A systematic analysis of experimental immunotherapies on tumors differing in size and duration of growth

We conducted a systematic analysis to determine the reason for the apparent disparity of success of immunotherapy between clinical and experimental cancers. To do this, we performed a search of PubMed using the keywords “immunotherapy” AND “cancer” for the years of 1980 and 2010. The midspread of experimental tumors used in all the relevant literature published in 2010 were between 0.5–121 mm3 in volume or had grown for four to eight days. Few studies reported large tumors that could be considered representative of clinical tumors, in terms of size and duration of growth. The predominant effect of cancer immunotherapies was slowed or delayed outgrowth. Regression of tumors larger than 200 mm3 was observed only after passive antibody or adoptive T cell therapy. The effectiveness of other types of immunotherapy was generally scattered. By comparison, very few publications retrieved by the 1980 search could meet our selection criteria; all of these used tumors smaller than 100 mm3, and none reported regression. In the entire year of 2010, only 13 used tumors larger than 400 mm3, and nine of these reported tumor regression. Together, these results indicate that most recent studies, using many diverse approaches, still treat small tumors only to report slowed or delayed growth. Nevertheless, a few recent studies indicate effective therapy against large tumors when using passive antibody or adoptive T cell therapy. For the future, we aspire to witness the increased use of experimental studies treating tumors that model clinical cancers in terms of size and duration of growth

Irritable bowel syndrome, inflammatory bowel disease and the microbiome

PURPOSE OF REVIEW: The review aims to update the reader on current developments in our understanding of how the gut microbiota impact on inflammatory bowel disease and the irritable bowel syndrome. It will also consider current efforts to modulate the microbiota for therapeutic effect. RECENT FINDINGS: Gene polymorphisms associated with inflammatory bowel disease increasingly suggest that interaction with the microbiota drives pathogenesis. This may be through modulation of the immune response, mucosal permeability or the products of microbial metabolism. Similar findings in irritable bowel syndrome have reinforced the role of gut-specific factors in this ‘functional’ disorder. Metagenomic analysis has identified alterations in pathways and interactions with the ecosystem of the microbiome that may not be recognized by taxonomic description alone, particularly in carbohydrate metabolism. Treatments targeted at the microbial stimulus with antibiotics, probiotics or prebiotics have all progressed in the past year. Studies on the long-term effects of treatment on the microbiome suggest that dietary intervention may be needed for prolonged efficacy. SUMMARY: The microbiome represents ‘the other genome’, and to appreciate its role in health and disease will be as challenging as with our own genome. Intestinal diseases occur at the front line of our interaction with the microbiome and their future treatment will be shaped as we unravel our relationship with it

Establishing What Constitutes a Healthy Human Gut Microbiome: State of the Science, Regulatory Considerations, and Future Directions.

On December 17, 2018, the North American branch of the International Life Sciences Institute (ILSI North America) convened a workshop "Can We Begin to Define a Healthy Gut Microbiome Through Quantifiable Characteristics?" with >40 invited academic, government, and industry experts in Washington, DC. The workshop objectives were to 1) develop a collective expert assessment of the state of the evidence on the human gut microbiome and associated human health benefits, 2) see if there was sufficient evidence to establish measurable gut microbiome characteristics that could serve as indicators of "health," 3) identify short- and long-term research needs to fully characterize healthy gut microbiome-host relationships, and 4) publish the findings. Conclusions were as follows: 1) mechanistic links of specific changes in gut microbiome structure with function or markers of human health are not yet established; 2) it is not established if dysbiosis is a cause, consequence, or both of changes in human gut epithelial function and disease; 3) microbiome communities are highly individualized, show a high degree of interindividual variation to perturbation, and tend to be stable over years; 4) the complexity of microbiome-host interactions requires a comprehensive, multidisciplinary research agenda to elucidate relationships between gut microbiome and host health; 5) biomarkers and/or surrogate indicators of host function and pathogenic processes based on the microbiome need to be determined and validated, along with normal ranges, using approaches similar to those used to establish biomarkers and/or surrogate indicators based on host metabolic phenotypes; 6) future studies measuring responses to an exposure or intervention need to combine validated microbiome-related biomarkers and/or surrogate indicators with multiomics characterization of the microbiome; and 7) because static genetic sampling misses important short- and long-term microbiome-related dynamic changes to host health, future studies must be powered to account for inter- and intraindividual variation and should use repeated measures within individuals

Natural polymorphisms in C. elegans HECW-1 E3 ligase affect pathogen avoidance behaviour

available in PMC 2012 June 22.Heritable variation in behavioural traits generally has a complex genetic basis1, and thus naturally occurring polymorphisms that influence behaviour have been defined in only rare instances2,3. The isolation of wild strains of Caenorhabditis elegans has facilitated the study of natural genetic variation in this species4 and provided insights into its diverse microbial ecology5. C. elegans responds to bacterial infection with conserved innate immune responses6-8 and, while lacking the immunological memory of vertebrate adaptive immunity, exhibits an aversive learning response to pathogenic bacteria9. Here, we report the molecular characterization of naturally occurring coding polymorphisms in a C. elegans gene encoding a conserved HECT domain-containing E3 ubiquitin ligase, HECW-1. We show that two distinct polymorphisms in neighbouring residues of HECW-1 each affect C. elegans behavioural avoidance of a lawn of Pseudomonas aeruginosa. Neuronspecific rescue and ablation experiments, and genetic interaction analysis suggest that HECW-1 functions in a pair of sensory neurons to inhibit P. aeruginosa lawn avoidance behaviour through inhibition of the neuropeptide receptor NPR-110, which we have previously shown promotes P. aeruginosa lawn avoidance behaviour11. Our data establish a molecular basis for natural variation in a C. elegans behaviour that may undergo adaptive changes in response to microbial pathogens.National Institutes of Health (U.S.) (NIH Grant GM084477

A Metasystem of Framework Model Organisms to Study Emergence of New Host-Microbe Adaptations

An unintended consequence of global industrialization and associated societal rearrangements is new interactions of microbes and potential hosts (especially mammals and plants), providing an opportunity for the rapid emergence of host-microbe adaptation and eventual establishment of new microbe-related diseases. We describe a new model system comprising the model plant Arabidopsis thaliana and several microbes, each representing different modes of interaction, to study such “maladaptations”. The model microbes include human and agricultural pathogens and microbes that are commonly considered innocuous. The system has a large knowledge base corresponding to each component organism and is amenable to high-throughput automation assisted perturbation screens for identifying components that modulate host-pathogen interactions. This would aid in the study of emergence and progression of host-microbe maladaptations in a controlled environment

Fecal Microbiota in Premature Infants Prior to Necrotizing Enterocolitis

Intestinal luminal microbiota likely contribute to the etiology of necrotizing enterocolitis (NEC), a common disease in preterm infants. Microbiota development, a cascade of initial colonization events leading to the establishment of a diverse commensal microbiota, can now be studied in preterm infants using powerful molecular tools. Starting with the first stool and continuing until discharge, weekly stool specimens were collected prospectively from infants with gestational ages ≤32 completed weeks or birth weights≤1250 g. High throughput 16S rRNA sequencing was used to compare the diversity of microbiota and the prevalence of specific bacterial signatures in nine NEC infants and in nine matched controls. After removal of short and low quality reads we retained a total of 110,021 sequences. Microbiota composition differed in the matched samples collected 1 week but not <72 hours prior to NEC diagnosis. We detected a bloom (34% increase) of Proteobacteria and a decrease (32%) in Firmicutes in NEC cases between the 1 week and <72 hour samples. No significant change was identified in the controls. At both time points, molecular signatures were identified that were increased in NEC cases. One of the bacterial signatures detected more frequently in NEC cases (p<0.01) matched closest to γ-Proteobacteria. Although this sequence grouped to the well-studied Enterobacteriaceae family, it did not match any sequence in Genbank by more than 97%. Our observations suggest that abnormal patterns of microbiota and potentially a novel pathogen contribute to the etiology of NEC

Comparative Analysis of Fecal Microbiota in Infants with and without Eczema

Eczema is a chronic form of childhood disorder that is gaining in prevalence in affluent societies. Previous studies hypothesized that the development of eczema is correlated with changes in microbial profile and composition of early life endemic microbiota, but contradictory conclusions were obtained, possibly due to the lack of minimization of apparent non-health related confounders (e.g., age, antibiotic consumption, diet and mode of delivery). In this study, we recruited seven caesarean-delivered and total formula-fed infants, and comparatively examined the early-life endemic microbiota in these infants with and without eczema. Using 16S pyrosequencing, infants' fecal microbiota were observed to comprise Proteobacteria, Firmicutes, Actinobacteria and Bacteroidetes as the four main phyla, and the presence and absence of specific populations within these four phyla are primarily mediated by ageing. Quantitative analysis of bacterial targets on a larger sample size (n = 36 at 1, 3, and 12 months of age) revealed that the abundances of Bifidobacterium and Enterobacteriaceae were different among caesarean-delivered infants with and without eczema, and the bacterial targets may be potential biomarkers that can correlate to the health status of these infants. Our overall findings suggest that the minimization of possible confounders is essential prior to comparative evaluation and correlation of fecal microbiota to health status, and that stool samples collected from caesarean-delivered infants at less than 1 year of age may represent a good cohort to study for potential biomarkers that can distinguish infants with eczema from those without. These findings would greatly facilitate future efforts in understanding the possible pathogenesis behind certain bacterial targets, and may lead to a timely intervention that reduces the occurrence of early life eczema and possibly allergic disorders in later life

Metagenomic Profile of the Bacterial Communities Associated with Ixodes ricinus Ticks

Assessment of the microbial diversity residing in arthropod vectors of medical importance is crucial for monitoring endemic infections, for surveillance of newly emerging zoonotic pathogens, and for unraveling the associated bacteria within its host. The tick Ixodes ricinus is recognized as the primary European vector of disease-causing bacteria in humans. Despite I. ricinus being of great public health relevance, its microbial communities remain largely unexplored to date. Here we evaluate the pathogen-load and the microbiome in single adult I. ricinus by using 454- and Illumina-based metagenomic approaches. Genomic DNA-derived sequences were taxonomically profiled using a computational approach based on the BWA algorithm, allowing for the identification of known tick-borne pathogens at the strain level and the putative tick core microbiome. Additionally, we assessed and compared the bacterial taxonomic profile in nymphal and adult I. ricinus pools collected from two distinct geographic regions in Northern Italy by means of V6-16S rRNA amplicon pyrosequencing and community based ecological analysis. A total of 108 genera belonging to representatives of all bacterial phyla were detected and a rapid qualitative assessment for pathogenic bacteria, such as Borrelia, Rickettsia and Candidatus Neoehrlichia, and for other bacteria with mutualistic relationship or undetermined function, such as Wolbachia and Rickettsiella, was possible. Interestingly, the ecological analysis revealed that the bacterial community structure differed between the examined geographic regions and tick life stages. This finding suggests that the environmental context (abiotic and biotic factors) and host-selection behaviors affect their microbiome