Diet, microbes, and host genetics: the perfect storm in inflammatory bowel diseases

The incidence of inflammatory bowel diseases (IBD), as well as other inflammatory conditions, has dramatically increased over the past half century. While many studies have shown that IBD exhibits a genetic component via genome-wide association studies, genetic drift alone cannot account for this increase, and other factors, such as those found in the environment must play a role, suggesting a “multiple hit” phenomenon that precipitates disease. One major environmental factor, dietary intake, has shifted to a high fat, high carbohydrate Western-type diet in developing nations, nearly in direct correlation with the increasing incidence of IBD. Recent evidence suggests that specific changes in dietary intake have led to a shift in the composite human gut microbiota, resulting in the emergence of pathobionts that can thrive under specific conditions. In the genetically susceptible host, the emerging pathobionts can lead to increasing incidence and severity of IBD and other inflammatory disorders. Since the gut microbiota is plastic and responds to dietary modulations, the use of probiotics, prebiotics, and/or dietary alterations are all intriguing complementary therapeutic approaches to alleviate IBD symptoms. However, the interactions are complex and it is unlikely that a one-size-fits all approach can be utilized across all populations affected by IBD. Exploration into and thoroughly understanding the interactions between host and microbes, primarily in the genetically susceptible host, will help define strategies that can be tailored to an individual as we move towards an era of personalized medicine to treat IBD

Robustness of interdependent networks under targeted attack

When an initial failure of nodes occurs in interdependent networks, a cascade of failure between the networks occurs. Earlier studies focused on random initial failures. Here we study the robustness of interdependent networks under targeted attack on high or low degree nodes. We introduce a general technique and show that the {\it targeted-attack} problem in interdependent networks can be mapped to the {\it random-attack} problem in a transformed pair of interdependent networks. We find that when the highly connected nodes are protected and have lower probability to fail, in contrast to single scale free (SF) networks where the percolation threshold $p_c=0$, coupled SF networks are significantly more vulnerable with $p_c$ significantly larger than zero. The result implies that interdependent networks are difficult to defend by strategies such as protecting the high degree nodes that have been found useful to significantly improve robustness of single networks.Comment: 11 pages, 2 figure

Butyrate and bioactive proteolytic form of Wnt-5a regulate colonic epithelial proliferation and spatial development

Proliferation and spatial development of colonic epithelial cells are highly regulated along the crypt vertical axis, which, when perturbed, can result in aberrant growth and carcinogenesis. In this study, two key factors were identified that have important and counterbalancing roles regulating these processes: pericrypt myofibroblast-derived Wnt-5a and the microbial metabolite butyrate. Cultured YAMC cell proliferation and heat shock protein induction were analzyed after butryate, conditioned medium with Wnt5a activity, and FrzB containing conditioned medium. In vivo studies to modulate Hsp25 employed intra-colonic wall Hsp25 encoding lentivirus. To silence Wnt-5a in vivo, intra-colonic wall Wnt-5a silencing RNA was used. Wnt-5a, secreted by stromal myofibroblasts of the lower crypt, promotes proliferation through canonical β-catenin activation. Essential to this are two key requirements: (1) proteolytic conversion of the highly insoluble ~40 kD Wnt-5a protein to a soluble 36 mer amino acid peptide that activates epithelial β-catenin and cellular proliferation, and (2) the simultaneous inhibition of butyrate-induced Hsp25 by Wnt-5a which is necessary to arrest the proliferative process in the upper colonic crypt. The interplay and spatial gradients of these factors insures that crypt epithelial cell proliferation and development proceed in an orderly fashion, but with sufficient plasticity to adapt to physiological perturbations including inflammation

Chronic sleep disruption alters gut microbiota, induces systemic and adipose tissue inflammation and insulin resistance in mice.

Chronic sleep fragmentation (SF) commonly occurs in human populations, and although it does not involve circadian shifts or sleep deprivation, it markedly alters feeding behaviors ultimately promoting obesity and insulin resistance. These symptoms are known to be related to the host gut microbiota. Mice were exposed to SF for 4 weeks and then allowed to recover for 2 weeks. Taxonomic profiles of fecal microbiota were obtained prospectively, and conventionalization experiments were performed in germ-free mice. Adipose tissue insulin sensitivity and inflammation, as well as circulating measures of inflammation, were assayed. Effect of fecal water on colonic epithelial permeability was also examined. Chronic SF-induced increased food intake and reversible gut microbiota changes characterized by the preferential growth of highly fermentative members of Lachnospiraceae and Ruminococcaceae and a decrease of Lactobacillaceae families. These lead to systemic and visceral white adipose tissue inflammation in addition to altered insulin sensitivity in mice, most likely via enhanced colonic epithelium barrier disruption. Conventionalization of germ-free mice with SF-derived microbiota confirmed these findings. Thus, SF-induced metabolic alterations may be mediated, in part, by concurrent changes in gut microbiota, thereby opening the way for gut microbiome-targeted therapeutics aimed at reducing the major end-organ morbidities of chronic SF

Financing Direct Democracy: Revisiting the Research on Campaign Spending and Citizen Initiatives

The conventional view in the direct democracy literature is that spending against a measure is more effective than spending in favor of a measure, but the empirical results underlying this conclusion have been questioned by recent research. We argue that the conventional finding is driven by the endogenous nature of campaign spending: initiative proponents spend more when their ballot measure is likely to fail. We address this endogeneity by using an instrumental variables approach to analyze a comprehensive dataset of ballot propositions in California from 1976 to 2004. We find that both support and opposition spending on citizen initiatives have strong, statistically significant, and countervailing effects. We confirm this finding by looking at time series data from early polling on a subset of these measures. Both analyses show that spending in favor of citizen initiatives substantially increases their chances of passage, just as opposition spending decreases this likelihood

Patient-specific Bacteroides genome variants in pouchitis

© The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in mBio 7 (2016): e01713-16, doi:10.1128/mBio.01713-16.A 2-year longitudinal microbiome study of 22 patients who underwent colectomy with an ileal pouch anal anastomosis detected significant increases in distinct populations of Bacteroides during 9 of 11 patient visits that coincided with inflammation (pouchitis). Oligotyping and metagenomic short-read annotation identified Bacteroides populations that occurred in early samples, bloomed during inflammation, and reappeared after antibiotic treatment. Targeted cultivation of Bacteroides isolates from the same individual at multiple time points and from several patients detected subtle genomic changes, including the identification of rapidly evolving genomic elements that differentiate isogenic strains of Bacteroides fragilis from the mucosa versus lumen. Each patient harbored Bacteroides spp. that are closely related to commonly occurring clinical isolates, including Bacteroides ovatus, B. thetaiotaomicron, B. vulgatus, and B. fragilis, which contained unique loci in different patients for synthesis of capsular polysaccharides. The presence of unique Bacteroides capsular polysaccharide loci within different hosts and between the lumen and mucosa may represent adaptations to stimulate, suppress, and evade host-specific immune responses at different microsites of the ileal pouch.Leona M. and Harry B. Helmsley Charitable Trust; Bay and Paul Foundations; Frank R. Lillie Research Innovation Award; Gastrointestinal Research Foundation of Chicag

Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer’s disease

Severe amyloidosis and plaque-localized neuro-inflammation are key pathological features of Alzheimer’s disease (AD). In addition to astrocyte and microglial reactivity, emerging evidence suggests a role of gut microbiota in regulating innate immunity and influencing brain function. Here, we examine the role of the host microbiome in regulating amyloidosis in the APP(SWE)/PS1(ΔE9) mouse model of AD. We show that prolonged shifts in gut microbial composition and diversity induced by long-term broad-spectrum combinatorial antibiotic treatment regime decreases Aβ plaque deposition. We also show that levels of soluble Aβ are elevated and that levels of circulating cytokine and chemokine signatures are altered in this setting. Finally, we observe attenuated plaque-localised glial reactivity in these mice and significantly altered microglial morphology. These findings suggest the gut microbiota community diversity can regulate host innate immunity mechanisms that impact Aβ amyloidosis

Scaling of the distribution of fluctuations of financial market indices

We study the distribution of fluctuations over a time scale $\Delta t$ (i.e., the returns) of the S&P 500 index by analyzing three distinct databases. Database (i) contains approximately 1 million records sampled at 1 min intervals for the 13-year period 1984-1996, database (ii) contains 8686 daily records for the 35-year period 1962-1996, and database (iii) contains 852 monthly records for the 71-year period 1926-1996. We compute the probability distributions of returns over a time scale $\Delta t$, where $\Delta t$ varies approximately over a factor of 10^4 - from 1 min up to more than 1 month. We find that the distributions for $\Delta t \leq$ 4 days (1560 mins) are consistent with a power-law asymptotic behavior, characterized by an exponent $\alpha \approx 3$, well outside the stable L\'evy regime $0 < \alpha < 2$. To test the robustness of the S&P result, we perform a parallel analysis on two other financial market indices. Database (iv) contains 3560 daily records of the NIKKEI index for the 14-year period 1984-97, and database (v) contains 4649 daily records of the Hang-Seng index for the 18-year period 1980-97. We find estimates of $\alpha$ consistent with those describing the distribution of S&P 500 daily-returns. One possible reason for the scaling of these distributions is the long persistence of the autocorrelation function of the volatility. For time scales longer than $(\Delta t)_{\times} \approx 4$ days, our results are consistent with slow convergence to Gaussian behavior.Comment: 12 pages in multicol LaTeX format with 27 postscript figures (Submitted to PRE May 20, 1999). See http://polymer.bu.edu/~amaral/Professional.html for more of our work on this are

Scaling of the distribution of price fluctuations of individual companies

We present a phenomenological study of stock price fluctuations of individual companies. We systematically analyze two different databases covering securities from the three major US stock markets: (a) the New York Stock Exchange, (b) the American Stock Exchange, and (c) the National Association of Securities Dealers Automated Quotation stock market. Specifically, we consider (i) the trades and quotes database, for which we analyze 40 million records for 1000 US companies for the 2-year period 1994--95, and (ii) the Center for Research and Security Prices database, for which we analyze 35 million daily records for approximately 16,000 companies in the 35-year period 1962--96. We study the probability distribution of returns over varying time scales $\Delta t$, where $\Delta t$ varies by a factor of $\approx 10^5$---from 5 min up to $\approx$ 4 years. For time scales from 5~min up to approximately 16~days, we find that the tails of the distributions can be well described by a power-law decay, characterized by an exponent $\alpha \approx 3$ ---well outside the stable L\'evy regime $0 < \alpha < 2$. For time scales $\Delta t \gg (\Delta t)_{\times} \approx 16$days, we observe results consistent with a slow convergence to Gaussian behavior. We also analyze the role of cross correlations between the returns of different companies and relate these correlations to the distribution of returns for market indices.Comment: 10pages 2 column format with 11 eps figures. LaTeX file requiring epsf, multicol,revtex. Submitted to PR