Gregory L. Austin

An altered intestinal mucosal microbiome in HIV-1 infection is associated with mucosal and systemic immune activation and endotoxemia

Human immunodeficiency virus-1 (HIV-1) infection disrupts the intestinal immune system, leading to microbial translocation and systemic immune activation. We investigated the impact of HIV-1 infection on the intestinal microbiome and its association with mucosal T-cell and dendritic cell (DC) frequency and activation, as well as with levels of systemic T-cell activation, inflammation, and microbial translocation. Bacterial 16S ribosomal DNA sequencing was performed on colon biopsies and fecal samples from subjects with chronic, untreated HIV-1 infection and uninfected control subjects. Colon biopsies of HIV-1-infected subjects had increased abundances of Proteobacteria and decreased abundances of Firmicutes compared with uninfected donors. Furthermore at the genus level, a significant increase in Prevotella and decrease in Bacteroides was observed in HIV-1-infected subjects, indicating a disruption in the Bacteroidetes bacterial community structure. This HIV-1-associated increase in Prevotella abundance was associated with increased numbers of activated colonic T cells and myeloid DCs. Principal coordinates analysis demonstrated an HIV-1-related change in the microbiome that was associated with increased mucosal cellular immune activation, microbial translocation, and blood T-cell activation. These observations suggest that an important relationship exists between altered mucosal bacterial communities and intestinal inflammation during chronic HIV-1 infection.

A Very Low-Carbohydrate Diet Improves Symptoms and Quality of Life in Diarrhea-Predominant Irritable Bowel Syndrome

BACKGROUND & AIMS Patients with diarrhea-predominant irritable bowel syndrome (IBS-D) anecdotally report symptom improvement after initiating a very low-carbohydrate diet (VLCD). This study prospectively evaluated a VLCD in IBS-D. METHODS Participants with moderate to severe IBS-D were provided a 2-week standard diet, then 4 weeks of a VLCD (20 g carbohydrates/d). A responder was defined as having adequate relief of gastrointestinal symptoms for 2 or more weeks during the VLCD. Changes in abdominal pain, stool habits, and quality of life also were measured. RESULTS Of the 17 participants enrolled, 13 completed the study and all met the responder definition, with 10 (77%) reporting adequate relief for all 4 VLCD weeks. Stool frequency decreased (2.6 +/- 0.8/d to 1.4 +/- 0.6/d; P < .001). Stool consistency improved from diarrheal to normal form (Bristol Stool Score, 5.3 +/- 0.7 to 3.8 +/- 1.2; P < .001). Pain scores and quality-of-life measures significantly improved. Outcomes were independent of weight loss. CONCLUSIONS A VLCD provides adequate relief, and improves abdominal pain, stool habits, and quality of life in IBS-D.

Level of fellowship training increases adenoma detection rates.

BACKGROUND & AIMS The adenoma detection rate (ADR) is critical to the success of colonoscopy for colorectal cancer screening. The effects of involving gastroenterology fellows in screening colonoscopies are uncertain. We assessed the effects of gastroenterology fellow participation on ADR and whether outcomes vary with year of fellowship training. METHODS We performed a retrospective review of all average-risk screening colonoscopies performed from April 2005-April 2007 at the University of Colorado Hospital. A gastroenterology attending physician alone performed 2895 colonoscopies; 699 were performed by a gastroenterology fellow supervised by an attending physician. Statistical analyses of polyp, adenoma, and advanced adenoma (or cancer) detection were performed by using logistic regression. RESULTS The ADR was significantly higher (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.10-1.59) among colonoscopies that included a gastroenterology fellow compared with those performed by only a gastroenterology attending physician. Similarly, the polyp detection rate was higher (OR, 1.28; 95% CI, 1.08-1.52) among colonoscopies involving a gastroenterology fellow. There was no difference in the detection of advanced adenomas or cancers (OR, 1.05; 95% CI, 0.77-1.44) among colonoscopies involving a gastroenterology fellow. The ADR differed greatly by year of training. Compared with colonoscopies performed by an attending gastroenterologist alone, the ADR increased with each year of training: OR, 0.89 (95% CI, 0.66-1.22) for first-year fellows; OR, 1.31 (95% CI, 0.89-1.93) for second-year fellows; and OR, 1.70 (95% CI, 1.33-2.17) for third-year fellows. CONCLUSIONS Involvement of fellows in screening colonoscopies increases the ADR, primarily because of the increased ADR in procedures involving third-year gastroenterology fellows.

Gut dendritic cell activation links an altered colonic microbiome to mucosal and systemic T-cell activation in untreated HIV-1 infection

HIV-1-associated disruption of intestinal homeostasis is a major factor contributing to chronic immune activation and inflammation. Dendritic cells (DCs) are crucial in maintaining intestinal homeostasis, but the impact of HIV-1 infection on intestinal DC number and function has not been extensively studied. We compared the frequency and activation/maturation status of colonic myeloid DC (mDC) subsets (CD1c+ and CD1cneg) and plasmacytoid DCs in untreated HIV-1-infected subjects with uninfected controls. Colonic mDCs in HIV-1-infected subjects had increased CD40 but decreased CD83 expression, and CD40 expression on CD1c+ mDCs positively correlated with mucosal HIV-1 viral load, with mucosal and systemic cytokine production, and with frequencies of activated colon and blood T cells. Percent of CD83+CD1c+ mDCs negatively correlated with frequencies of IFN-γ-producing colon CD4+ and CD8+ T cells. CD40 expression on CD1c+ mDCs positively associated with abundance of high prevalence mucosal Prevotella copri and P. stercorea, but negatively associated with a number of low prevalence mucosal species including Rumminococcus bromii. CD1c+ mDC cytokine production was greater in response to in vitro stimulation with Prevotella species relative to R. bromii. These findings suggest that during HIV infection, colonic mDCs become activated upon exposure to mucosal pathobiont bacteria leading to mucosal and systemic immune activation.

Defective leukocyte GM-CSF receptor (CD116) expression and function in inflammatory bowel disease.

BACKGROUND & AIMS Inflammatory bowel disease (IBD) refers to 2 chronic inflammatory diseases of the intestine, ie, ulcerative colitis and Crohns disease. IBD results from environmental factors (eg, bacterial antigens) triggering a dysregulated immune response in genetically predisposed hosts. Although the basis of IBD is incompletely understood, a number of recent studies have implicated defective innate immune responses in the pathogenesis of IBD. In this regard, there is much interest in therapies that activate innate immunity (eg, recombinant granulocyte-macrophage colony-stimulating factor). METHODS In this study, we screened expression and function of circulating leukocyte granulocyte-macrophage colony-stimulating factor receptor (CD116) messenger RNA and surface protein in 52 IBD patients and 52 healthy controls. RESULTS Our results show that both granulocyte and monocyte CD116 levels, but not CD114 or interleukin-3Rα, were significantly decreased in IBD compared to control (P<.001) and disease controls (irritable bowel syndrome; P<.001; rheumatoid arthritis; P<.025). IBD-associated CD116 repression was more prominent in patients with ulcerative colitis compared to Crohns disease (P<.05), was independent of disease activity (P>.05), and was not influenced by current medications (P>.05). Receiver operating characteristic curve analysis revealed that leukocyte CD116 expression is a sensitive (85%) and specific (92%) biomarker for IBD. Moreover, granulocyte CD116-mediated function (phosphorylation of signal transducers and activators of transcription 3) paralleled decreased expression of CD116 in IBD granulocytes compared to control (P<.001). CONCLUSIONS These studies identify defective expression and function of CD116 as a distinguishing feature of IBD and implicate an associated defect in innate immune responses toward granulocyte-macrophage colony-stimulating factor.

Can Colonoscopy Remain Cost-Effective for Colorectal Cancer Screening? The Impact of Practice Patterns and the Will Rogers Phenomenon on Costs

OBJECTIVES:The adenoma detection rate (ADR) in screening colonoscopy is higher than original cost-effectiveness models estimated. Future colorectal cancer (CRC) risk is decreased once the ADR is 20%, but it is unclear how much additional protection is provided with higher ADRs. We modeled the impact of a high ADR on future CRC risk and surveillance colonoscopy burden.METHODS:We created three hypothetical scenarios for 100,000 average-risk individuals undergoing screening colonoscopy at age 50: (i) 20% ADR with 30% future CRC risk reduction; (ii) 50% ADR with 30% future CRC risk reduction; and (iii) 50% ADR with 50% future CRC risk reduction. After colonoscopy, patients could have high-risk or low-risk adenomas, or no adenomas.RESULTS:When the ADR increases from 20% to 50% but no additional CRC cases are prevented, future CRC risk for each group is still reduced, because lower-risk patients migrate into apparently higher-risk groups (the Will Rogers phenomenon). Future risk is further reduced if a 50% ADR leads to greater protection from CRC. However, despite the reductions in group-specific and overall future CRC risk, 34,635 additional surveillance colonoscopies are performed before the cohort is 60 years old when the ADR is 50% compared with 20%.CONCLUSIONS:If current surveillance practices continue along with high ADRs, screening colonoscopy may not remain cost-effective.

Are Colorectal Cancer Screening Recommendations for First-Degree Relatives of Patients With Adenomas Too Aggressive?

Consensus guidelines of the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology recommend first-degree relatives of individuals diagnosed with an adenoma before age 60 should be screened every 5 years with colonoscopy starting at age 40. This is the identical recommendation for those with a first-degree relative diagnosed with colorectal cancer (CRC) before age 60. There is good evidence that first-degree relatives of individuals diagnosed with CRC before age 60 are at substantially increased risk for developing cancer at a young age. However, it is unclear whether an individual with a first-degree relative with an adenoma diagnosed before age 60 is at increased risk of CRC. Because not all adenomas portend the same cancer risk in the individual who has the adenoma, they would not be expected to portend the same risk in their first-degree relatives. Because of these uncertainties, the US Preventive Services Task Force does not recommend more aggressive screening of first-degree relatives of individuals with an adenoma. The adenoma detection rate for individuals 50 to 59 years old without a first-degree relative with CRC is sufficiently high (approximately 25%-30%) that almost half the population would be high risk on the basis of one first-degree relative having an adenoma. Given the weakness of evidence supporting the guidelines, suboptimal levels of screening in the general population, and lack of resources to comply with the recommendation, first-degree relatives of individuals with adenomas should be screened as average-risk persons until more compelling data are available to justify more aggressive screening.

Low abundance of colonic butyrate-producing bacteria in HIV infection is associated with microbial translocation and immune activation.

Objective:Gut microbial translocation is a major driving force behind chronic immune activation during HIV-1 infection. HIV-1-related intestinal dysbiosis, including increases in mucosa-associated pathobionts, may influence microbial translocation and contribute to mucosal and systemic inflammation. Thus, it is critical to understand the mechanisms by which gut microbes and their metabolic products, such as butyrate, influence immune cell function during HIV-1 infection. Design:A cross-sectional study was performed to compare the relative abundance of butyrate-producing bacterial (BPB) species in colonic biopsies and stool of untreated, chronic HIV-1-infected (n = 18) and HIV-1-uninfected (n = 14) study participants. The effect of exogenously added butyrate on gut T-cell activation and HIV-1 infection was evaluated using an ex-vivo human intestinal cell culture model. Methods:Species were identified in 16S ribosomal RNA sequence datasets. Ex-vivo isolated lamina propria mononuclear cells were infected with C-C chemokine receptor type 5-tropic HIV-1Bal, cultured with enteric gram-negative bacteria and a range of butyrate doses, and lamina propria T-cell activation and HIV-1 infection levels measured. Results:Relative abundance of total BPB and specifically of Roseburia intestinalis, were lower in colonic mucosa of HIV-1-infected versus HIV-1-uninfected individuals. In HIV-1-infected study participants, R. intestinalis relative abundance inversely correlated with systemic indicators of microbial translocation, immune activation, and vascular inflammation. Exogenous butyrate suppressed enteric gram-negative bacteria-driven lamina propria T-cell activation and HIV-1 infection levels in vitro. Conclusion:Reductions in mucosal butyrate from diminished colonic BPB may exacerbate pathobiont-driven gut T-cell activation and HIV replication, thereby contributing to HIV-associated mucosal pathogenesis.

Acid suppression medications are associated with suboptimal weight loss after laparoscopic Roux-en-Y gastric bypass in patients older than 40 years.

BACKGROUND Bariatric surgery, including laparoscopic Roux-en-Y gastric bypass (LRYGB), achieves the greatest long-term weight loss in severe obesity. Approximately 50%-60% of severely obese patients have gastroesophageal reflux disease, and a substantial proportion is taking a proton pump inhibitor (PPI) or histamine-2 blocker (H2 B) at the time of LRYGB. The objective of this study was to explore the association of PPI/H2 B use before LRYGB with suboptimal percent weight loss (PWL) after LRYGB. METHODS This was a cohort study of 472 consecutive patients who underwent LRYGB at a single center from 2004-2011. Suboptimal PWL was defined as<14% at 2 months,<25% at 6 months, and<30% at 12 months. Because of effect modification by age, stratified analyses (by median age of 40 yr) were performed. All models were adjusted for appropriate covariates, including obesity-associated co-morbidities. RESULTS For patients aged ≤40 years, PPI/H2 B use leading up to LRYGB was not associated with suboptimal PWL at 2 months (P = .86), 6 months (P = .47), or 12 months (P = .66). However, for patients aged>40 years, PPI/H2 B use leading up to LRYGB was associated with a nonsignificant increase in suboptimal PWL at 2 months (odds ratio [OR] 2.23; P = .08) and significant increases in suboptimal PWL at 6 months (OR 7.23; P = .002) and 12 months (OR 11.1; P = .02). Results were independent of GERD. CONCLUSIONS Mechanisms for the poorer weight loss in patients aged>40 years who were using a PPI/H2 B just before LRYGB should be explored.

Increasing the Percentage of Energy from Dietary Sugar, Fats, and Alcohol in Adults Is Associated with Increased Energy Intake but Has Minimal Association with Biomarkers of Cardiovascular Risk

The optimal diet composition to prevent obesity and its complications is unknown. Study aims were to determine the association of diet composition with energy intake, homeostatic model assessment-insulin resistance (HOMA-IR), and C-reactive protein (CRP). Data were from the NHANES for eligible adults aged 20-74 y from 2005 to 2006 (n = 3073). Energy intake and diet composition were obtained by dietary recall. HOMA-IR was calculated from fasting insulin and glucose concentrations, and CRP was measured directly. Changes for a 1-point increase in percentage of sugar, saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), polyunsaturated fatty acids (PUFAs), and alcohol were determined across their means in exchange for a 1-point decrease in percentage of nonsugar carbohydrates. Regression analyses were performed, and means ± SEs were estimated. Increasing the percentage of sugar was associated with increased energy intake in men (23 ± 5 kcal; P < 0.001) and women (12 ± 3 kcal; P = 0.002). In men, increasing percentages of SFAs (58 ± 13 kcal; P = 0.001) and PUFAs (66 ± 19 kcal; P < 0.001) were associated with increased energy intake. In women, increasing percentages of SFAs (27 ± 10 kcal; P = 0.02), PUFAs (43 ± 6 kcal; P < 0.001), and MUFAs (36 ± 13 kcal; P = 0.01) were associated with increased energy intake. Increasing the percentage of alcohol was associated with increased energy intake in men (38 ± 7 kcal; P < 0.001) and women (25 ± 8 kcal; P = 0.001). Obesity was associated with increased HOMA-IR and CRP in both genders (all P ≤ 0.001). Increasing PUFAs was associated with decreasing CRP in men (P = 0.02). In conclusion, increasing the percentage of calories from sugar, fats, and alcohol was associated with substantially increased energy intake but had minimal association with HOMA-IR and CRP.