Faculty Bibliography

Patients with resected, high-risk melanoma receive adjuvant immune checkpoint blockade (ICB), yet clinical benefit remains unpredictable, with 25%-40% of patients experiencing recurrence. To evaluate whether pre-treatment gut microbiome (GMB) features predict recurrence, we analyzed stool samples from 674 patients enrolled in a phase 3 clinical trial, CheckMate 915, which investigated the combination of nivolumab plus ipilimumab versus nivolumab as a single agent across five geographic regions. Region-specific and cross-region meta-analyses identified pre-treatment taxa associated with recurrence, including Eubacterium, Ruminococcus, Firmicutes, and Clostridium. Recurrence prediction was strongest when the validation cohort exhibited GMB profiles similar to those in the discovery cohort. Among closely matched individuals (Jensen-Shannon divergence [JSD] ≤ 0.11), the area under the curve (AUC) for recurrence prediction ranged from 0.78 to 0.94 across regions. GMB composition remained largely stable following treatment. These findings suggest that gut bacterial markers can predict recurrence after adjuvant ICB treatment in melanoma, supporting their potential as clinically actionable biomarkers to guide personalized therapy.

BACKGROUND:Asian American (AsA) and Native Hawaiian and Pacific Islander (NHPI) populations are underrepresented in U.S. health studies. OBJECTIVES/OBJECTIVE:The MOSAAIC (Multi-ethnic Observational Study in American Asian and Pacific Islander Communities) is a cohort study designed to improve understanding of disparities in cardiovascular disease and other health conditions affecting AsA and NHPI groups. METHODS:Through broad eligibility criteria and outreach tailored to each study community, MOSAAIC will include 11,500 adults aged 18+ years living in 5 field center regions: New York, Philadelphia, Chicago, San Francisco Bay Area, and Honolulu. The protocol specifies sample-size targets to allow valid comparisons among persons having personal or family origins in 4 geographically defined regions, including East Asia (the largest groups being Chinese and Korean), South Asia (Indian), Southeast Asia (Vietnamese and Filipino) and Oceania (NHPI). Measurements to be obtained at an in-person examination include clinical laboratory tests, medical history, medication use, spirometry, cognitive and physical function, anthropometry, and electrocardiogram. Surveys in multiple languages to assess medical, behavioral, lifestyle, social and environmental influences on health were developed by a multistep process to ensure equivalency between translations and cultural appropriateness. Biospecimens are stored for future studies. Long-term follow-up will be conducted to ascertain and adjudicate major health events including myocardial infarction, stroke, heart failure, and mortality. CONCLUSIONS:The National Institutes of Health established MOSAAIC as a resource for wide-ranging epidemiologic investigation of factors related to cardiometabolic, pulmonary, or mental health in persons of diverse AsA and NHPI background.

IMPORTANCE/UNASSIGNED:The oral microbiota may be involved in the development of pancreatic cancer, yet current evidence is largely limited to bacterial 16S amplicon sequencing and small retrospective case-control studies. OBJECTIVE/UNASSIGNED:To test whether the oral bacterial and fungal microbiome is associated with the subsequent development of pancreatic cancer. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This cohort study used data from 2 epidemiological cohorts: the American Cancer Society Cancer Prevention Study-II Nutrition Cohort and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Among cohort participants who provided oral samples, those who prospectively developed pancreatic cancer were identified during follow-up. Control participants who remained free of cancer were selected by 1:1 frequency matching on cohort, 5-year age band, sex, race and ethnicity, and time since oral sample collection. Data were collected from August 2023 to September 2024, and data were analyzed from August 2023 to January 2025. EXPOSURES/UNASSIGNED:The oral bacterial and fungal microbiome were characterized via whole-genome shotgun sequencing and internal transcribed spacer (ITS) sequencing, respectively. The association of periodontal pathogens of the red complex (Treponema denticola, Porphyromonas gingivalis, and Tannerella forsythia) and orange complex (Fusobacterium nucleatum, F periodonticum, Prevotella intermedia, P nigrescens, Parvimonas micra, Eubacterium nodatum, Campylobacter shower, and C gracilis) with pancreatic cancer was tested via logistic regression. The association of the microbiome-wide bacterial and fungal taxa with pancreatic cancer was assessed by Analysis of Compositions of Microbiomes With Bias Correction 2 (ANCOM-BC2). Microbial risk scores (MRS) for pancreatic cancer were calculated from the risk-associated bacterial and fungal species. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Pancreatic cancer incidence. RESULTS/UNASSIGNED:Of 122 000 cohort participants who provided samples, 445 developed pancreatic cancer over a median (IQR) follow-up of 8.8 (4.9-13.4) years and were matched with 445 controls. Of these 890 participants, 474 (53.3%) were male, and the mean (SD) age was 67.2 (7.5) years. Three oral bacterial periodontal pathogens-P gingivalis, E nodatum, and P micra-were associated with increased risk of pancreatic cancer. A bacteriome-wide scan revealed 8 oral bacteria associated with decreased and 13 oral bacteria associated with increased risk of pancreatic cancer (false discovery rate-adjusted Q statistic less than .05). Of the fungi, genus Candida was associated with increased risk of pancreatic cancer. The MRS, based on 27 oral species, was associated with an increase in pancreatic cancer risk (multivariate odds ratio per 1-SD increase in MRS, 3.44; 95% CI, 2.63-4.51). CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this cohort study, oral bacteria and fungi were significant risk factors for pancreatic cancer development. Oral microbiota hold promise as biomarkers to identify individuals at high risk of pancreatic cancer, potentially contributing to personalized prevention.

The pancreas tumor microbiota may influence tumor microenvironment and influence survival in early-stage pancreatic ductal adenocarcinoma (PDAC); however, current studies are limited and small. We investigated the relationship of tumor microbiota to survival in 201 surgically resected patients with localized PDAC (Stages I-II), from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) cohorts. We characterized the tumor microbiome using RNA-sequencing data. We examined the association of the tumor microbiome with overall survival (OS), via meta-analysis with the Cox PH model. A microbial risk score (MRS) was calculated from the OS-associated microbiota. We further explored whether the OS-associated microbiota is related to host tumor immune infiltration. PDAC tumor microbiome α- and β-diversities were not associated with OS; however, 11 bacterial species, including species of Gammaproteobacteria, confirmed by extensive resampling, were significantly associated with OS (all Q < 0.05). The MRS summarizing these bacteria was related to a threefold change in OS (hazard ratio = 2.96 per standard deviation change in the MRS, 95% confidence interval = 2.26-3.86). This result was consistent across the two cohorts and in stratified analyses by adjuvant therapy (chemotherapy/radiation). Identified microbiota and the MRS also exhibited association with memory B cells and naïve CD4⁺ T cells, which may be related to the immune landscape through BCR and TCR signaling pathways. Our study shows that a unique tumor microbiome structure, potentially affecting the tumor immune microenvironment, is associated with poorer survival in resected early-stage PDAC. These findings suggest that microbial mechanisms may be involved in PDAC survival, potentially informing PDAC prognosis and guiding personalized treatment strategies.IMPORTANCEMuch of the available data on the PDAC tumor microbiome and survival are derived from relatively small and heterogeneous studies, including those involving patients with advanced stages of pancreatic cancer. There is a critical knowledge gap in terms of the tumor microbiome and survival in early-stage patients treated by surgical resection; we expect that advancements in survival may initially be best achieved in these patients who are treated with curative intent.

The gut microbiome (GMB) has been associated with outcomes of immune checkpoint blockade therapy in melanoma, but there is limited consensus on the specific taxa involved, particularly across different geographic regions. We analyzed pre-treatment stool samples from 674 melanoma patients participating in a phase-III trial of adjuvant nivolumab plus ipilimumab versus nivolumab, across three continents and five regions. Longitudinal analysis revealed that GMB was largely unchanged following treatment, offering promise for lasting GMB-based interventions. In region-specific and cross-region meta-analyses, we identified pre-treatment taxonomic markers associated with recurrence, including Eubacterium, Ruminococcus, Firmicutes, and Clostridium. Recurrence prediction by these markers was best achieved across regions by matching participants on GMB compositional similarity between the intra-regional discovery and external validation sets. AUCs for prediction ranged from 0.83-0.94 (depending on the initial discovery region) for patients closely matched on GMB composition (e.g., JSD ≤0.11). This evidence indicates that taxonomic markers for prediction of recurrence are generalizable across regions, for individuals of similar GMB composition.

IMPORTANCE/UNASSIGNED:The oral microbiota may be involved in development of head and neck squamous cell cancer (HNSCC), yet current evidence is largely limited to bacterial 16S amplicon sequencing or small retrospective case-control studies. OBJECTIVE/UNASSIGNED:To test whether oral bacterial and fungal microbiomes are associated with subsequent risk of HNSCC development. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:Prospective nested case-control study among participants providing oral samples in 3 epidemiological cohorts, the American Cancer Society Cancer Prevention Study II Nutrition Cohort, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, and the Southern Community Cohort Study. Two hundred thirty-six patients who prospectively developed HNSCC were identified during a mean (SD) of 5.1 (3.6) years of follow-up. Control participants who remained HNSCC free were selected by 2:1 frequency matching on cohort, age, sex, race and ethnicity, and time since oral sample collection. Data analysis was conducted in 2023. EXPOSURES/UNASSIGNED:Characterization of the oral bacterial microbiome using whole-genome shotgun sequencing and the oral fungal microbiome using internal transcribed spacer sequencing. Association of bacterial and fungal taxa with HNSCC was assessed by analysis of compositions of microbiomes with bias correction. Association with red and orange oral pathogen complexes was tested by logistic regression. A microbial risk score for HNSCC risk was calculated from risk-associated microbiota. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary outcome was HNSCC incidence. RESULTS/UNASSIGNED:The study included 236 HNSCC case participants with a mean (SD) age of 60.9 (9.5) years and 24.6% women during a mean of 5.1 (3.6) years of follow-up, and 485 matched control participants. Overall microbiome diversity at baseline was not related to subsequent HNSCC risk; however 13 oral bacterial species were found to be differentially associated with development of HNSCC. The species included the newly identified Prevotella salivae, Streptococcus sanguinis, and Leptotrichia species, as well as several species belonging to beta and gamma Proteobacteria. The red/orange periodontal pathogen complex was moderately associated with HNSCC risk (odds ratio, 1.06 per 1 SD; 95% CI, 1.00-1.12). A 1-SD increase in microbial risk score (created based on 22 bacteria) was associated with a 50% increase in HNSCC risk (multivariate odds ratio, 1.50; 95% CI, 1.21-1.85). No fungal taxa associated with HNSCC risk were identified. CONCLUSIONS AND RELEVANCE/UNASSIGNED:This case-control study yielded compelling evidence that oral bacteria are a risk factor for HNSCC development. The identified bacteria and bacterial complexes hold promise, along with other risk factors, to identify high-risk individuals for personalized prevention of HNSCC.

The human oral microbiome may alter oral and systemic disease risk. Consuming high sugar content beverages (HSB) can lead to caries development by altering the microbial composition in dental plaque, but little is known regarding HSB-specific oral microbial alterations. Therefore, we conducted a large, population-based study to examine associations of HSB intake with oral microbiome diversity and composition. Using mouthwash samples of 989 individuals in two nationwide U.S. cohorts, bacterial 16S rRNA genes were amplified, sequenced, and assigned to bacterial taxa. HSB intake was quantified from food frequency questionnaires as low (< 1 serving/week), medium (1-3 servings/week), or high (> 3 servings/week). We assessed overall bacterial diversity and presence of specific taxa with respect to HSB intake in each cohort separately and combined in a meta-analysis. Consistently in the two cohorts, we found lower species richness in high HSB consumers (> 3 cans/week) (p = 0.027), and that overall bacterial community profiles differed from those of non-consumers (PERMANOVA p = 0.040). Specifically, presence of a network of commensal bacteria (Lachnospiraceae, Peptostreptococcaceae, and Alloprevotella rava) was less common in high compared to non-consumers, as were other species including Campylobacter showae, Prevotella oulorum, and Mycoplasma faucium. Presence of acidogenic bacteria Bifodobacteriaceae and Lactobacillus rhamnosus was more common in high consumers. Abundance of Fusobacteriales and its genus Leptotrichia, Lachnoanaerobaculum sp., and Campylobacter were lower with higher HSB consumption, and their abundances were correlated. No significant interaction was found for these associations with diabetic status or with microbial markers for caries (S. mutans) and periodontitis (P. gingivalis). Our results suggest that soft drink intake may alter the salivary microbiota, with consistent results across two independent cohorts. The observed perturbations of overrepresented acidogenic bacteria and underrepresented commensal bacteria in high HSB consumers may have implications for oral and systemic disease risk.

Lower socioeconomic status (SES) is related to increased incidence and mortality due to chronic diseases in adults. Association between SES variables and gut microbiome variation has been observed in adults at the population level, suggesting that biological mechanisms may underlie the SES associations; however, there is a need for larger studies that consider individual- and neighborhood-level measures of SES in racially diverse populations. In 825 participants from a multi-ethnic cohort, we investigated how SES shapes the gut microbiome. We determined the relationship of a range of individual- and neighborhood-level SES indicators with the gut microbiome. Individual education level and occupation were self-reported by questionnaire. Geocoding was applied to link participants' addresses with neighborhood census tract socioeconomic indicators, including average income and social deprivation in the census tract. Gut microbiome was measured using 16SV4 region rRNA gene sequencing of stool samples. We compared α-diversity, β-diversity, and taxonomic and functional pathway abundance by SES. Lower SES was significantly associated with greater α-diversity and compositional differences among groups, as measured by β-diversity. Several taxa related to low SES were identified, especially an increasing abundance of Prevotella copri and Catenibacterium sp000437715, and decreasing abundance of Dysosmobacter welbionis in terms of their high log-fold change differences. In addition, nativity and race/ethnicity have emerged as ecosocial factors that also influence the gut microbiota. Together, these results showed that lower SES was strongly associated with compositional and taxonomic measures of the gut microbiome, and may contribute to shaping the gut microbiota.