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

A high protein moderate carbohydrate diet fed at discrete meals reduces early progression of N-methyl-N-nitrosourea-induced breast tumorigenesis in rats

Breast cancer is the most prevalent cancer in American women. Dietary factors are thought to have a strong influence on breast cancer incidence. This study utilized a meal-feeding protocol with female Sprague-Dawley rats to evaluate effects of two ratios of carbohydrate:protein on promotion and early progression of breast tissue carcinomas. Mammary tumors were induced by N-methyl-N-nitrosourea (MNU) at 52 d of age. Post-induction, animals were assigned to consume either a low protein high carbohydrate diet (LPHC; 15% and 60% of energy, respectively) or a high protein moderate carbohydrate diet (HPMC; 35% and 40% of energy, respectively) for 10 wk. Animals were fed 3 meals/day to mimic human absorption and metabolism patterns. The rate of palpable tumor incidence was reduced in HPMC relative to LPHC (12.9 ± 1.4%/wk vs. 18.2 ± 1.3%/wk). At 3 wk, post-prandial serum insulin was larger in the LPHC relative to HPMC (+136.4 ± 33.1 pmol/L vs. +38.1 ± 23.4 pmol/L), while at 10 wk there was a trend for post-prandial IGF-I to be increased in HPMC (P = 0.055). There were no differences in tumor latency, tumor surface area, or cumulative tumor mass between diet groups. The present study provides evidence that reducing the dietary carbohydrate:protein ratio attenuates the development of mammary tumors. These findings are consistent with reduced post-prandial insulin release potentially diminishing the proliferative environment required for breast cancer tumors to progress

Regional Mucosa-Associated Microbiota Determine Physiological Expression of TLR2 and TLR4 in Murine Colon

Many colonic mucosal genes that are highly regulated by microbial signals are differentially expressed along the rostral-caudal axis. This would suggest that differences in regional microbiota exist, particularly mucosa-associated microbes that are less likely to be transient. We therefore explored this possibility by examining the bacterial populations associated with the normal proximal and distal colonic mucosa in context of host Toll-like receptors (TLR) expression in C57BL/6J mice housed in specific pathogen-free (SPF) and germ-free (GF) environments. 16S rRNA gene-based terminal restriction fragment length polymorphism (T-RFLP) and clone library analysis revealed significant differences in the community structure and diversity of the mucosa-associated microbiota located in the distal colon compared to proximal colon and stool, the latter two clustering closely. Differential expression of colonic TLR2 and TLR4 along the proximal-distal axis was also found in SPF mice, but not in GF mice, suggesting that enteric microbes are essential in maintaining the regional expression of these TLRs. TLR2 is more highly expressed in proximal colon and decreases in a gradient to distal while TLR4 expression is highest in distal colon and a gradient of decreased expression to proximal colon is observed. After transfaunation in GF mice, both regional colonization of mucosa-associated microbes and expression of TLRs in the mouse colon were reestablished. In addition, exposure of the distal colon to cecal (proximal) microbiota induced TLR2 expression. These results demonstrate that regional colonic mucosa-associated microbiota determine the region-specific expression of TLR2 and TLR4. Conversely, region-specific host assembly rules are essential in determining the structure and function of mucosa-associated microbial populations. We believe this type of host-microbial mutualism is pivotal to the maintenance of intestinal and immune homeostasis

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Going Viral: a Novel Role for Bacteriophage in Colorectal Cancer

Microbiome-based signatures of disease have focused primarily on the bacterial component of the microbiome for numerous reasons, including ease of sample preparation and depth of the curated bacterial database. However, even more numerous than bacteria are the bacteriophages of the viral portion of the microbiome, which have emerged with identifiable disease signatures in other diseases, such as inflammatory bowel diseases.Microbiome-based signatures of disease have focused primarily on the bacterial component of the microbiome for numerous reasons, including ease of sample preparation and depth of the curated bacterial database. However, even more numerous than bacteria are the bacteriophages of the viral portion of the microbiome, which have emerged with identifiable disease signatures in other diseases, such as inflammatory bowel diseases. Here, G. D. Hannigan, M. B. Duhaime, M. T. Ruffin, IV, C. C. Koumpouras, and P. D. Schloss (mBio 9:e02248-18, https://doi.org/10.1128/mBio.02248-18) present a study that explores the potential bacteriophage signatures in patients with colorectal cancer (CRC) and the associated changes in bacterial signatures. Sampling from a cross section of 60 patients at different stages of CRC in addition to 30 healthy controls, this study highlights the need for greater exploration into the virome, including the “dark matter” of diverse forms that viruses assume in the gastrointestinal tract

Increased ratio of dietary carbohydrate to protein shifts the focus of metabolic signaling from skeletal muscle to adipose

Abstract Background The Dietary Reference Intakes (DRI) established acceptable macronutrient distribution ranges (AMDR) for carbohydrates and protein, however little is known about differences in glycemic regulations and metabolic signaling across this range. This study examined metabolic outcomes associated with intake of two diets differing in carbohydrate:protein ratios representing the upper and lower ends of the AMDR. Methods Adult, male rats were fed either a high carbohydrate (CHO) diet (60% of energy from carbohydrates, 12% protein, 28% fat; n = 30) or a high protein (PRO) diet (35% carbohydrate, 35% protein, 30% fat; n = 30). Rats were meal-fed 3x/d the respective diets for 10 d and then terminated after overnight food deprivation or 30, 60, 90, 120 min post-prandial (PP). Plasma was collected at each of these points to provide a time course for glucose, insulin and C-peptide. Skeletal muscle and adipose tissues were collected at 0, 30 and 90 min for measurements of basal, early and delayed activation of Akt, p70S6K and Erk 1/2. Data were analyzed by two-way ANOVA. Results The CHO group produced a consistently elevated response in plasma glucose, insulin and C-peptide following the meal through the 120 min time course. In addition, Akt and Erk 1/2 activation in adipose was much higher than in skeletal muscle. Conversely, the PRO group PP glucose response was minimal and insulin maintained a response similar to a biphasic pattern. Tissue responses for the PRO group were greater for Akt and p70S6K signaling in skeletal muscle compared with adipose. Conclusion Taken together these data suggest that altering CHO:PRO ratios within the AMDR produce different glycemic response patterns accompanied by differential metabolic signaling in skeletal muscle and adipose.</p

The changing microbial landscape of Western society: Diet, dwellings and discordance

Background: The last 50–100 years has been marked by a sharp rise in so-called “Western-diseases” in those countries that have experienced major industrial advances and shifts towards urbanized living. These diseases include obesity, type 2 diabetes, inflammatory bowel diseases, and food allergies in which chronic dysregulation of metabolic and/or immune processes appear to be involved, and are likely a byproduct of new environmental influences on our ancient genome. What we now appreciate is that this genome consists of both human and co-evolved microbial genes of the trillions of microbes residing in our body. Together, host–microbe interactions may be determined by the changing diets and behaviors of the Western lifestyle, influencing the etiopathogenesis of “new-age” diseases. Scope of review: This review takes an anthropological approach to the potential interplay of the host and its gut microbiome in the post-industrialization rise in chronic inflammatory and metabolic diseases. The discussion highlights both the changes in diet and the physical environment that have co-occurred with these diseases and the latest evidence demonstrating the role of host–microbe interactions in understanding biological responses to the changing environment. Major conclusions: Technological advances that have led to changes in agriculture and engineering have altered our eating and living behaviors in ways never before possible in human history. These changes also have altered the bacterial communities within the human body in ways that are seemingly linked with the rise of many intestinal and systemic metabolic and inflammatory diseases. Insights into the mechanisms of this reciprocal exchange between the environment and the human gut microbiome may offer potential to attenuate the chronic health conditions that derail quality of life. This article is part of a special issue on microbiota