The gut microbiota and inflammatory noncommunicable diseases: associations and potentials for gut microbiota therapies

Rapid environmental transition and modern lifestyles are likely driving changes in the biodiversity of the human gut microbiota. With clear effects on physiologic, immunologic, and metabolic processes in human health, aberrations in the gut microbiome and intestinal homeostasis have the capacity for multisystem effects. Changes in microbial composition are implicated in the increasing propensity for a broad range of inflammatory diseases, such as allergic disease, asthma, inflammatory bowel disease (IBD), obesity, and associated noncommunicable diseases (NCDs). There are also suggestive implications for neurodevelopment and mental health. These diverse multisystem influences have sparked interest in strategies that might favorably modulate the gut microbiota to reduce the risk of many NCDs. For example, specific prebiotics promote favorable intestinal colonization, and their fermented products have anti-inflammatory properties. Specific probiotics also have immunomodulatory and metabolic effects. However, when evaluated in clinical trials, the effects are variable, preliminary, or limited in magnitude. Fecal microbiota transplantation is another emerging therapy that regulates inflammation in experimental models. In human subjects it has been successfully used in cases of Clostridium difficile infection and IBD, although controlled trials are lacking for IBD. Here we discuss relationships between gut colonization and inflammatory NCDs and gut microbiota modulation strategies for their treatment and prevention. (J Allergy Clin Immunol 2015;135:3-13.)

A systematic review of published interventions for primary and secondary prevention of ischaemic heart disease (IHD) in rural populations of Australia

BACKGROUND: Rural Australians are known to experience a higher burden of ischaemic heart disease (IHD) than their metropolitan counterparts and the reasons for this appear to be highly complex and not well understood. It is not clear what interventions and prevention efforts have occurred specifically in rural Australia in terms of IHD. A summary of this evidence could have implications for future action and research in improving the health of rural communities. The aim of this study was to review all published interventions conducted in rural Australia that were aimed at the primary and/or secondary prevention of ischaemic heart disease (IHD) in adults.

METHODS: Systematic review of the peer-reviewed literature published between January 1990 and December 2015. Search terms were derived from four major topics: (1) rural; (2) ischaemic heart disease; (3) Australia and; (4) intervention/prevention. Terms were adapted for six databases and three independent researchers screened results. Studies were included if the published work described an intervention focussed on the prevention or reduction of IHD or risk factors, specifically in a rural population of Australia, with outcomes specific to participants including, but not limited to, changes in diet, exercise, cholesterol or blood pressure levels.

RESULTS: Of 791 papers identified in the search, seven studies met the inclusion criteria, and one further study was retrieved from searching reference lists of screened abstracts. Typically, excluded studies focused on cardiovascular diseases without specific reference to IHD, or presented intervention results without stratification by rurality. Larger trials that included metropolitan residents without stratification were excluded due to differences in the specific needs, characteristics and health service access challenges of rural populations. Six interventions were primary prevention studies, one was secondary prevention only and one included both primary and secondary intervention strategies. Two interventions were focussed exclusively on Aboriginal and Torres Strait Islander (Australian Indigenous) populations.

CONCLUSIONS: Few interventions were identified that exclusively focussed on IHD prevention in rural communities, despite these populations being at increased risk of IHD in Australia, and this is consistent with comparable countries, internationally. Although limited, available evidence shows that primary and secondary interventions targeted at IHD and related risk factors can be effective in a rural setting.

Spatial and Functional Organization of Pig Trade in Different European Production Systems: Implications for Disease Prevention and Control

Understanding the complexity of live pig trade organization is a key factor to predict and control major infectious diseases, such as classical swine fever (CSF) or African swine fever (ASF). Whereas the organization of pig trade has been described in several European countries with indoor commercial production systems, little information is available on this organization in other systems, such as outdoor or small-scale systems. The objective of this study was to describe and compare the spatial and functional organization of live pig trade in different European countries and different production systems. Data on premise characteristics and pig movements between premises were collected during 2011 from Bulgaria, France, Italy, and Spain, which swine industry is representative of most of the production systems in Europe (i.e., commercial vs. small-scale and outdoor vs. indoor). Trade communities were identified in each country using the Walktrap algorithm. Several descriptive and network metrics were generated at country and community levels. Pig trade organization showed heterogeneous spatial and functional organization. Trade communities mostly composed of indoor commercial premises were identified in western France, northern Italy, northern Spain, and north-western Bulgaria. They covered large distances, overlapped in space, demonstrated both scale-free and small-world properties, with a role of trade operators and multipliers as key premises. Trade communities involving outdoor commercial premises were identified in western Spain, south-western and central France. They were more spatially clustered, demonstrated scale-free properties, with multipliers as key premises. Small-scale communities involved the majority of premises in Bulgaria and in central and Southern Italy. They were spatially clustered and had scale-free properties, with key premises usually being commercial production premises. These results indicate that a disease might spread very differently according to the production system and that key premises could be targeted to more cost-effectively control diseases. This study provides useful epidemiological information and parameters that could be used to design risk-based surveillance strategies or to more accurately model the risk of introduction or spread of devastating swine diseases, such as ASF, CSF, or foot-and-mouth disease.

Salmonella Enterica serovar Typhimurium Infection in Mouse Pregnancy

Salmonella are Gram-negative, intracellular food-borne pathogens that cause pregnancy complications. In pregnant mice, Salmonella enterica serovar Typhimurium (S.Tm) infection results in placental bacterial replication, inflammation, necrosis, and fetal loss by unknown mechanisms. Necroptosis, or programmed necrosis mediated by RIPK3 (receptor-interacting protein kinase 3), an inflammatory cell death pathway, is implicated in the pathogenesis of S.Tm in non-pregnant mice. This goal of this thesis was to investigate the role of necroptosis in the pathogenesis of S.Tm infection during mouse pregnancy. I hypothesized that elimination of the key necroptotic cell death protein RIPK3 would decrease placental inflammation and trophoblast cell death, and increase conceptus survival compared to controls. Mice expressing a functional Slc11a1 (encodes the natural resistance-associated macrophage protein 1, NRAMP1) gene with or without RIPK3 function (Ripk3-/-Slc11a1+/+ compared to Slc11a1+/+) were infected with 103 S.Tm by tail vein injection on gestational day (GD) 12. Mice were euthanized on GD 14 (48h post-infection) or GD 15 (72h post-infection) and implantation sites (IS) and maternal serum were harvested for analyses. In nearly all challenged mice (except one outlier), S.Tm were detected in most IS within a litter but there was limited immune cell infiltration, placental damage or cell death in Slc11a1 competent mice regardless of Ripk3 gene deletion. Maternal serum cytokine analyses confirmed lack of maternal immune responses to S.Tm infection. IS amongst the litter of a single dam (Ripk3-/-Slc11a1+/+ at 72h postinfection) displayed heavy but not universal placental S.Tm infection of decidual tissues and spongiotrophoblast, associated with elevated maternal serum pro-inflammatory cytokines. S.Tm infection of the fetal yolk sac (YS) was observed in 54.5% of IS from this dam. YS infection was confirmed in archival samples in mice expressing Ripk3 with intact Slc11a1 and in mice lacking functional Slc11a1. In Slc11a1 incompetent mice, S.Tm were detected in placental labyrinthine trophoblast. Based on the available data, this thesis suggests that Ripk3 and necroptosis have no significant roles in either promotion or prevention of progressive Salmonella infection during mouse pregnancy. It also provides pilot data that NRAMP1 controls placental localization and lethality due to YS infection.

Assessing the sustained impact of a school-based obesity prevention program for adolescent boys: the ATLAS cluster randomized controlled trial

BACKGROUND: Obesity prevention interventions targeting 'at-risk' adolescents are urgently needed. The aim of this study is to evaluate the sustained impact of the 'Active Teen Leaders Avoiding Screen-time' (ATLAS) obesity prevention program.

METHODS: Cluster RCT in 14 secondary schools in low-income communities of New South Wales, Australia. Participants were 361 adolescent boys (aged 12-14 years) 'at risk' of obesity. The intervention was based on Self-Determination Theory and Social Cognitive Theory and involved: professional development, fitness equipment for schools, teacher-delivered physical activity sessions, lunch-time activity sessions, researcher-led seminars, a smartphone application, and parental strategies. Assessments for the primary (body mass index [BMI], waist circumference) and secondary outcomes were conducted at baseline, 8- (post-intervention) and 18-months (follow-up). Analyses followed the intention-to-treat principle using linear mixed models.

RESULTS: After 18-months, there were no intervention effects for BMI or waist circumference. Sustained effects were found for screen-time, resistance training skill competency, and motivational regulations for school sport.

CONCLUSIONS: There were no clinically meaningful intervention effects for the adiposity outcomes. However, the intervention resulted in sustained effects for secondary outcomes. Interventions that more intensively target the home environment, as well as other socio-ecological determinants of obesity may be needed to prevent unhealthy weight gain in adolescents from low-income communities.