Pangenome comparison of Bacteroides fragilis genomospecies unveils genetic diversity and ecological insights.

Bacteroides fragilis is a Gram-negative commensal bacterium commonly found in the human colon, which differentiates into two genomospecies termed divisions I and II. Through a comprehensive collection of 694 B. fragilis whole genome sequences, we identify novel features distinguishing these divisions. Our study reveals a distinct geographic distribution with division I strains predominantly found in North America and division II strains in Asia. Additionally, division II strains are more frequently associated with bloodstream infections, suggesting a distinct pathogenic potential. We report differences between the two divisions in gene abundance related to metabolism, virulence, stress response, and colonization strategies. Notably, division II strains harbor more antimicrobial resistance (AMR) genes than division I strains. These findings offer new insights into the functional roles of division I and II strains, indicating specialized niches within the intestine and potential pathogenic roles in extraintestinal sites. IMPORTANCE: Understanding the distinct functions of microbial species in the gut microbiome is crucial for deciphering their impact on human health. Classifying division II strains as Bacteroides fragilis can lead to erroneous associations, as researchers may mistakenly attribute characteristics observed in division II strains to the more extensively studied division I B. fragilis. Our findings underscore the necessity of recognizing these divisions as separate species with distinct functions. We unveil new findings of differential gene prevalence between division I and II strains in genes associated with intestinal colonization and survival strategies, potentially influencing their role as gut commensals and their pathogenicity in extraintestinal sites. Despite the significant niche overlap and colonization patterns between these groups, our study highlights the complex dynamics that govern strain distribution and behavior, emphasizing the need for a nuanced understanding of these microorganisms.

Aberrant Epithelial Differentiation Contributes to Pathogenesis in a Murine Model of Congenital Tufting Enteropathy.

BACKGROUND & AIMS: Congenital tufting enteropathy (CTE) is an intractable diarrheal disease of infancy caused by mutations of epithelial cell adhesion molecule (EpCAM). The cellular and molecular basis of CTE pathology has been elusive. We hypothesized that the loss of EpCAM in CTE results in altered lineage differentiation and defects in absorptive enterocytes thereby contributing to CTE pathogenesis. METHODS: Intestine and colon from mice expressing a CTE-associated mutant form of EpCAM (mutant mice) were evaluated for specific markers by quantitative real-time polymerase chain reaction, Western blotting, and immunostaining. Body weight, blood glucose, and intestinal enzyme activity were also investigated. Enteroids derived from mutant mice were used to assess whether the decreased census of major secretory cells could be rescued. RESULTS: Mutant mice exhibited alterations in brush-border ultrastructure, function, disaccharidase activity, and glucose absorption, potentially contributing to nutrient malabsorption and impaired weight gain. Altered cell differentiation in mutant mice led to decreased enteroendocrine cells and increased numbers of nonsecretory cells, though the hypertrophied absorptive enterocytes lacked key features, causing brush border malfunction. Further, treatment with the Notch signaling inhibitor, DAPT, increased the numbers of major secretory cell types in mutant enteroids (graphical abstract 1). CONCLUSIONS: Alterations in intestinal epithelial cell differentiation in mutant mice favor an increase in absorptive cells at the expense of major secretory cells. Although the proportion of absorptive enterocytes is increased, they lack key functional properties. We conclude that these effects underlie pathogenic features of CTE such as malabsorption and diarrhea, and ultimately the failure to thrive seen in patients.

Sarcomatoid Renal Cell Carcinoma and Collecting Duct Carcinoma: Discrimination From Common Renal Cell Carcinoma Subtypes and Benign RCC Mimics on Multiphasic MDCT.

RATIONALE AND OBJECTIVES: To investigate whether imaging features on multiphasic multidetector computed tomography (MDCT) can help discriminate sarcomatoid renal cell carcinoma (RCC) and collecting duct carcinoma (CDC) from other solid renal masses. MATERIALS AND METHODS: With institutional review board approval for this HIPAA-compliant study, we derived a cohort of 7 sarcomatoid RCCs, 4 CDCs, 165 clear cell RCCs, 56 papillary RCCs, 22 chromophobe RCCs, 49 oncocytomas, and 16 lipid-poor angiomyolipomas with preoperative multiphasic MDCT with up to four phases (unenhanced, corticomedullary, nephrographic, and excretory). Each lesion was reviewed for contour, spread pattern, pattern of enhancement, neovascularity, and calcification. RESULTS: Sarcomatoid RCCs and CDCs were more likely than other solid renal masses to have an irregular contour (64% vs 2%, P < 0.001) and an infiltrative spread pattern, defined as infiltration into adjacent renal parenchyma, collecting system, or neighboring structures (82% vs 7%, P < 0.001). When used to discriminate sarcomatoid RCC and CDC from other solid renal masses, an infiltrative spread pattern had a specificity of 93% (287/308) and sensitivity of 82% (9/11), and an irregular contour had a specificity of 98% (303/308) and sensitivity of 64% (7/11). CONCLUSIONS: Solid renal lesions with an irregular contour or an infiltrative spread pattern are suspicious for sarcomatoid RCC or CDC.

Clear cell renal cell carcinoma: identifying the gain of chromosome 20 on multiphasic MDCT.

PURPOSE: To investigate whether multiphasic multidetector computed tomography (MDCT) enhancement can help identify the gain of chromosome 20 in clear cell renal cell carcinomas (RCCs), a rare prognostically significant cytogenetic abnormality. METHODS: With the Institutional Review Board approval, we queried our institution's pathology database to derive a cohort of 52 cases of clear cell RCC with preoperative four-phase renal mass protocol MDCT and karyotypes of the resected specimens during a 10-year period. Each lesion was evaluated for absolute and relative (compared to contralateral normal renal cortex) attenuations in each phase. Relative attenuation was calculated as [(lesion attenuation - cortex attenuation)/cortex attenuation] × 100. The absolute and relative attenuations were compared using t-tests. RESULTS: Clear cell RCCs with the gain of 20 had significantly less nephrographic and excretory phase enhancement than clear cell RCCs without the gain of 20 (86.4 HU vs. 111.4 HU, p = 0.007; 70.0 HU vs. 89.4 HU, p = 0.003; respectively). Additionally, the relative nephrographic and excretory phase attenuations of clear cell RCCs with the gain of 20 were significantly less than that of clear cell RCCs without the gain of 20 (-52.7 vs. -34.7, p = 0.002; -44.9 vs. -31.1, p = 0.005; respectively). CONCLUSION: Multiphasic MDCT enhancement may assist in identifying the gain of chromosome 20 in clear cell RCCs, if validated in a large prospective trial.

Clear cell renal cell carcinoma: multiphasic MDCT enhancement can predict the loss of chromosome 8p.

PURPOSE: To investigate whether imaging features on multiphasic multidetector computed tomography (MDCT) can predict the loss of chromosome 8p in clear cell renal cell carcinomas (RCCs), a cytogenetic abnormality associated with a higher tumor grade and greater risk of recurrence. METHODS: With IRB approval for this HIPAA-compliant retrospective study, we queried our institution's pathology database to derive all histologically proven cases of clear cell RCC with preoperative multiphasic MDCT with as many as four phases (unenhanced, corticomedullary, nephrographic, and excretory) from January 2000 to July 2010. Of 170 clear cell RCCs with preoperative multiphasic MDCT, 105 clear cell RCCs, representing 98 unique patients, had karyotypes of the resected specimens. Lesions were evaluated for magnitude and pattern of enhancement, contour, neovascularity, calcifications, and size. RESULTS: The corticomedullary phase mean enhancement of clear cell RCCs with a loss of 8p was significantly greater than that of clear cell RCCs without a loss of 8p (169.5 vs. 127.2 HU, p = 0.004). A threshold of 165 HU predicted the loss of 8p in clear cell RCCs with an accuracy of 78% (69/88), a specificity of 81% (62/77), and a negative predictive value of 94% (62/66). There were no significant differences in the pattern of enhancement, contour, neovascularity, calcification, or size between clear cell RCCs with a loss of 8p and those without this abnormality. CONCLUSION: Enhancement on multiphasic MDCT can predict the loss of 8p in clear cell RCCs and can thus provide a non-invasive means of guiding further management, including surgery, ablation, watchful waiting, or medical management.