Tuft cells in the biliary tree modulate inflammatory responses

Alyson Kim BA¹; Lillias H. Maguire, MD^2,3

Affiliations:
¹ Drexel University College of Medicine, Philadelphia, Pennsylvania
² Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania
³ Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania

Creeping fat (CrF), migrating mesenteric adipose tissue (MAT), is a hallmark of Crohn’s Disease1 (CD) frequently associated with intestinal fibrosis. Surgeons operating for CD recognize CrF not only as a disease-specific phenomenon, but also as a technical challenge. Mesenteric transection is complicated in CrF as vessels retract with thickened, fibrotic fatty tissue resulting in haemorrhage and making haemostasis more difficult. Despite clinical familiarity with CrF however, its aetiology remains largely unknown. Additionally, it is unclear whether CrF represents an adaptive response in an attempt by the mesentery to seal off a “leaky” inflamed gut or is a pathological one, worsening the cycle of CD-related intestinal inflammation, scarring, stenosis, and ultimately development of surgical complications such as obstruction, perforation and fistula.   This study sheds new light on CrF, explaining how this adipose tissue transitions from the traditional storage role to an active component, generating an adipogenic, fibrotic, and inflammatory environment. The authors hypothesize that CrF is a both a response to translocated gut microbiota and a driving force in fibrosis. They investigate these theories by identifying the bacterium Clostridium innocuum as a signature organism in CrF, characterizing CrF as a milieu distinguished by immune response and fibrosis, determining that C. innocuum gavage promotes this milieu and recapitulates CrF in gnotobiotic mice, and demonstrating in vitro that selective promotion of M2a macrophages may be the means by which C. innocuum drives fibrosis. The authors identify and focus on C. innocuum by first performing a metagenomic sequencing analysis on surgical samples of ileal tissue in CrF, grossly normal CD MAT, ulcerative colitis (UC) MAT, and healthy controls. The authors found that healthy MAT contains bacteria, suggesting that bacterial translocation to MAT is not in itself pathogenic. CD MAT, however, contained higher numbers of bacteria, but with lower biodiversity than healthy controls, consistent with mucosal data and previous studies2,3. 16S-RNA sequencing comparison to healthy MAT and UC-MAT identified a CD-specific expansion of the Erysipelotrichae lineage including C. innocuum. To assure the sequencing findings represented viable bacteria, the authors cultured MAT-derived bacterial isolates. Five bacteria were isolated as CD-specific and viable after cultivation.Among those, C. innocuum was most frequently isolated and selected for further study.  A whole genome sequencing and comparative genomics study of C. innocuum revealed a conserved core of genes advantageous for translocation in adipose-like environments, such as protection against oxidative damage, cell motility, lipid detoxification, and evasion from immune functions and strain divergence between C. innocuum isolated from MAT and that isolated from mucosa. Factors potentially promoting viability in creeping fat also include type IV pili and mobility, lipid catabolism, and preference for b-hydroxybutyrate, a product of fatty acid oxidation.

F.F. van den Berg¹, M.A. Boermeester<sup>2

1</sup>Department of Medical Microbiology, Amsterdam UMC, Amsterdam, the Netherlands
²Department of Surgery, Amsterdam UMC, Amsterdam, the Netherlands

Article review Long, D. R. et al. Contribution of the patient microbiome to surgical site infection and antibiotic prophylaxis failure in spine surgery. Sci. Transl. Med.16, eadk8222 (2024). https://www.science.org/doi/10.1126/scitranslmed.adk8222

¹Aikaterini Dedeilia, M.D, ²Genevieve Boland, MD, PhD

¹Postdoctoral Research Fellow, Surgical Oncology Research Laboratories; Department of Surgery, Massachusetts General Hospital; Research Fellow in Surgery, Harvard Medical School.

²Vice Chair of Research, Department of Surgery; Section Head, Melanoma/Sarcoma Surgery; Surgical Director, Termeer Center for Targeted Therapies; Director, Surgical Oncology Research Laboratories, Massachusetts General Hospital; Associate Professor of Surgery, Harvard Medical School.

Background While significant changes have occurred in the management of microscopic stage III disease due to the data from MSLT-21, the current standard of care for macroscopic stage III nodal malignant melanoma consists of initial surgical treatment with therapeutic lymph node dissection (TLND), followed by consideration for adjuvant therapy consisting of either anti-PD-1 monotherapy2 or BRAF/MEK inhibitors3. This results in improved relapse-free survival, but recurrence is still observed in almost half of the patients within 3-5 years4-6. Preclinical trials7-9 and emerging clinical data10 suggest that neoadjuvant immune checkpoint inhibition may have clinical benefit over adjuvant approaches. Given increasing enthusiasm for adjuvant and neoadjuvant approaches, the OpACIN (NCT02437279, phase I) and OpACIN-neo (NCT02977052, phase II) studies were established to investigate the safety and efficacy of neoadjuvant treatment with immune checkpoint inhibitors (ICI) combination, and to establish optimal dosing regimens to maximize clinical benefit while minimizing toxicity in patients with stage III melanoma. The OpACIN and OpACIN-neo trials