Matthew Zhao

The pathogenesis of Crohn’s disease involves genetic and environmental factors, with the gut microbiome playing a crucial role. The Crohn’s disease-associated variant rs13107325 in the SLC39A8 gene results in an A391T substitution in the ZIP8 metal ion transporter and has previously been linked to alterations in the colonic microbiome in variant carriers. We hypothesized that the A391T substitution alters metal ion homeostasis in the colonic mucosal-luminal interface, thereby inducing dysbiosis which may promote intestinal inflammation. To evaluate this hypothesis, we generated a SLC39A8 A393T mouse model (matching human A391T). Consistent with an effect of the variant on ZIP8 function, homozygous A393T mice exhibited increased cobalt in the colonic mucosa, but reduced iron, zinc, manganese, cobalt, copper, and cadmium in the colonic lumen. We performed 16S rRNA gene sequencing of colon samples and histological scoring of colon tissue collected from the SLC39A8 A393T mouse model at different ages. We identified variant-linked effects on microbiome beta diversity in 2-month, 3-4 month, and 12-month old mice and spontaneous intestinal inflammation in 10-month but not 5-month old mice. Predicted pathway analysis of the microbiome samples revealed differential enrichment of iron-, zinc- and cobalt-dependent pathways in A393T mice compared to wild-type controls. These results suggest that the variant in SLC39A8 primarily restricts metal availability to the microbiota, resulting in compositions that can adapt to the environment, and that A393T-linked dysbiosis occurs prior to the onset of inflammation. This study paves the way for future studies investigating risk variants as microbiome-disease modifiers. NEW & NOTEWORTHY Mice recapitulating the human A391T Crohn’s disease-linked risk variant in the SLC39A8-encoded ZIP8 transporter exhibit reduced luminal trace metals and an altered microbiome composition. The microbiome compositional shift occurs prior to the onset of spontaneous colonic inflammation. This study supports an emerging paradigm by which genetic risk for inflammatory bowel disease may confer disease susceptibility through modulation of the gut microbiome.

INTRODUCTION: Federally Qualified Health Centers (FQHC) provide preventive health services such as colorectal cancer (CRC) screening to low-income and underinsured individuals. Overall CRC screening participation in the United States declined during the COVID-19 pandemic and recovered by 2021; however, trends in underresourced settings are unknown. METHODS: Using Uniform Data System data from 2014 to 2022, we assessed trends in FQHC CRC screening rates nationally, in California, and in Los Angeles County and determined clinic-level factors associated with recent screening rate changes. For each FQHC, we calculated the screening rate change from 2019 to 2020, 2020 to 2021, and 2020 to 2022. We used mixed-effects linear regression to determine clinic-level characteristics associated with each screening rate change. RESULTS: Across all FQHC (n = 1,281), 7,016,181 patients were eligible for CRC screening in 2022. Across the United States and in California, median screening rates increased from 2014 to 2019, severely declined in 2020, and failed to return to prepandemic levels by 2022. Both nationally and in California, CRC screening declined most dramatically from 2019 to 2020 in FQHC serving majority Hispanic/Latino patients or a high proportion of patients experiencing homelessness. From 2020 to 2022, screening rates did not recover completely in US FQHC, with disproportionate recovery among FQHC serving majority non-Hispanic Black patients. DISCUSSION: CRC screening rates at FQHC did not return to prepandemic levels by 2022, and recovery varied by FQHC patient characteristics. Tailored interventions addressing low and decreasing CRC screening rates in FQHC are urgently needed to mitigate worsening CRC disparities.

Background: The impact of renal function on hepatic encephalopathy (HE) following transjugular intrahepatic portosystemic shunt (TIPS) placement for refractory ascites is poorly understood. We investigated the role of renal function on HE following TIPS placement. Methods: A retrospective study was performed for patients undergoing TIPS for refractory ascites from 2007–2019. Patients were stratified by GFR at time of TIPS placement and by whether they were on hemodialysis (HD). Chronic kidney disease (CKD) stage 3 or higher was defined as pre-TIPS GFR < 60 for at least 3 months. Logistic regression analyses were used to identify the role of GFR and CKD at time of TIPS placement on HE within 60 days post TIPS placement. Results: Among 201 TIPS patients for refractory ascites (61% male; mean age 59.1), 78 (39%) patients were in CKD, and 16 (21%) were on HD. Mean GFR at time of TIPS placement was 62.7 ± 28.2 for all non-HD patients (n = 185). Compared with the GFR ≥ 90 group, GFR < 30 or HD (OR, 3.56; 95%CI, 1.19–10.7; p = 0.023) and CKD (OR, 2.52; 95%CI, 1.40–4.53; p = 0.002) at time of TIPS placement were significant predictors of post-TIPS placement HE within 60 days. GFRs between 30–60 and 60–90 were not significant predictors. Conclusions: In TIPS patients for recurrent ascites, patients with acutely impaired renal function or chronic renal dysfunction were at an increased risk for HE after TIPS.

The prevalence of food allergies continues to rise, and with limited existing therapeutic options there is a growing need for new and innovative treatments. Food allergies are, in a large part, related to environmental influences on immune tolerance in early life, and represent a significant therapeutic challenge. An expanding body of evidence on molecular mechanisms in murine models and microbiome associations in humans have highlighted the critical role of gut dysbiosis in the pathogenesis of food allergies. As such, the gut microbiome is a rational target for novel strategies aimed at preventing and treating food allergies, and new methods of modifying the gastrointestinal microbiome to combat immune dysregulation represent promising avenues for translation to future clinical practice. In this review, we discuss the intersection between the gut microbiome and the development of food allergies, with particular focus on microbiome therapeutic strategies. These emerging microbiome approaches to food allergies are subject to continued investigation and include dietary interventions, pre- and probiotics, microbiota metabolism-based interventions, and targeted live biotherapeutics. This exciting frontier may reveal disease-modifying food allergy treatments, and deserves careful study through ongoing clinical trials.

INTRODUCTION: The outcomes of transjugular intrahepatic portosystemic shunt (TIPS) placement in patients with hepatic encephalopathy (HE) are controversial. We studied the relationship of pre-TIPS HE in patients undergoing TIPS for refractory ascites on all-cause mortality and development of post-TIPS HE. METHODS: A single-center retrospective comparison study was performed for patients undergoing TIPS for refractory ascites. Survival by history of pre-TIPS HE was demonstrated with Kaplan-Meier curves. Univariate and multivariate logistic regression analyses were performed to identify the predictors of post-TIPS clinical outcomes for patients with and without pre-TIPS HE. RESULTS: We identified 202 TIPS recipients (61% male, mean ± SD; age 59.1 ± 10.2 years; mean model for end-stage liver disease score 17.3 ± 6.9). Pre-TIPS HE did not predispose patients for increased all-cause mortality, increased risk of experiencing HE within 60 days, or increased risk of hospital admission for HE within 6 months. A multivariate analysis demonstrated that total bilirubin (odds ratio [OR] 1.03; P = 0.016) and blood urea nitrogen (OR 1.15; P = 0.002) were predictors for all-cause mortality within 6 months post-TIPS. Age ≥65 years (OR 3.92; P = 0.004), creatinine (OR 2.22; P = 0.014), and Child-Pugh score (OR 1.53; P = 0.006) were predictors for HE within 60 days post-TIPS. Predictors of intensive care admission for HE within 6 months post-TIPS included age ≥65 years (OR 8.84; P = 0.018), history of any admission for HE within 6 months pre-TIPS (OR 8.42; P = 0.017), and creatinine (OR 2.22; P = 0.015). DISCUSSION: If controlled, pre-TIPS HE does not adversely impact patient survival or clinical outcomes, such as development of HE within 60 days of TIPS or hospital admission for HE within 6 months. Patients may be able to undergo TIPS for refractory ascites despite a history of HE.