in locations near irrigation or dam sites.

Effect of irrigated rice agriculture on Japanese encephalitis, including challenges and opportunities for integrated vector management.

Japanese encephalitis (JE) is a disease caused by an arbovirus that is spread by marsh birds, amplified by pigs, and mainly transmitted by the bite of infected Culex tritaeniorhynchus mosquitoes. The estimated annual incidence and mortality rates are 30,000--50,000 and 10,000, respectively, and the estimated global burden of JE in 2002 was 709,000 disability-adjusted life years lost. Here, we discuss the contextual determinants of JE, and systematically examine studies assessing the relationship between irrigated rice agriculture and clinical parameters of JE. Estimates of the sizes of the rural population and population in irrigated areas are presented, and trends of the rural population, the rice-irrigated area, and the rice production are analyzed from 1963 to 2003. We find that approximately 1.9 billion people currently live in rural JE-prone areas of the world. Among them 220 million people live in proximity to rice-irrigation schemes. In 2003, the total rice harvested area of all JE-endemic countries (excluding the Russian Federation and Australia) was 1,345,000 km(2). This is an increase of 22% over the past 40 years. Meanwhile, the total rice production in these countries has risen from 226 millions of tonnes to 529 millions of tonnes (+134%). Finally, we evaluate the effect of different vector control interventions in rice fields, including environmental measures (i.e. alternate wet and dry irrigation (AWDI)), and biological control approaches (i.e. bacteria, nematodes, invertebrate predators, larvivorous fish, fungi and other natural products). We conclude that in JE-endemic rural settings, where vaccination rates are often low, an integrated vector management approach with AWDI and the use of larvivorous fish as its main components can reduce vector populations, and hence has the potential to reduce the transmission level and the burden of JE.