Search

Background Peripheral blood eosinophilia (PBE) is a biomarker of an aggressive multiyear natural history in adults with inflammatory bowel diseases (IBDs). Additionally, PBE at diagnosis is associated with higher disease activity in pediatric-onset IBD. We sought to determine if PBE can function as a biomarker of long-term disease severity in pediatric-onset IBD patients who are followed into adulthood. Methods We analyzed a consented, prospective, natural history IBD registry at an adult tertiary center from 2009 to 2018. Prevalence of PBE was evaluated in both pediatric- and adult-onset IBD patients. Demographics, clinical characteristics, and health care utilization data were compared in patients with and without PBE. Results Among 2800 adult IBD patients, 23.4% had pediatric-onset disease. PBE was found in 34% of the pediatric-onset patients compared with 26.8% of the adult-onset IBD patients (P < 0.001). In the pediatric-onset IBD cohort, PBE was associated with higher rates of allergies (P < 0.0001), but not of asthma, allergic rhinitis, or primary sclerosing cholangitis. In the adult IBD patients with pediatric-onset disease, PBE was associated with higher rates of C-reactive protein elevation (P < 0.0001), erythrocyte sedimentation rate elevation (P < 0.0001), higher health care utilization, and higher average health care charges per year (P < 0.00001). Conclusions Peripheral blood eosinophilia was more prevalent in adult IBD patients with pediatric-onset compared with adult-onset disease. Among all IBD patients with long-term follow-up, PBE defined a subgroup with more severe illness. These data suggest that PBE may be a biomarker for a high-risk subgroup with high cost trajectory and long-term severity in pediatric-onset IBD that persists into adulthood.

IntroductionDiet, shown to impact colorectal cancer (CRC) risk, is a modifiable environmental factor. Fibre foods fermented by gut microbiota produce metabolites that not only provide food for the colonic epithelium but also exert regulatory effects on colonic mucosal inflammation and proliferation. We describe methods used in a double-blinded, randomised, controlled trial with Alaska Native (AN) people to determine if dietary fibre supplementation can substantially reduce CRC risk among people with the highest reported CRC incidence worldwide.Methods and analysesEligible patients undergoing routine screening colonoscopy consent to baseline assessments and specimen/data collection (blood, urine, stool, saliva, breath and colon mucosal biopsies) at the time of colonoscopy. Following an 8-week stabilisation period to re-establish normal gut microbiota post colonoscopy, study personnel randomise participants to either a high fibre supplement (resistant starch, n=30) or placebo (digestible starch, n=30) condition, repeating stool sample collection. During the 28-day supplement trial, each participant consumes their usual diet plus their supplement under direct observation. On day 29, participants undergo a flexible sigmoidoscopy to obtain mucosal biopsy samples to measure the effect of the supplement on inflammatory and proliferative biomarkers of cancer risk, with follow-up assessments and data/specimen collection similar to baseline. Secondary outcome measures include the impact of a high fibre supplement on the oral and colonic microbiome and biofluid metabolome.Ethics and disseminationApprovals were obtained from the Alaska Area and University of Pittsburgh Institutional Review Boards and Alaska Native Tribal Health Consortium and Southcentral Foundation research review bodies. A data safety monitoring board, material transfer agreements and weekly study team meetings provide regular oversight throughout the study. Study findings will first be shared with AN tribal leaders, health administrators, providers and community members. Peer-reviewed journal articles and conference presentations will be forthcoming once approved by tribal review bodies.Trial registration numberNCT03028831.

OBJECTIVES: Colon cancer (CRC) is one of the westernized diseases, common in the USA and Europe (>50:100,000), rare in Africa (50g/d vs 10g/d). High fiber increases colonic microbial butyrogenesis, which is strongly anticarcinogenic. There is grave concern that CRC is becoming more common throughout Africa with migration to the cities. We hypothesize that this is due to reduced consumption of fiber with westernization. METHODS: Groups of 20 healthy middle aged adults of either sex were compared from urban and rural South Africa, and rural Zimbabwe. A fecal sample was collected from each participant for analysis of fecal short chain fatty acids (SCFA) and the functional microbial gene involved in butyrate synthesis, butyryl CoA: acetate-CoA transferase (bcoA) were performed by GC-FID and qPCR, respectively. Dietary information was collected using food frequency and 24-h recall questionnaires. Unpaired Student's t-test for normally distributed parameters and Mann-Whitney U-test for not normally distributed parameters were used for statistical analysis. RESULTS: Surprisingly, fiber intake was not decreased in urban SA and Zimbabweans. In fact, the median dietary fiber intakes of the EH (26g/d) were significantly lower than KH (38g/d) (P = 0.043). However, food quantities consumed by urban participants was significantly higher for calories, fat and meat. Obesity (BMI > 35) was found in 5 urban SA and only 1 rural SA. Comparison of SCFA between the rural and urban SA groups showed no significant differences. In keeping with this, there was no significant differences in the copies of microbial genes responsible for butyrate synthesis. CONCLUSIONS: These results did not support our hypothesis that the increase in CRC with urbanization is due to the loss of the high fiber diet. Alternatively, the increased risk could be related to the higher energy consumption and obesity, and/or the higher fat intake, which increases the microbial synthesis of carcinogenic secondary bile acids. More attention should be given to the quality and quantity of food consumed by urbanized Africans to avoid the otherwise inevitable increase in non-communicable diseases. FUNDING SOURCES: Stellenbosch University Rector's Strategic Fund.

A one-vial extraction method for the quantitation of short-chain fatty acids (SCFAs) in human stool was developed. Samples were extracted with an acidified aqueous internal standard solution, sodium sulfate, and diethyl ether, followed by analysis with GC-FID. Accuracy, in terms of relative recovery, was typically between 90 and 110% for most analytes; without internal standard, the accuracy was about 5–34%; the linear dynamic range (LDR) was 0.05–50 μmol per gram; the limit of detection (LOD) was less than or equal to 0.05 μmol per gram; and the (lower) limit of quantitation (LOQ) was 1 μmol per gram. The method is suitable for quantitating acetic acid, propanoic acid, isobutyric acid, butyric acid, isovaleric acid, valeric acid, isohexanoic acid, hexanoic acid, and heptanoic acid. It is not suitable for the quantitation of formic acid. Application to human biological research was tested by the measurement of SCFA in heathy humans. This confirmed that the method performed adequately, and even better than expected, with values up to 150 μmol per gram.

Book review

This review summarizes the key results of recently published studies on the effects of dietary change and nutritional intervention on the human microbiome from around the world, focusing on the USA, Canada, Europe, Asia, and Africa. It first explores mechanisms that might explain the ability of fiber-rich foods to suppress the incidence and mortality from westernized diseases, notably cancers of the colon, breast, liver, cardiovascular, infectious, and respiratory diseases, diabetes, and obesity (O’Keefe in Lancet Gastroenterol Hepatol 4(12):984–996, 2019; Am J Clin Nutr 110:265–266, 2019). It summarizes studies from Africa which suggest that disturbance of the colonic microbiome may exacerbate chronic malnutrition and growth failure in impoverished communities and highlights the importance of breast feeding. The American section discusses the role of the microbiome in the swelling population of patients with obesity and type 2 diabetes and examines the effects of race, ethnicity, geography, and climate on microbial diversity and metabolism. The studies from Europe and Asia extoll the benefits of whole foods and plant-based diets. The Asian studies examine the worrying changes from low-fat, high-carbohydrate diets to high-fat, low-carbohydrate ones and the increasing appearance of westernized diseases as in Africa and documents the ability of high-fiber traditional Chinese diets to reverse type 2 diabetes and control weight loss. In conclusion, most of the studies reviewed demonstrate clear changes in microbe abundances and in the production of fermentation products, such as short-chain fatty acids and phytochemicals following dietary change, but the significance of the microbiota changes to human health, with the possible exception of the stimulation of butyrogenic taxa by fiber-rich foods, is generally implied and not measured. Further studies are needed to determine how these changes in microbiota composition and metabolism can improve our health and be used to prevent and treat disease.

BACKGROUND: Alaska Native (AN) people have the world's highest recorded incidence of sporadic colorectal cancer (CRC) (∼91:100,000), whereas rural African (RA) people have the lowest risk (

To review recent data on the role and interactions of fiber and fat as dietary risk factors associated with colorectal cancer (CRC) risk in humans. Fiber intake shows convincing and linear dose-response negative correlation with CRC risk. Dietary fiber stimulates butyrogenic activity of the gut microbiota, providing high amounts of butyrate that shows extensive anti-neoplastic effects. A high-fat diet promotes CRC risk through stimulated bile acid metabolism, facilitating bile acid conversion by the gut microbiota to tumor-promoting deoxycholic acid. Comprehensive interactions of these microbial metabolites are likely to underlie mechanisms driving diet-dependent CRC risk in different populations, but require further experimental investigation. Dietary fiber and fat shape the composition and metabolic function of the gut microbiota, resulting in altered amounts of butyrate and deoxycholic acid in the colon. Fiber supplementation and restriction of fat intake represent promising strategies to reduce CRC risk in healthy individuals.

The incidence of colorectal cancer (CRC) is gradually rising in sub-Saharan Africa. This may be due to dietary changes associated with urbanization, which may induce tumor-promoting gut microbiota composition and function. We compared fecal microbiota composition and activity in 10 rural and 10 urban Zimbabweans for evidence of a differential CRC risk. Dietary intake was assessed by a food frequency questionnaire. Fecal microbiota composition, metabolomic profile, functional microbial genes were analyzed, and bile acids and short chain fatty acids quantified. Animal protein intake was higher among urban volunteers, but carbohydrate and fiber intake were similar. Bacteria related to Blautia obeum, Streptococcus bovis, and Subdoligranulum variabile were higher in urban residents, whereas bacteria related to Oscillospira guillermondii and Sporobacter termitidis were higher in rural volunteers. Fecal levels of primary bile acids, cholic acid, and chenodeoxycholic acid (P

Draws on Milton’s Artis Plenior Logicae (1672) to read the logic of his God, arguing “that the poem is good not primarily because it makes God either good or bad,” pace Empson, “but because it lays bare the cosmic structure to which we are all subject.” In this structure “God will be justified, because [the cosmic structure] is his own creation; yet that justification does not have to make him good or kind within human definitions of those terms.” Ultimately “Paradise Lost is good because God is bad and justified at the same time.”

This chapter examines Marvell’s education, from his boyhood in Hull through to his student days at Trinity College, Cambridge, to consider how these learning experiences informed the discursive tactics that he used as a poet, politician, and polemicist. Marvell’s father’s manuscript sermonbook (c.1603) bears witness to the poet’s early exposure to Ramist reasoning and discourse, both in his family home and in Hull’s Holy Trinity Church. Logic formed the backbone of early modern discursive training, and in c.1633, Marvell’s education in this field continued at Trinity College, Cambridge. The chapter draws on a range of discursive logic textbooks used by Marvell and his Cantabrigian contemporaries, applying their methods as a new way of understanding Marvell’s style and tactics in his writings, from his polemics in Mr. Smirke to his pastoral poetry.

Acute Pancreatitis is a substantial health care challenge with increasing incidence. Patients who develop severe disease have considerable mortality. Currently, no reliable predictive marker to identify patients at risk for severe disease exists. Treatment is limited to rehydration and supporting care suggesting an urgent need to develop novel approaches to improve standard care. Activin is a critical modulator of inflammatory responses, but has not been assessed in pancreatitis. Here, we demonstrate that serum activin is elevated and strongly correlates with disease severity in two established murine models of acute pancreatitis induced by either cerulein or IL-12 + IL-18. Furthermore, in mice, inhibition of activin conveys survival benefits in pancreatitis. In addition, serum activin levels were measured from a retrospective clinical cohort of pancreatitis patients and high activin levels in patients at admission are predictive of worse outcomes, indicated by longer overall hospital and intensive care unit stays. Taken together, activin is a novel candidate as a clinical marker to identify those acute pancreatitis patients with severe disease who would benefit from aggressive treatment and activin may be a therapeutic target in severe acute pancreatitis.

Alaska Native People (AN) suffer the highest recorded incidence of CRC globally (100:100,000) and thus have the greatest risk of dying from this disease. Diet drives genetic susceptibility risk factors, and there is convincing evidence that high consumption rates of red and processed meats and fat increase risk, while a diet rich in fiber suppresses risk. We have shown that the high risk of colon cancer in African Americans (~65:100,000) is suppressed by increasing the consumption of high-fiber foods, in part driven by the health-promoting and antineoplastic influence of colonic microbiome cometabolites (e.g., short chain fatty acids [SCFA] and butyrate) and the suppression of inflammatory and procarcinogenic cometabolites (e.g., conjugated bile acids, nitrogenous end products). This study aimed to determine if dietary-microbiome metabolism explains the extreme risk of colon cancer in AN. 20 adults living in Anchorage and 9 in Barrow (age range 40-65 years) were prospectively recruited and dietary data were recorded. This cohort was compared to 25 native Africans who consume a high-fiber diet (>50g/day) and have an extremely low risk of colon cancer ( Citation Format: Stephen O'Keefe, Annette Wilson, Kathryn Koller, Christie Flanagan, Flora Sapp, Gretchen Day, Peter Holck, Barbara Methe, Alison Morris, Jia Li, James Kinross, Timothy Thomas. Changes in the composition and activity of the colonic microbiome that may explain the extreme risk of colon cancer in Alaskan Native People [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr IA06.