When Gut Microbiota Creep into Fat, the Fat Creeps Back.

Ha and colleagues describe a previously unappreciated diversity of microbes in the mesenteric adipose tissue (MAT) surrounding the GI tract. Viable bacteria that are mislocalized from the gut microbiota and metabolically adapted to the MAT contribute to the "creeping fat" of Crohn's disease.

Translocation of Viable Gut Microbiota to Mesenteric Adipose Drives Formation of Creeping Fat in Humans.

A mysterious feature of Crohn's disease (CD) is the extra-intestinal manifestation of "creeping fat" (CrF), defined as expansion of mesenteric adipose tissue around the inflamed and fibrotic intestine. In the current study, we explore whether microbial translocation in CD serves as a central cue for CrF development. We discovered a subset of mucosal-associated gut bacteria that consistently translocated and remained viable in CrF in CD ileal surgical resections, and identified Clostridium innocuum as a signature of this consortium with strain variation between mucosal and adipose isolates, suggesting preference for lipid-rich environments. Single-cell RNA sequencing characterized CrF as both pro-fibrotic and pro-adipogenic with a rich milieu of activated immune cells responding to microbial stimuli, which we confirm in gnotobiotic mice colonized with C. innocuum. Ex vivo validation of expression patterns suggests C. innocuum stimulates tissue remodeling via M2 macrophages, leading to an adipose tissue barrier that serves to prevent systemic dissemination of bacteria.

Ileitis-associated tertiary lymphoid organs arise at lymphatic valves and impede mesenteric lymph flow in response to tumor necrosis factor.

Lymphangitis and the formation of tertiary lymphoid organs (TLOs) in the mesentery are features of Crohn's disease. Here, we examined the genesis of these TLOs and their impact on disease progression. Whole-mount and intravital imaging of the ileum and ileum-draining collecting lymphatic vessels (CLVs) draining to mesenteric lymph nodes from TNFΔARE mice, a model of ileitis, revealed TLO formation at valves of CLVs. TLOs obstructed cellular and molecular outflow from the gut and were sites of lymph leakage and backflow. Tumor necrosis factor (TNF) neutralization begun at early stages of TLO formation restored lymph transport. However, robustly developed, chronic TLOs resisted regression and restoration of flow after TNF neutralization. TNF stimulation of cultured lymphatic endothelial cells reprogrammed responses to oscillatory shear stress, preventing the induction of valve-associated genes. Disrupted transport of immune cells, driven by loss of valve integrity and TLO formation, may contribute to the pathology of Crohn's disease.

Microbiota-Dependent Sequelae of Acute Infection Compromise Tissue-Specific Immunity.

Infections have been proposed as initiating factors for inflammatory disorders; however, identifying associations between defined infectious agents and the initiation of chronic disease has remained elusive. Here, we report that a single acute infection can have dramatic and long-term consequences for tissue-specific immunity. Following clearance of Yersinia pseudotuberculosis, sustained inflammation and associated lymphatic leakage in the mesenteric adipose tissue deviates migratory dendritic cells to the adipose compartment, thereby preventing their accumulation in the mesenteric lymph node. As a consequence, canonical mucosal immune functions, including tolerance and protective immunity, are persistently compromised. Post-resolution of infection, signals derived from the microbiota maintain inflammatory mesentery remodeling and consequently, transient ablation of the microbiota restores mucosal immunity. Our results indicate that persistent disruption of communication between tissues and the immune system following clearance of an acute infection represents an inflection point beyond which tissue homeostasis and immunity is compromised for the long-term. VIDEO ABSTRACT.

Creeping Fat in Crohn's Disease: Innocuous or innocuum?

In Crohn's disease, the characteristic expansion of mesenteric tissue on sites of intestinal inflammation is known as creeping fat. In a recent issue of Cell, Ha et al. report that translocation of gut bacteria to the mesenteries is associated with the formation of creeping fat.

Hemodynamic Characteristics of a Tortuous Microvessel Using High-Fidelity Red Blood Cell Resolved Simulations.

OBJECTIVE: Tortuous microvessels are characteristic of microvascular remodeling associated with numerous physiological and pathological scenarios. Three-dimensional (3D) hemodynamics in tortuous microvessels influenced by red blood cells (RBCs), however, are largely unknown, and important questions remain. Is blood viscosity influenced by vessel tortuosity? How do RBC dynamics affect wall shear stress (WSS) patterns and the near-wall cell-free layer (CFL) over a range of conditions? The objective of this work was to parameterize hemodynamic characteristics unique to a tortuous microvessel. METHODS: RBC-resolved simulations were performed using an immersed boundary method-based 3D fluid dynamics solver. A representative tortuous microvessel was selected from a stimulated angiogenic network obtained from imaging of the rat mesentery and digitally reconstructed for the simulations. The representative microvessel was a venule with a diameter of approximately 20 µm. The model assumes a constant diameter along the vessel length and does not consider variations due to endothelial cell shapes or the endothelial surface layer. RESULTS: Microvessel tortuosity was observed to increase blood apparent viscosity compared to a straight tube by up to 26%. WSS spatial variations in high curvature regions reached 23.6 dyne/cm2 over the vessel cross-section. The magnitudes of WSS and CFL thickness variations due to tortuosity were strongly influenced by shear rate and negligibly influenced by tube hematocrit levels. CONCLUSIONS: New findings from this work reveal unique tortuosity-dependent hemodynamic characteristics over a range of conditions. The results provide new thought-provoking information to better understand the contribution of tortuous vessels in physiological and pathological processes and help improve reduced-order models.

Laparoscopic Dissection of Lymph Node Station 16-Why and How?

BACKGROUND: Dissection of para-aortic lymph nodes (Station 16) provides an important prognosticator for patients with gastrointestinal, colorectal, and hepatobiliary cancers.1-4 For example, a positive Station 16 lymph node has been shown to lead to 2-year survival of 3% in patients with pancreas adenocarcinoma, akin to stage IV disease.5,6 Thereby, Station 16 involvement can help with the risk/benefit stratification of the decision to move forward with radical surgery.7-9 Furthermore, it has been shown for gallbladder cancer that involvement of Station 16 cannot necessarily be predicted from the dissection of the hepatoduodenal ligament lymph nodes only.10,11 TECHNIQUE: With the patient in the French position, a complete Kocherization and a Cattel-Braasch maneuver is performed, allowing for visualization of LN station 16b. Station 16b is the inferior border of the station 16 compartment. The left renal vein (LRV) serves as an important landmark to identify the superior border of the dissection comprised by Stations 16a2 and 16b1. Station 16a2 dissection may be associated with a traction injury of the left renal vein or damage of right renal or suprarenal arteries and is dissected if there are specific concerns regarding involvement. CONCLUSIONS: While station 16 provides important prognostic information for risk stratification, a strategic and stepwise approach is needed for a safe sampling. This is accomplished by wide mobilization of the duodenum, implementation of thermal fusion to minimize chyle leak, and careful dissection below the left renal vein.

Age-Associated B Cell Features of the Murine High-Grade B Cell Lymphoma Bc.DLFL1 and Its Extranodal Expansion in Abdominal Adipose Tissues.

Diffuse large B cell lymphoma comprises a heterogeneous group of B cell-derived tumors, with different degrees of aggressiveness, as defined by their cellular origin and tissue microenvironment. Using the spontaneous Bc.DLFL1 lymphoma originating from a BALB/c mouse as a diffuse large B cell lymphoma model, in this study we demonstrate that the lymphoma cells display surface phenotype, IgH V-region somatic mutations, transcription factor characteristics and in vivo location to splenic extrafollicular regions of age-associated B cells (ABCs), corresponding to T-bet+ and Blimp-1+/CD138- plasmablasts derivation. The expansion of lymphoma cells within lymphoid tissues took place in a close arrangement with CD11c+ dendritic cells, whereas the extranodal infiltration occurred selectively in the mesentery and omentum containing resident gp38/podoplanin+ fibroblastic reticular cells. Antagonizing BAFF-R activity by mBR3-Fc soluble receptor fusion protein led to a significant delay of disease progression. The extranodal expansion of Bc.DLFL1 lymphoma within the omental and mesenteric adipose tissues was coupled with a significant change of the tissue cytokine landscape, including both shared alterations and tissue-specific variations. Our findings indicate that while Bc.DLFL1 cells of ABC origin retain the positioning pattern within lymphoid tissues of their physiological counterpart, they also expand in non-lymphoid tissues in a BAFF-dependent manner, where they may alter the adipose tissue microenvironment to support their extranodal growth.

An RB-EZH2 Complex Mediates Silencing of Repetitive DNA Sequences.

Repetitive genomic regions include tandem sequence repeats and interspersed repeats, such as endogenous retroviruses and LINE-1 elements. Repressive heterochromatin domains silence expression of these sequences through mechanisms that remain poorly understood. Here, we present evidence that the retinoblastoma protein (pRB) utilizes a cell-cycle-independent interaction with E2F1 to recruit enhancer of zeste homolog 2 (EZH2) to diverse repeat sequences. These include simple repeats, satellites, LINEs, and endogenous retroviruses as well as transposon fragments. We generated a mutant mouse strain carrying an F832A mutation in Rb1 that is defective for recruitment to repetitive sequences. Loss of pRB-EZH2 complexes from repeats disperses H3K27me3 from these genomic locations and permits repeat expression. Consistent with maintenance of H3K27me3 at the Hox clusters, these mice are developmentally normal. However, susceptibility to lymphoma suggests that pRB-EZH2 recruitment to repetitive elements may be cancer relevant.

The mesenteric entry site as a potential weak point in gastrointestinal anastomoses - findings from an ex-vivo biomechanical analysis.

PURPOSE: Gastrointestinal disorders frequently necessitate surgery involving intestinal resection and anastomosis formation, potentially leading to severe complications like anastomotic leakage (AL) which is associated with increased morbidity, mortality, and adverse oncologic outcomes. While extensive research has explored the biology of anastomotic healing, there is limited understanding of the biomechanical properties of gastrointestinal anastomoses, which was aimed to be unraveled in this study. METHODS: An ex-vivo model was developed for the biomechanical analysis of 32 handsewn porcine end-to-end anastomoses, using interrupted and continuous suture techniques subjected to different flow models. While multiple cameras captured different angles of the anastomosis, comprehensive data recording of pressure, time, and temperature was performed simultaneously. Special focus was laid on monitoring time, location and pressure of anastomotic leakage (LP) and bursting pressures (BP) depending on suture techniques and flow models. RESULTS: Significant differences in LP, BP, and time intervals were observed based on the flow model but not on the suture techniques applied. Interestingly, anastomoses at the insertion site of the mesentery exhibited significantly higher rates of leakage and bursting compared to other sections of the anastomosis. CONCLUSION: The developed ex-vivo model facilitated comparable, reproducible, and user-independent biomechanical analyses. Assessing biomechanical properties of anastomoses offers an advantage in identifying technical weak points to refine surgical techniques, potentially reducing complications like AL. The results indicate that mesenteric insertion serves as a potential weak spot for AL, warranting further investigations and refinements in surgical techniques to optimize outcomes in this critical area of anastomotic procedures.

Mesenteric and omental lymphatic malformations in children: seven-year surgical experience from two centers in China.

PURPOSE: To compare the clinical characteristics, surgical management and prognosis of mesenteric lymphatic malformations (ML) and omental lymphatic malformations (OL) in children. METHODS: This retrospective study included 148 ML patients and 53 OL patients who underwent surgical treatment at two centers between January 2016 and December 2022. Details about the patients' clinical characteristics, cyst characteristics, preoperative complications, surgical methods, and prognosis were retrieved and compared. RESULTS: No significant differences in sex ratio, prenatal diagnosis, or age of diagnosis were noted between ML and OL patients. Vomiting was more common in ML patients than in OL patients (46.6% vs. 22.6%, P = 0.002), but OL patients were more likely to be misdiagnosed (35.8% vs. 18.9%, P = 0.012). The size of the cysts in OL patients was significantly larger than that in ML patients (14.0 [4.0-30.0] vs. 10.0 [2.0-50.0] cm, P<0.001), and cysts with turbid fluid were more common in OL patients (38.0% vs. 20.6%, P<0.001). More OL patients than ML patients had preoperative hemorrhage or infection of cysts (41.5% vs. 31.8%, P<0.016). Cyst excision was performed in 137 (92.6%) ML patients and 51 (96.2%) OL patients, and the incidence of postoperative complications was lower (12.6% vs. 4.2%, P = 0.165) among OL patients. The main postoperative complications included adhesive ileus and recurrence of cysts. Additionally, more OL patients than ML patients were treated with laparoscopic surgery (69.8% vs. 39.2%, P<0.001). CONCLUSIONS: There were differences in clinical characteristics, cyst characteristics and preoperative complications between ML and OL patients. Cyst excision was the most common surgical method that was used to treat both ML and OL patients, and laparoscopic surgery could be a feasible surgical approach for treating OL patients with a good prognosis. TRIAL REGISTRATION: Retrospectively registered.

A rare presentation of mesenteric cyst as persistent ascites: A case report.

BACKGROUND: Mesenteric cysts have been typically described as cystic lesions of mesentery or omentum occurring either intra-abdominally or in the retroperitoneum. With no typical symptoms, the preoperative diagnosis of mesenteric cyst becomes challenging to establish. PATIENT AND METHODS: In this case report, we describe the case of a 29-year-old female who presented with abdominal distension for seven years associated with intermittent constipation. Following complete history, a meticulous physical examination was performed. Laboratory investigations and radiological imaging techniques were used to facilitate the diagnosis which was confirmed on laparotomy. RESULTS: Physical examination revealed abdominal ascites. Laboratory investigations were unremarkable. Abdominal ultrasound revealed multiloculated massive ascites. A well-defined cystic area 27 × 18cm displacing abdominal viscera was observed on computed tomography (abdomen and pelvis) with contrast medium. Exploratory laparotomy revealed a massive cyst involving almost the entire peritoneal cavity. On histopathology, no signs of malignancy were reported. The post-operative course was excellent, and the patient was discharged following surgery. CONCLUSION: As this lesion is rarely considered preoperatively, and the clinical manifestations can be non-specific, we report this case of mesenteric cyst mimicking ascites in order to inform improved decision making among healthcare professionals regarding the timely diagnosis and appropriate management.

Mesentery-Sparing Technique: a New Intracorporeal Approach for Urinary Diversion in Robot-Assisted Radical Cystectomy.

BACKGROUND: Robotic-assisted radical cystectomy (RARC) with intracorporeal urinary diversion (ICUD) is associated with significant morbidity and mortality. We present an alternative technique that preserves the complete mesenteric vascularization during the isolation of the intestinal segment used in ICUD, including distal vessels. This approach aims to minimize the risk of ischemia in both the ileal anastomosis and the isolated loop at the diversion site. METHODS: This cohort study included 31 patients, both male and female, who underwent RARC with ICUD from February 2018 to November 2023, performed by a single surgeon. Intraoperative and postoperative complications data were retrieved for analysis, employing our proposed mesentery-sparing technique in all cases. The primary endpoint was the incidence of intraoperative and postoperative complications directly attributable to the mesentery-sparing approach in ICUD. Secondary endpoints included other postoperative variables not directly related to mesentery preservation, such as the incidence of postoperative ileus requiring parenteral nutrition and the duration of hospitalization. RESULTS: None of the patients experienced intraoperative or postoperative complications directly related to mesentery-sparing, such as intestinal fistulae or internal hernias. The median duration of hospitalization was 6 days, and postoperative ileus necessitating total parenteral nutrition occurred in 19% of the patients. Minor complications (Clavien-Dindo grades I-II) accounted for 27.6% of the cases and major complications (grades III-V) accounted for 20.6%. CONCLUSION: The mesentery-sparing technique outlined herein offers an alternative method for preserving the vascularization of intestinal segments and reducing the risk of intestinal complications in ICUD during RARC.

NR4A3 fusions characterize a distinctive peritoneal mesothelial neoplasm of uncertain biological potential with pure adenomatoid/microcystic morphology.

A focal adenomatoid-microcystic pattern is not uncommon in peritoneal mesothelioma, but tumors composed almost exclusively of this pattern are distinctly rare and have not been well characterized. A small subset of mesotheliomas (mostly in children and young adults) are characterized by gene fusions including EWSR1/FUS::ATF1, EWSR1::YY1, and NTRK and ALK rearrangements, and often have epithelioid morphology. Herein, we describe five peritoneal mesothelial neoplasms (identified via molecular screening of seven histologically similar tumors) that are pure adenomatoid/microcystic in morphology and unified by the presence of an NR4A3 fusion. Patients were three males and two females aged 31-70 years (median, 40 years). Three presented with multifocal/diffuse and two with a localized disease. The size of the individual lesions ranged from 1.5 to 8 cm (median, 4.7). The unifocal lesions originated in the small bowel mesentery and the mesosigmoid. Treatment included surgery, either alone (three) or combined with hyperthermic intraperitoneal chemotherapy (two), and neoadjuvant or adjuvant chemotherapy (one case each). At the last follow-up (6-13 months), all five patients were alive and disease-free. All tumors were morphologically similar, characterized by extensive sieve-like microcystic growth with bland-looking flattened cells lining variably sized microcystic spaces and lacked a conventional epithelioid or sarcomatoid component. Immunohistochemistry confirmed mesothelial differentiation, but most cases showed limited expression of D2-40 and calretinin. Targeted RNA sequencing revealed an NR4A3 fusion (fusion partners were EWSR1 in three cases and CITED2 and NIPBL in one case each). The nosology and behavior of this morphomolecularly defined novel peritoneal mesothelial neoplasm of uncertain biological potential and its distinction from adenomatoid variants of conventional mesothelioma merit further delineation as more cases become recognized.

Primary EGIST of the greater omentum - a rare presentation.

Extragastrointestinal stromal tumors (EGISTs) are rare mesenchymal neoplasms, which develop in the retroperitoneum, mesentery, and omentum, lacking continuity to the stomach or intestines. Authors hereby present a female patient with a large heterogeneous abdominal mass as a case of an omental EGIST. A 46-year-old woman was referred to our hospital due to an insidious enlargement and colicky pain in the right iliac fossa. Abdominal palpation revealed a voluminous, freely mobile, and non-pulsatile mesoabdominal bulge expanding to the hypogastrium. On exploratory midline laparotomy, the tumor was densely fused to the greater omentum, not connected to the stomach, without gross involvement of adjacent structures. The large mass was completely excised after adequate mobilization. Immunohistochemical techniques showed strong and diffuse expression of WT1, actin and DOG-1, as well as multifocal c-KIT marking. Mutational study concluded a double mutation of KIT exon 9 and a mutation of PDGFRA exon 18. The patient was submitted to adjuvant treatment with imatinib mesylate 800 mg/day. Despite an extremely diverse presentation, omental EGISTs often remain clinically silent for a long time having enough space to grow before becoming symptomatic. These tumors have a consistent pattern of metastasis that typically spares lymph nodes unlike epithelial gut neoplasms. Surgery remains the preferred treatment for non-metastatic EGISTs of the greater omentum. It is possible that DOG-1 will supplant KIT as the leading marker in the future. The scarcity of knowledge on omental EGISTs implies a close monitoring of these patients to detect local relapse or distant metastasis.

Influence of Photodynamic Therapy with Subsequent Surgical Treatment of Experimental Breast Cancer on Quantitative Changes in miRNAs in a Mesenteric Lymph Node.

In female Wistar rats with breast cancer, quantitative changes of pro-oncogenic miRNAs (miR-21, -27a, and -221) and tumor-suppressive miR-429 in the mesenteric lymph node were assessed after photodynamic therapy for breast cancer and after photodynamic therapy followed surgical treatment. The level of pro-oncogenic miR-221 in the mesenteric lymph node decreased, and the level of pro-oncogenic miR-21 increased after photodynamic therapy for breast cancer followed by surgical treatment in comparison with the corresponding parameters after photodynamic therapy alone. The content of tumor-suppressive miR-429 remained reduced, as in the group of animals receiving photodynamic therapy alone.

A case of significant loss of mesenteric fat: Educational and clinical relevance.

Mesenteric fat, a type of intraperitoneal adipose tissue, plays a critical role in protection and the immune response. Loss of mesenteric fat is a known consequence of a variety of clinical conditions; however, visual documentation of this rare occurrence is not available in the literature searched. Here we report a case of significant loss of mesenteric fat identified during educational dissection of a 79-year-old male fresh frozen donor cadaver, causing the mesenteric folds to appear transparent. The gross anatomical characteristics, clinical importance, and educational significance of this abnormality are described in this report. Knowledge of this condition may be of interest to clinicians, and documentation could benefit anatomists and educators dissecting and teaching in the laboratory setting.

[A Case of the Huge GIST in the Transverse Colon Mesentery with Intra-Tumoral Hemorrhage and Jejunal Infiltration].

A 38-year-old woman was admitted to our hospital due to severe anemia. CT showed a 13×12 cm tumor with moderately enhanced wall thickening in the right upper abdomen. The huge tumor located adjacent to the jejunum and compressed the right transverse colon. Hemorrhagic necrosis and air were observed within the tumor, suspecting tumor penetration into the jejunum. The patient was diagnosed with abdominal GIST with jejunal infiltration. Laparotomy revealed a 13× 11 cm solid mass with intra-tumoral hemorrhage and invasion into the jejunum, located in the transverse mesocolon. Tumor resection combined with partial jejunectomy and transverse colectomy were performed. Immunohistochemical findings of the resected specimen was positive for c-kit and DOG-1, and the MIB-1 positive rate was 10%. Three weeks after the operation, re-anastomosis was performed due to transverse colon anastomotic stricture. She was discharged 45 days after first operation. Currently, 9 months after the operation, patient has been prescribed imatinib and is alive without recurrence.

[A Case of Desmoid-Type Fibromatosis of the Mesentery of Small Intestine].

Desmoid-type fibromatosis is a relatively rare disease, often associated with familial adenomatous polyposis and a history of abdominal surgery. A 43-year-old male patient presented with abdominal pain and contrast-enhanced CT showed a mass in the lower abdomen. The mass was a 4×4×3 cm white, dense tumor with a wreath-like arrangement of eosinophilic spindle-shaped cells. Immunostaining showed KIT(-), CD34(-), desmin(-), ß-catenin(+), SMA(few+), and the diagnosis was desmoid-type fibrosis. Six months after surgery, there was no apparent recurrence.

[A Case of Intestinal Obstruction Due to an Internal Hernia in the Mesenteric Defect after Laparoscopic Resection of Transverse Colon].

72-year-old man who was diagnosed with transverse colon cancer cT3N1aM0, Stage Ⅲb, and underwent laparoscopic- assisted resection of the transverse colon. Postoperatively, the patient was discharged from the hospital after 24 days due to complications such as paralytic ileus and intra-abdominal abscess caused by prolonged intestinal congestion. On postoperative day 91, the patient developed abdominal pain and vomiting at home, and was rushed to our hospital on the same day. Abdominal CT showed that an internal hernia had formed in the mesenteric defect after resection of the transverse colon, which was suspected to have caused obstruction of the small intestine. After adequate preoperative decompression of the intestinal tract, a laparoscopic surgery was performed on the 9th day. The operative findings were that the jejunum(100- 160 cm from the Treitz ligament)had strayed into the mesenteric defect of the transverse colon, resulting in an internal hernia. After the internal hernia was repaired laparoscopically, the mesenteric defect was closed with a 3-0 V-Loc(non- absorbable). The patient had a good postoperative course and was discharged home 6 days after surgery.