Role of the Mesentery in Crohn's Terminal Ileitis

Abstract

Despite the longstanding awareness of the presence of mesenteric alterations in Crohn's disease, the functional and clinical consequences of these alterations remain a topic of debate. Guidelines advise a limited resection without resection of the adjacent mesentery to prevent short bowel syndrome and postoperative complications. However, recently mesenteric resection has been proposed as an alternative to reduce recurrence rates in Crohn's disease patients. Here, we evaluate the data available on this topic in terminal ileitis, both from a fundamental research point of view and clinical perspective.

Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. A role of the mesentery in CD has been suggested already by Dr. Crohn in 1932 with the description of “creeping fat” (wrapping of the mesentery around the inflamed parts of the intestine) as one of the hallmarks of CD. This paper supported extensive surgery as treatment of the disease, but did not provide mechanistic support for that contention. ¹ Currently, guidelines advise a mesenteric sparing resection, without resection of the adjacent mesentery, due to the benign nature of the disease. ² Leaving the mesentery in situ simplifies the resection and preserves vascularization thereby lowering the risk of postoperative morbidity.

More recently, the role of the mesentery gained renewed interest. Most studies now agree that the mesentery is not just an innocent bystander but can actively participate in the inflammatory response. ^{3 4} In that context, the creeping fat, i.e., thickened adipose tissue present at the site of intestinal inflammation (mainly around the ileum) is of particular interest. However, whether the net contribution of the mesentery is pathogenic or protective remains a matter of debate.

Mesentery as Inflammatory Contributor

Many studies reported the presence of pro-inflammatory proteins including CCL5, C-reactive protein and chemokines such as MCP-1 in creeping fat in patients with Crohn's disease. ^{3 4 5 6} While many of these proteins can be secreted by adipocytes, they may also be derived from local immune infiltrates. Several studies identified increased immune populations in creeping fat tissue including macrophages, T cells, and B cells. ^{7 8} Originally, this increased immune presence was attributed to the local inflammatory environment, and potentially to the effects of translocated intestinal bacteria. ^{5 6 7 8 9} In addition, an early study described alterations in mesenteric levels of PPAR gamma, prior to the development of morphological abnormalities, suggesting a potential role in disease development rather than just a response. ³ More recent data suggest the accumulation of immune cells may not only be the result of an increased influx of cells, but may also stem from decreased leucocyte egress due to impaired lymphatic flow. Defects in the morphology and molecular characteristics of the mesenteric lymphatic system have been described. ^{10 11}

Mesentery as Protective Contributor

In contrast, several studies have suggested a protective role for the creeping fat tissue. Most studies reporting secretion of pro-inflammatory cytokines report concomitant secretion of anti-inflammatory proteins including IL10, resistin, and adiponectin. ^{6 12 13} In addition, detailed analysis of the myeloid cell compartment points to a regulatory role, with increased expression of CD163 and IL10. ⁸ Recently, we showed that creeping fat adjacent to the affected bowel contains high levels of CD206+ regulatory macrophages, pointing toward a protective effect. Notably, the opposite was found in the central ileal region of the mesentery, where the macrophages were strongly skewed toward a pro-inflammatory phenotype. ¹⁴ This gradient of the macrophage phenotype from pro-inflammatory in the proximal central mesentery to a regulatory phenotype in the more distal mesentery around the affected bowel contrasted with findings in the mesorectum where a gradient from proinflammatory to regulatory phenotype was observed in mesentery adjacent the rectum. ¹⁵ These findings are supported by observations related to the expression of the tissue remodeling macrophage marker “CD163,” in the mesenteric macrophages. A large proportion of macrophages in creeping fat near the diseased ileum, express CD163 ( Fig. 1A ). The expression of CD163 decreased toward the central region of the mesentery. Patients with a penetrating disease phenotype had high levels of CD163+ cells, both in the diseased area and the central mesentery, suggesting that the continuous structure of the mesentery reacts on the penetrating disease by expressing tissue remodeling macrophages ( Table 1 , Fig. 1B ). In patients operated for stenotic complications, creeping fat macrophages express high levels of CD163. However, in these patients, there is a reduction in the CD163 +/CD163− ratio toward the central mesentery. These findings suggest that although the mesentery may be one continuous structure, observations in one anatomical location may not apply in another region. In addition, findings may be influenced by disease phenotype.

Fig. 1.

Mesenteric macrophages show a remodeling phenotype near the creeping fat. ( A ) CD163 ⁺ /CD163 ⁻ ratios in the ileocecal region of patients with Crohn's disease with terminal ileitis ( n  = 20). Mesentery samples from 3 different locations: creeping fat, resection margin and more centrally. ( B ) CD163 ⁺ /CD163 ⁻ ratios in patients with active ( n  = 1), penetrating ( n  = 6), and stenotic ( n  = 13) disease. Bars represent means, error bars represent SEM. * p  < 0.05. ** p  < 0.01. Calculated by t -test.

Table 1. Demographics.

Characteristic	Number
Patients, n	20
Male sex n (%)	4 (20%)
Median age, years (IQR)	34 (24–45)
Median disease duration, years (IQR)	2,5 (0–6)
Smoking n(%)
Yes	3 (15%)
No	13 (65%)
Stopped	4 20%)
Indication surgery n (%)
Active disease	1 (5%)
Penetrating	6 (30%)
Clinical stenosis	13 (65%)
Anti-TNF therapy n (%)
Ever prior to surgery	6 (30%)
At time of surgery	4 (20%)
Never	14 (70%)
Montreal classification n (%)
A1 ≤16 years	0 (0%)
A2 17–40 years	15 (75%)
A3 >40 years	5 (25%)
Disease location n (%)
L1 Ileum	15 (75%)
L2 Colon	0 (0%)
L3 Ileum and colon	5 (25%)
L4 Upper GI disease	0 (0%)
Disease behavior n (%)
B1 Inflammatory	1 (5%)
B2 Stricturing	10 (50%)
B3 Penetrating	9 (45%)
Baseline IBD medication n (%)
No medication	2 (10%)
Thiopurines	11 (55%)
Corticosteroids	8 (40%)
Other mediation	1 (5%)

Note: Number [ n ], standard deviation [SD], interquartile range [IQR].

A recent study by Ha et al further supports a protective regulatory effect of creeping fat, and provided a potential mechanism for this. ¹⁶ They observed consistent bacterial translocation to mesenteric adipose tissue, both in healthy controls and Crohn's patients. In creeping fat in Crohn's disease, a species of Clostridium ( C. innocuum ) was detected which in vitro induced polarization of macrophages into M2a (wound healing/pro-fibrotic) macrophages, expressing high CD206.

Clinical Implications of Crohn's Mesentery Phenotypes

As mentioned, Crohn and colleagues proposed removal of the creeping fat in Crohn's disease patients. They proposed a wide excision with generous margins of healthy bowel on either side, as well as resection of all involved lymph nodes. At that time, this resulted in high postoperative morbidity and mortality, leading to the introduction of bypass surgery without resection. The subsequent finding that resection led to improved long-term outcomes compared with bypass with the result that bypass surgery was abandoned. Currently, a mesenteric sparing resection is advised in all guidelines as Crohn's disease is a benign condition. This guideline derives mainly from practical concerns; it is assumed that that a less extensive resection would decrease complications. Over the last few decades, improved surgical techniques have made extensive resection safer. This in turn rekindled interest resectional options and the biological rationale for these. However, as data regarding the pro- or anti-inflammatory role of the mesentery are conflicting, one turns to clinical trials to identify the optimal resectional strategy.

Currently, a limited number of clinical studies are available on the topic of mesenteric excision in terminal ileitis. To date, a single study compared conventional ileocecal resection ( Fig. 2A ) to resection with inclusion of the mesentery ( Fig. 2B ). The study showed inclusion of the mesentery was associated with significantly reduced surgical recurrence rates. ¹⁷ However, the retrospective data may have been confounded by differences in length and intensity of follow-up and management. Intensified postoperative surveillance programs have resulted in decreased recurrence rates and recent 5-year surgical recurrence rates as published by Stevens et al. are similar or better than the mesenterectomy group of Coffey et al. ^{17 18} Additionally, due to its crucial role in vascularization of the bowel, resection of a substantial part of the mesentery could result in a more extensive intestinal resection. As Crohn's patients often require multiple resections, resecting as little bowel tissue as possible is strongly preferred to prevent a short bowel syndrome.

Fig. 2.

Postoperative specimen of ileocecal resection in Crohn's disease patients. ( A ) Postoperative specimen following conventional ileocecal resection. ( B ) Postoperative specimen following ileocecal resection with inclusion of the mesentery.

Indirect clinical evidence supporting a net pathological effect of the mesentery comes from an interesting study analyzing a novel anastomotic technique that excludes the mesentery. Luglio et al compared the conventional standard stapled ileocolic side-to-side anastomosis to a Kono-S anastomosis in a prospective randomized clinical trial. ¹⁹ Because anastomotic lesions often recur on the side of the mesentery, the anti-mesenteric Kono-S anastomosis was developed to prevent anastomotic recurrences. ²⁰ In the Kono-S anastomosis, a side-to-side hand-sewn anastomosis is supported underneath, by two stapled transection ends. The later serves as a supporting bridge which should avoid narrowing of the anastomosis. The RCT by Luglio et al showed a significantly lower endoscopic recurrence (Rutgeerts score ≥ i2) at 6 months postoperatively in the Kono-S group (22% vs. 63%). Interestingly, at 12 months, there was no difference in clinical recurrence. ¹⁹ Essentially, the RCT compared a stapled side-to-side anastomosis with a hand-sewn side-to-side anastomosis. Healing is different in hand-sewn anastomosis versus stapled. Staple lines have a higher incidence of ischemic ulceration. This difference may have effected scoring according to the modified Rutgeerts classification.

Currently, several trials are ongoing, comparing extended mesenteric resection to the standard close bowel resection (NCT04538638, NCT04573892, NCT03769922). Most of these are randomized prospective studies, designed to avoid follow up bias or the effects of alterations in therapeutic practice over time. Given the conflicting results available in literature, careful assessment of the results of these trials will hopefully shed light on the requirement for mesenteric inclusion or sparing in ileocecal resection.

Mesentery as Innocent Bystander

Although it is now generally accepted that the mesentery is an active participant in the inflammatory response in Crohn's disease, opinions differ on whether the mesentery is a driver of the disease or that mesenteric inflammation is reactive to changes in adjoining bowel activity. In this context, the results of a strictureplasty are interesting.

The strictureplasty has been suggested as an alternative to resection in specific circumstances. It relieves tension on stenotic intestinal tissue while allowing for bowel conservation. The procedure and its usage have evolved over time as experience and confidence with the technique grew. Short- and long-term outcomes of strictureplasty (compared with resection) speak to the safety and durability of stricturoplasty. ²¹ Short strictures can be managed by conventional strictureplasties such as Heineke Mikulicz (< 10 cm) or Finney (10–25 cm). For long stenotic segments or multiple, close strictures, non-conventional strictureplasties can be applied, e.g., the isoperistaltic side-to-side (or Michelassi) strictureplasty. ²²

Although initially intended to improve luminal transit of enteric content, patients undergoing strictureplasty also experience a reduction in local inflammation, despite the mesentery remaining in situ. Moreover, in the long strictureplasty, not only complete mucosal healing has been described, but follow-up MRI also suggests regression of the fat wrapping. This suggests that abnormalities in the mesentery are reflective of a luminal process.

Future Directions

Despite the longstanding awareness of the occurrence of mesenteric alterations in Crohn's disease, data on the functional effects and clinical consequences of these alteration, remain limited and conflicting. Results vary depending on the specific anatomic location or disease phenotype and cannot be extrapolated to the entire mesentery. Given the importance of the mesentery in intestinal function and viability, optimal removal of pathogenic tissue with preservation of non-involved tissue remains preferable. This balance may be improved by efforts to enable visualization of mesenteric alterations per-operatively, allowing a more precise resection and optimal clinical outcome. Fluorescence-guided surgery (FGS) has potential to improve the accuracy in oncological resections by in vivo imaging of aberrant tissue. Currently, we are in the preparatory phase of in vitro and in vivo studies to demonstrate the aberrant pro-inflammatory macrophages with fluorescence imaging during surgical resection to create a true ‘patient-tailored treatment approach’.