Fecal microbiota transplantation for the improvement of metabolism in obesity: The FMT-TRIM double-blind placebo-controlled pilot trial.

BACKGROUND: There is intense interest about whether modulating gut microbiota can impact systemic metabolism. We investigated the safety of weekly oral fecal microbiota transplantation (FMT) capsules from healthy lean donors and their ability to alter gut microbiota and improve metabolic outcomes in patients with obesity. METHODS AND FINDINGS: FMT-TRIM was a 12-week double-blind randomized placebo-controlled pilot trial of oral FMT capsules performed at a single US academic medical center. Between August 2016 and April 2018, we randomized 24 adults with obesity and mild-moderate insulin resistance (homeostatic model assessment of insulin resistance [HOMA-IR] between 2.0 and 8.0) to weekly healthy lean donor FMT versus placebo capsules for 6 weeks. The primary outcome, assessed by intention to treat, was change in insulin sensitivity between 0 and 6 weeks as measured by hyperinsulinemic euglycemic clamps. Additional metabolic parameters were evaluated at 0, 6, and 12 weeks, including HbA1c, body weight, body composition by dual-energy X-ray absorptiometry, and resting energy expenditure by indirect calorimetry. Fecal samples were serially collected and evaluated via 16S V4 rRNA sequencing. Our study population was 71% female, with an average baseline BMI of 38.8 ± 6.7 kg/m2 and 41.3 ± 5.1 kg/m2 in the FMT and placebo groups, respectively. There were no statistically significant improvements in insulin sensitivity in the FMT group compared to the placebo group (+5% ± 12% in FMT group versus -3% ± 32% in placebo group, mean difference 9%, 95% CI -5% to 28%, p = 0.16). There were no statistically significant differences between groups for most of the other secondary metabolic outcomes, including HOMA-IR (mean difference 0.2, 95% CI -0.9 to 0.9, p = 0.96) and body composition (lean mass mean difference -0.1 kg, 95% CI -1.9 to 1.6 kg, p = 0.87; fat mass mean difference 1.2 kg, 95% CI -0.6 to 3.0 kg, p = 0.18), over the 12-week study. We observed variable engraftment of donor bacterial groups among FMT recipients, which persisted throughout the 12-week study. There were no significant differences in adverse events (AEs) (10 versus 5, p = 0.09), and no serious AEs related to FMT. Limitations of this pilot study are the small sample size, inclusion of participants with relatively mild insulin resistance, and lack of concurrent dietary intervention. CONCLUSIONS: Weekly administration of FMT capsules in adults with obesity results in gut microbiota engraftment in most recipients for at least 12 weeks. Despite engraftment, we did not observe clinically significant metabolic effects during the study. TRIAL REGISTRATION: ClinicalTrials.gov NCT02530385.

Proof-of-concept Application of Continuous Glucose Monitoring Data Analytics to Identify Diabetes Glucotypes.

Background: In this proof-of-concept study, we evaluated if monogenic diabetes resulting from mutations of the HNF-1α gene (HNF1A-MODY) has a distinctive continuous glucose monitoring (CGM) glucotype, in comparison to type 1 diabetes (T1D). Methods: Using CGM data from 5 subjects with HNF1A-MODY and 115 subjects with T1D, we calculated multiple glucose metrics, including measures of within- and between-day variability (such as coefficient variation for each hour [CVb_1h]). Results: The MODY and T1D cohorts had minimum CVb_1h of 11.3 ± 4.4 and 18.0 ± 4.9, respectively (P = .02) and maximum CVb_1h of 33.9 ± 5.0 and 50.3 ± 10, respectively (P < .001). All subjects with HNF1A-MODY had a minimum %CVb_1h ≤ 17.3% and maximum %CVb_1h ≤ 37.1%. In contrast, only 12 of 115 subjects with T1D had both a minimum and maximum %CVb_1h below these thresholds (P < .001). Conclusion: HNF1A- MODY is characterized by a low hourly, between-day glucose variability. CGM-derived glucose metrics may have potential applicability for screening for atypical diabetes phenotypes in the T1D population.

Zoledronic acid for prevention of bone loss in patients receiving bariatric surgery.

PURPOSE: Bariatric surgery is an effective treatment for severe obesity but causes substantial bone loss and increased risk of fractures. To date, there have been no studies examining whether pharmacologic treatments can prevent bone loss after bariatric surgery. We performed an exploratory study to examine the preliminary safety and efficacy of zoledronic acid (ZOL), a potent anti-resorptive bisphosphonate, to suppress bone turnover markers (BTM) and prevent declines in bone mineral density (BMD) after Roux-en-Y gastric bypass (RYGB) surgery. METHODS: We performed an open-label pilot study of pre-operative ZOL in postmenopausal women with obesity who were planning RYGB (n = 4). A single dose of zoledronic acid 5 mg was given intravenously prior to RYGB. Serum bone biochemistries including C-telopeptide (CTX) and procollagen type 1 N-terminal propeptide (P1NP) were measured at multiple timepoints throughout the 24-week study. BMD was also obtained at the spine and hip by dual-energy x-ray absorptiometry (DXA) and at the trabecular spine by quantitative computed tomography (QCT) at pre-operative baseline and 24 weeks. Results were compared against pre-operative baseline and against changes among RYGB historical controls (n = 10). RESULTS: At 2 weeks after RYGB, there was a nonsignificant trend for CTX and P1NP levels to be lower than baseline levels in the ZOL group. By 24 weeks after RYGB, however, participants who received ZOL had a significant increase in CTX above pre-operative baseline (+0.228 ± 0.117 ng/dL, p = 0.030) but this CTX rise was less than that observed in the controls (+0.601 ± 0.307 ng/dL, p = 0.042 between groups). Despite ZOL use, participants had significant areal BMD loss at the total hip as compared to pre-operative baseline (-4.2 ± 1.5%, p = 0.012) that was similar in magnitude to total hip BMD loss in the controls (-5.5 ± 3.9%, p = 0.005). There was a suggestion that the ZOL group might be protected against trabecular spine volumetric bone loss as compared to the control group (+4.8 ± 8.0% vs. -5.9 ± 7.0%, p = 0.075 between groups). Serum calcium, 25-hydroxyvitamin D, and parathyroid hormone did not change in either group. No hypocalcemia or serious adverse events were reported after ZOL. CONCLUSION: In this proof of concept study, a single dose of ZOL prior to RYGB appeared to transiently mitigate but not fully prevent high bone turnover in the acute postoperative period. At 24 weeks after RYGB, our preliminary data suggest that ZOL was not sufficient to prevent bone loss at the hip, although it may preserve bone density at the trabecular spine. Further prospective, controlled studies are needed to confirm our findings and to identify the best strategies for preventing bone loss in bariatric patients receiving RYGB.

Bone Density and Trabecular Morphology at Least 10 Years After Gastric Bypass and Gastric Banding.

Roux-en-Y gastric bypass (RYGB) instigates high-turnover bone loss in the initial 5 years after surgery, whereas skeletal changes after adjustable gastric banding (AGB) are less pronounced. Long-term skeletal data are scarce, and the mechanisms of bone loss remain unclear. We sought to examine bone density and microarchitecture in RYGB and AGB patients a decade after surgery and to determine whether prior published reports of bone loss represent an appropriate adaptation to new postsurgical weight. In this cross-sectional study, 25 RYGB and 25 AGB subjects who had bariatric surgery ≥10 years ago were matched 1:1 with nonsurgical controls for age, sex, and current body mass index (BMI). We obtained bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA), volumetric BMD and microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT), trabecular morphology by individual trabecular segmentation, and metabolic bone laboratory results. As compared with BMI-matched controls, RYGB subjects had significantly lower hip BMD, and lower total volumetric BMD at the distal radius and tibia. Substantial deficits in cortical and trabecular microarchitecture were observed in the RYGB group compared to controls, with reduced trabecular plate bone volume fraction and estimated failure load at both the radius and tibia, respectively. Bone turnover markers CTX and P1NP were 99% and 77% higher in the RYGB group than controls, respectively, with no differences in serum calcium, 25-hydroxyvitamin D, or parathyroid hormone. In contrast, the AGB group did not differ from their BMI-matched controls in any measured bone density, microarchitecture, or laboratory parameter. Thus, RYGB, but not AGB, is associated with lower than expected hip and peripheral BMD for the new weight setpoint, as well as deleterious changes in bone microarchitecture. These findings suggest that pathophysiologic processes other than mechanical unloading or secondary hyperparathyroidism contribute to bone loss after RYGB, and have important clinical implications for the long-term care of RYGB patients. © 2020 American Society for Bone and Mineral Research.

Cone Photoreceptor Irregularity on Adaptive Optics Scanning Laser Ophthalmoscopy Correlates With Severity of Diabetic Retinopathy and Macular Edema.

Purpose: To determine whether cone density, spacing, or regularity in eyes with and without diabetes (DM) as assessed by high-resolution adaptive optics scanning laser ophthalmoscopy (AOSLO) correlates with presence of diabetes, diabetic retinopathy (DR) severity, or presence of diabetic macular edema (DME). Methods: Participants with type 1 or 2 DM and healthy controls underwent AOSLO imaging of four macular regions. Cone assessment was performed by independent graders for cone density, packing factor (PF), nearest neighbor distance (NND), and Voronoi tile area (VTA). Regularity indices (mean/SD) of NND (RI-NND) and VTA (RI-VTA) were calculated. Results: Fifty-three eyes (53 subjects) were assessed. Mean ± SD age was 44 ± 12 years; 81% had DM (duration: 22 ± 13 years; glycated hemoglobin [HbA1c]: 8.0 ± 1.7%; DM type 1: 72%). No significant relationship was found between DM, HbA1c, or DR severity and cone density or spacing parameters. However, decreased regularity of cone arrangement in the macular quadrants was correlated with presence of DM (RI-NND: P = 0.04; RI-VTA: P = 0.04), increasing DR severity (RI-NND: P = 0.04), and presence of DME (RI-VTA: P = 0.04). Eyes with DME were associated with decreased density (P = 0.04), PF (P = 0.03), and RI-VTA (0.04). Conclusions: Although absolute cone density and spacing don't appear to change substantially in DM, decreased regularity of the cone arrangement is consistently associated with the presence of DM, increasing DR severity, and DME. Future AOSLO evaluation of cone regularity is warranted to determine whether these changes are correlated with, or predict, anatomic or functional deficits in patients with DM.

Imaging polarimetry in central serous chorioretinopathy.

PURPOSE: To evaluate a noninvasive technique to detect the leakage point of central serous chorioretinopathy (CSR), using a polarimetry method. DESIGN: Prospective cohort study. SETTING: Institutional practice. PATIENTS: We examined 30 eyes of 30 patients with CSR. MAIN OUTCOME MEASURES: Polarimetry images were recorded using the GDx-N (Laser Diagnostic Technologies). We computed four images that differed in their polarization content: a depolarized light image, an average reflectance image, a parallel polarized light image, and a birefringence image. Each polarimetry image was compared with abnormalities seen on fluorescein angiography. RESULTS: In all eyes, leakage area could be clearly visualized as a bright area in the depolarized light images. Michelson contrasts for the leakage areas were 0.58 +/- 0.28 in the depolarized light images, 0.17 +/- 0.11 in the average reflectance images, 0.09 +/- 0.09 in the parallel polarized light images, and 0.11 +/- 0.21 in the birefringence images from the same raw data. Michelson contrasts in depolarized light images were significantly higher than for the other three images (P < .0001, for all tests, paired t test). The fluid accumulated in the retina was well-visualized in the average and parallel polarized light images. CONCLUSIONS: Polarization-sensitive imaging could readily localize the leakage point and area of fluid in CSR. This may assist with the rapid, noninvasive assessment of CSR.

Visualization of two image variables simultaneously using cardinal directions of color vision.

Visualization of medical image information can be achieved by using color scales to enhance aspects of the data. We have used the cardinal directions of color to make a continuous and representation of phase data that wraps around every 360 deg, and added in another dimension using luminance to illustrate amplidute.

Spatial distribution of macular birefringence associated with the Henle fibers.

The spatial distribution of macular birefringence was modeled to examine the contribution from the foveal Henle fiber layer, particularly cone axons. The model was tested in 20 normal subjects, age 17-55yr. Phase retardance due to Henle fibers was modeled for rings increasing in radius around the fovea, using a sinewave of two periods (2f). The 2f sinewave amplitude increased linearly with eccentricity for each individual, (p<0.004) in 19 of 20 subjects. A good fit to linearity implies regular cone distribution and radial symmetry, and the uniformly excellent fits indicate no effect of age in our sample. The peak of the 2f sinewave amplitude varied across subjects from 1.06 to 2.46deg. An increasingly eccentric peak with increasing age would indicate a relative decrease of cone axons in the central fovea, but the location of the peak was not associated with age for our sample, which did not include elderly subjects.

Imaging polarimetry and retinal blood vessel quantification at the epiretinal membrane.

We evaluated a polarimetry method to enhance retinal blood vessels masked by the epiretinal membrane. Depolarized light images were computed by removing the polarization retaining light reaching the instrument and were compared with parallel polarized light images, average reflectance images, and the corresponding images at 514 nm. Contrasts were computed for retinal vessel profiles for arteries and veins. Contrasts were higher in the 514 nm images in normal eyes but higher in the depolarized light image in the eyes with epiretinal membranes. Depolarized light images were useful for examining the retinal vasculature in the presence of retinal disease.

Imaging polarimetry in patients with neovascular age-related macular degeneration.

Imaging polarimetry was used to examine different components of neovascular membranes in age-related macular degeneration. Retinal images were acquired with a scanning laser polarimeter. An innovative pseudocolor scale, based on cardinal directions of color, displayed two types of image information: relative phases and magnitudes of birefringence. Membranes had relative phase changes that did not correspond to anatomical structures in reflectance images. Further, membrane borders in depolarized light images had significantly higher contrasts than those in reflectance images. The retinal birefringence in neovascular membranes indicates optical activity consistent with molecular changes rather than merely geometrical changes.