Biology subjects

Chan, A. T.

Publications and source records attributed to Chan, A. T..

7 recordsLinked to original sources

bioRxiv2026

Human Gut Bacteria Convert Endogenous Steroids into Host Cortisol Shuttle Inhibitors

11{beta}-hydroxysteroid dehydrogenase 2 (HSD11B2) protects the mineralocorticoid receptor from glucocorticoid overstimulation by inactivating cortisol. HSD11B2 inhibition can drive receptor overactivation and contribute to hypertension; however, endogenous inhibitors remain poorly defined. Glycyrrhetinic acid-like factors (GALFs) are steroid-like metabolites that inhibit HSD11B2. Given the capacity of gut bacteria to metabolize host steroids, we hypothesized that the gut microbiome could generate GALF-like inhibitors. Here, we identify two 11-oxygenated steroid metabolites that potently inhibit human HSD11B2 in colonic cells and organoids, enabling cortisol-dependent mineralocorticoid receptor activation. We identify gut bacteria and enzymes that produce these compounds and show that their levels are markedly reduced in antibiotic-treated humans. One metabolite is elevated during pregnancy, and both are higher in individuals with stage 2 hypertension-range blood pressure. These findings reveal a bacterial route to altered host cortisol signaling and suggest a potential link between microbiome-derived GALFs and blood pressure regulation.

microbiology↗

bioRxiv2024

Optimizing single-cell RNA sequencing methods for human colon biopsies: droplet-based vs. picowell-based platforms

Background & AimsSingle-cell RNA sequencing (scRNA) has empowered many insights into gastrointestinal microenvironments. However, profiling human biopsies using droplet-based scRNA (D-scRNA) is challenging since it requires immediate processing to minimize epithelial cell damage. In contrast, picowell-based (P-scRNA) platforms permit short-term frozen storage before sequencing. We compared P- and D-scRNA platforms on cells derived from human colon biopsies. MethodsEndoscopic rectosigmoid mucosal biopsies were obtained from two adults and conducted D-scRNA (10X Chromium) and P-scRNA (Honeycomb HIVE) in parallel using an individuals pool of single cells (> 10,000 cells/participant). Three experiments were performed to evaluate 1) P-scRNA with cells under specific storage conditions (immediately processed [fresh], vs. frozen at -20C vs. -80C [2 weeks]); 2) fresh P-scRNA versus fresh D-scRNA; and 3) P-scRNA stored at -80C with fresh D-scRNA. ResultsSignificant recovery of loaded cells was achieved for fresh (80.9%) and -80C (48.5%) P-scRNA and D-scRNA (76.6%), but not -20C P-scRNA (3.7%). However, D-scRNA captures more typeable cells among recovered cells (71.5% vs. 15.8% Fresh and 18.4% -80C P-scRNA), and these cells exhibit higher gene coverage at the expense of higher mitochondrial read fractions across most cell types. Cells profiled using D-scRNA demonstrated more consistent gene expression profiles among the same cell type than those profiled using P-scRNA. Significant intra-cell-type differences were observed in profiled gene classes across platforms. ConclusionsOur results highlight non-overlapping advantages of P-scRNA and D-scRNA and underscore the need for innovation to enable high-fidelity capture of colonic epithelial cells. The platform-specific variation highlights the challenges of maintaining rigor and reproducibility across studies that use different platforms.

genomics↗

bioRxiv2022

Gut feelings: Associations of emotions and emotion regulation with the gut microbiome in women

Accumulating evidence suggests that positive and negative emotions, as well as emotion regulation processes, influence the onset and the progression of multiple human diseases. However, the underlying mechanisms connecting these emotion-related factors with physical health are not fully understood. Recent work linking the gut microbiome with both mental and physical health suggests it may be a potential pathway. Yet, its association with emotions and emotion regulation are understudied. In this study, we examined whether positive and negative emotions, as well as two emotion regulation strategies (i.e., cognitive reappraisal and suppression), were associated with the diversity, overall structure, and specific species/pathways of the gut microbiome in 206 healthy women. We found that the alpha diversity was negatively associated with suppression. Moreover, using multivariate analysis, we found that positive emotions were inversely associated with the relative abundance of Firmicutes bacterium CAG 94 and Ruminococcaceae bacterium D16, while negative emotions were directly related to relative abundance of these same species. Moreover, we found associations of emotions and emotion regulation with microbial metabolic pathways. For example, negative emotions were inversely related to biosynthesis of pantothenate, coenzyme A, and adenosine. Taken together, our findings offer human evidence supporting linkages of emotions and related regulatory processes with the gut microbiome. These findings highlight the critical importance of incorporating the human gut microbiome in our understanding of emotion-related factors and their associations with physical health.

microbiology↗

bioRxiv2021

Innate immune signaling drives late cardiac toxicity following DNA damaging cancer therapies

Late cardiac toxicity is a potentially lethal complication of cancer therapy, yet the pathogenic mechanism remains largely unknown, and few treatment options exist. Here we report DNA damaging agents such as radiation and anthracycline chemotherapies induce delayed cardiac inflammation following therapy due to activation of cGAS and STING-dependent type I interferon signaling. Genetic ablation of cGAS-STING-signaling in mice inhibits DNA damage induced cardiac inflammation, rescues late cardiac functional decline, and prevents death from cardiac events. Treatment with a STING antagonist suppresses cardiac interferon signaling following DNA damaging therapies and effectively mitigates cardiotoxicity. These results identify a therapeutically targetable, pathogenic mechanism for one of the most vexing treatment-related toxicities in cancer survivors.

immunology↗

bioRxiv2020

A combined proteomics and Mendelian randomization approach to investigate the effects of aspirin-targeted proteins on colorectal cancer

BackgroundEvidence for aspirins chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk. MethodsHuman colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labelling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL (N=3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N=31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls). ResultsAltered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2 and ARFIP2 expression and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR:1.08, 95% CI:1.03-1.13, OR:3.33, 95% CI:2.46-4.50 and OR:1.15, 95% CI:1.02-1.29, respectively). ConclusionMCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation indicating a possible role in aspirins reduction of metastasis. ImpactOur approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.

cancer biology↗

bioRxiv2019

Physical activity and risks of breast and colorectal cancer: A Mendelian randomization analysis

Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomization analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.59, 95% confidence interval [CI]: 0.42 to 0.84, P-value=0.003) and colorectal cancer (OR: 0.66, 95% CI: 0.53 to 0.82, P-value=2*E-4). We found similar magnitude inverse associations by breast cancer subtype and by colorectal cancer anatomical site. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers.\n\nDisclaimerWhere authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organization.

genetics↗

bioRxiv2018

Intake of dietary fiber, fruits, and vegetables, and risk of diverticulitis

Background & AimsAlthough low fiber intake has been considered a risk factor for diverticulitis, prospective evidence is limited and conflicting, with little known about variation in the protective effects according to food sources. We assessed the associations of intakes of fiber and major food sources of fiber including fruits and vegetables with risk of diverticulitis.\n\nMethodsWe followed 50,019 women in the Nurses Health Study (1990-2014) and 48,292 men in the Health Professionals Follow-up Study (1986-2014) who were free of diverticulitis, cancer, and inflammatory bowel disease at baseline. Incident diverticulitis was identified through self-report with validity confirmed by review of medical records.\n\nResultsDuring a mean follow-up time of 22 years, we documented 4,343 incident cases of diverticulitis in women and 1,142 cases in men. Compared to participants in the lowest quintile, the multivariable HRs (95% CIs) of diverticulitis in the highest quintile of total fiber intake were 0.86 (0.78-0.95; P-trend=0.002) among women and 0.63 (0.51-0.79; P-trend<0.001) among men. Fiber from different food sources, except for vegetable fiber in women, was associated with a decreased risk of diverticulitis. Furthermore, total whole fruit intake was associated with reduced risk of diverticulitis in both cohorts with a multivariable HR for diverticulitis of 0.95 (0.92-0.98; P-trend<0.001) in women and 0.91 (0.86-0.96; P-trend<0.001) in men for every serving increase of total whole fruit intake per day.\n\nConclusionsHigher intake of dietary fiber and fiber from different food sources are associated with a lower risk of diverticulitis. A greater intake of whole fruit is also associated with reduced risk.

epidemiology↗