There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

http://www.klinikaikozpont.u-szeged.hu/pedia/images/pdf/CME_TEL/Full-Text/25.pdf

The Hallmarks of Aging

This study describes and validates a new method for metagenomic biomarker discovery by way of class comparison, tests of biological consistency and effect size estimation. This addresses the challenge of finding organisms, genes, or pathways that consistently explain the differences between two or more microbial communities, which is a central problem to the study of metagenomics. We extensively validate our method on several microbiomes and a convenient online interface for the method is provided at http://huttenhower.sph.harvard.edu/lefse/.

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Metagenomic biomarker discovery and explanation

We have catalogued the protein kinase complement of the human genome (the "kinome") using public and proprietary genomic, complementary DNA, and expressed sequence tag (EST) sequences. This provides a starting point for comprehensive analysis of protein phosphorylation in normal and disease states, as well as a detailed view of the current state of human genome analysis through a focus on one large gene family. We identify 518 putative protein kinase genes, of which 71 have not previously been reported or described as kinases, and we extend or correct the protein sequences of 56 more kinases. New genes include members of well-studied families as well as previously unidentified families, some of which are conserved in model organisms. Classification and comparison with model organism kinomes identified orthologous groups and highlighted expansions specific to human and other lineages. We also identified 106 protein kinase pseudogenes. Chromosomal mapping revealed several small clusters of kinase genes and revealed that 244 kinases map to disease loci or cancer amplicons.

http://science.sciencemag.org/content/sci/298/5600/1912.full.pdf

The Protein Kinase Complement of the Human Genome

An expert panel was convened in October 2013 by the International Scientific Association for Probiotics and Prebiotics (ISAPP) to discuss the field of probiotics. It is now 13 years since the definition of probiotics and 12 years after guidelines were published for regulators, scientists and industry by the Food and Agriculture Organization of the United Nations and the WHO (FAO/WHO). The FAO/WHO definition of a probiotic--"live microorganisms which when administered in adequate amounts confer a health benefit on the host"--was reinforced as relevant and sufficiently accommodating for current and anticipated applications. However, inconsistencies between the FAO/WHO Expert Consultation Report and the FAO/WHO Guidelines were clarified to take into account advances in science and applications. A more precise use of the term 'probiotic' will be useful to guide clinicians and consumers in differentiating the diverse products on the market. This document represents the conclusions of the ISAPP consensus meeting on the appropriate use and scope of the term probiotic.

/pdf/expert-consensus-document-the-international-scientific-1zd5d1fmxy.pdf

Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic

Microbial colonization of the gastrointestinal tract plays a crucial role in the development of enteric and central nervous system functionality. The serotonergic system has been heavily implicated in microbiota-gut-brain axis signaling, particularly in proof-of-principle studies in germ-free (GF) animals. One aspect of the serotonergic system that has been left unexplored in relation to the microbiota is the unique ability of the serotonin receptor 2C (5-HT2C) to undergo post-transcriptional editing, which has been implicated in decreased receptor functionality. We investigated whether GF mice, with absent microbiota from birth, have altered 5-HT2C receptor expression and editing in the brain, and if colonization of the microbiota is able to restore editing patterns. Next, we investigated whether microbiota depletion later in life using a chronic antibiotic treatment could affect 5-HT2C receptor editing patterns in rats. We found that GF mice have an increased prevalence of the edited 5-HT2C receptor isoforms in the amygdala, hypothalamus, prefrontal cortex, and striatum, which was partially normalized upon colonization post-weaning. However, no alterations were observed in the hypothalamus after microbiota depletion using an antibiotic treatment in adult rats. This suggests that alterations in the microbiome during development, but not later in life, could influence 5-HT2C receptor editing patterns. Overall, these results demonstrate that the microbiota affects 5-HT2C receptor editing in the brain and may inform novel therapeutic strategies in conditions in which 5-HT2C receptor editing is altered, such as depression.

Host Microbiota Regulates Central Nervous System Serotonin Receptor 2C Editing in Rodents

Antibiotics have been described as one of the great “underground” therapies for Crohn’s disease. This implies widespread, poorly documented usage despite weak or lacking evidence for efficacy. Perhaps this is so, although in view of the multitude of biologic and other agents in clinical trials worldwide, the level of deployment of antibiotics as a first-line therapy in most tertiary care centers varies. The robust enthusiasm for antibiotics expressed by some clinicians is at variance with the remarkable paucity of controlled clinical trials in the area during the past five decades. Indeed, the scarcity of data seems to be the single area of agreement in the opposing opinion pieces expressed by Drs. Greenberg and Wild in this issue of the journal. Though lack of interest from the pharmaceutical sector might account for the relative paucity of effort applied to controlled clinical trials of antibiotics in Crohn’s disease, there must also be a sneaking suspicion that many clinician investigators lack motivation and true enthusiasm for the proposition. Are clinician investigators a different group than the inflammatory bowel disease (IBD) clinicians asserted by Dr. Greenberg to “attest to the marked benefit of antibiotic therapy in individual patients”? The old dictum “those who have enthusiasm have no controls and those who have controls have no enthusiasm” seems to apply to antibiotic therapy in Crohn’s disease. Whether IBD clinicians are enthusiastic about antibiotics for treating luminal Crohn’s disease, they have enthusiastically (and without rigorous evidence) embraced the use of these agents in perianal Crohn’s disease. While two veteran IBD clinicians argue the merits of antibiotic therapy in the pages of this journal, individual IBD clinicians (like Dr. Wild) avoid antibiotics for treating luminal disease on the basis of lack of evidence but advocate for antibiotics for perianal disease, despite the lack of evidence. Notwithstanding the wealth of evidence in support of immunomodifiers and other forms of non-antibiotic therapy for Crohn’s disease, it must be conceded that comprehensive management cannot be based on evidence alone. There remain numerous clinical aspects of patient care that have not yet been addressed in clinical trials. This means that clinicians must base their therapeutic strategy upon considerations such as: Is there a sound rationale or biologic plausibility for the use of antibiotics in Crohn’s disease? What is the quality of existing evidence for efficacy? How significant is the risk of broadspectrum antibiotic usage as a first-line strategy? What are the alternatives? The notion that antibiotics are a suitable first-line therapy for Crohn’s disease has gained some credence with the popularization of the concept that the pathogenesis involves a convergence of genes, T cells, and bacteria. In common with most chronic inflammatory disorders, a body of evidence favors the triad of genetic susceptibility, environmental triggers or modifiers, and immune-mediated tissue injury. An inappropriate response to normal indigenous flora in genetically susceptible individuals rather than an appropriate immune response to abnormal flora (or infectious agent) is the most widely held working hypothesis. The most persuasive evidence cited in support of this is derived from experimental animal models. A diversity of genetically determined defects either at the level of the immune regulation or at the level of mucosal barrier function predispose to Crohn’s-like disease. Irrespective of the underlying defect, the enteric flora is an essential requirement for full clinical expression of the inflammatory disease. This is usually cited as circumstantial support for the plausibility of antibiotic therapy in Crohn’s disease. However, one might counter-argue that the flora only has a permissive role rather than a stimulatory effect. The flora is required for immune development and immune activation; without enteric bacteria it is doubtful that the mucosal immune system could mount a vigorous inflammatory response. The occurrence of various antibodies in the serum of patients with Received for publication February 2, 2004; accepted February 12, 2004. From the *Alimentary Pharmabiotic Centre and Department of Medicine, National University of Ireland, Cork; and †University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre, and Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. Reprints: Charles Bernstein, MD, 804F 715 McDermot Avenue, John Buhler Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2 (e-mail: cbernst@cc.umanitoba.ca). Copyright © 2004 by Lippincott Williams & Wilkins

Antibiotics as a first-line therapy for Crohn's disease: is there any consensus?

We commend the editors of Gut for publishing the article by Hugerth et al 1 given that negative results are conspicuously missing from the microbiome literature. The paper reports that in a randomly recruited Swedish cohort of individuals meeting Rome IV criteria for irritable bowel syndrome (IBS), there was marked heterogeneity of the gut microbiota, but no distinct ‘signature’ was evident. However, some qualifying caveats for future research are worth highlighting.

First, while the overall pool of study subjects was drawn from a large population of volunteers, the actual numbers studied by Hugerth et al 1 with respect to IBS were modest: 63 sigmoid biopsy samples from confirmed IBS cases, and 32 …

https://gut.bmj.com/content/gutjnl/69/12/2263.full.pdf

Microbiome alterations in IBS

The gastrointestinal tract and its associated mucosal immune system have been extensively studied in the context of their involvement in disease processes, both within the tract itself and in its associated organs. However, historically a number of aspects of both gastrointestinal physiology and pathophysiology have been to some extent overlooked. In particular, the relationship of the gastrointestinal tract with its indigenous microbiota, and also the influence of the tract on behavior and neural systems and vice versa. Here, we describe recent advances in our knowledge and understanding of these areas, and attempt to put these advances in perspective with regard to potential therapeutic strategies.

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Fergus Shanahan

Papers

Host Microbiota Regulates Central Nervous System Serotonin Receptor 2C Editing in Rodents

Antibiotics as a first-line therapy for Crohn's disease: is there any consensus?

Microbiome alterations in IBS

The emerging role of the microbial-gastrointestinal-neural axis

Gene-targeted immunologic knockouts: New models of inflammatory bowel disease