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46 M. G. Kiernan et al.
Mesenteric adipocytes, irrespective of disease state, express a wide range of
pattern recognition molecules (PR Ms), such as TLR2, TLR4, NOD1 and NOD2,
indicating they may respond to bacterial stimulation or challenge. Zulian et al.
(2013) also demonstrated that co-culture of adipocytes with E. faecalis results in a
significant increase in their rate of proliferation. Bacterial or LPS stimulation of
adipocytes has also been shown to increase expression of pro-inflammatory and
pro-fibrotic cytokines and adipokines. These may contribute to increased production of pro-inflammatory and pro-fibrotic cytokines and adipokines observed in the
mesentery in Crohn’s disease. The knowledge that bacteria or their components
occur in mesenteric fat, and that adipocytes are responsive to these elements, could
provide a novel pathogenic mechanism, and therefore novel therapeutic targets, in
IBD.
The Microbiome of Mesenteric Lymph Nodes
Since development of molecular anlysis techniques, only two studies have utilised
culture-independent methods to investigate bacteria present in MLNs in IBD
patients. O’Brien et al. (2014) focused on patients with Crohn’s disease. Mirroring
the outcomes of earlier studies, E. coli was commonly found in Crohn’s disease
MLNs. The bacterial profile of MLNs resembled that of the associated mucosa,
suggesting a general movement of bacteria from the mucosa to the MLNs and not
selective bacterial translocation. The overall microbial profile of MLNs from
patients with Crohn’s disease reflected a dominance of Firmicutes and Bacteroidetes phyla, sli ghtly favouring Bacteroidetes, which was similar to the profile
observed in MLNs from non-IBD controls. Although species diversity was
decreased in MLNs in Crohn’s disease, a unique bacterial profile was not evident.
Differences in MLN microbial profiles stemmed from inter-patient variation, rather
than location of sampling.
The second study, Kiernan et al. [21], reported collection of MLNs from patients
with Crohn’s disease or ulcerative colitis undergoing resection (Figs. 6.1 and 6.2).
Crohn’s disease MLNs presented a distinctly different microbial profile to that
observed in ulcerative colitis (Fig. 6.3). The relative abundance of Firmicutes were
found to have greater relative abundance in nodes from ulcerative colitis patients,
whereas Proteobacteria were more abundant in Crohn’s disease. While species
diversity was reduced in the MLNs of patients with Crohn’s disease, these lymph
nodes contained greater numbers of less dominant phyla, especially Fu sobacteria.
In summary, this study confirmed distinct differences between the Crohn’s disease
and ulcerative colitis MLN microbiota suggesting potential for diagnosis of Crohn’s
disease or ulcerative colitis, particularly in cases of indeterminate colitis at time of
resection.
6 Emergence of the Human Gut Microbiota … 47
Fig. 6.1 Relative abundance of predominant bacterial phyla in mesenteric lymph nodes [MLNs]
from inflammatory bowel disease [IBD] patients. There was a distinct difference in the profile of
phyla from MLNs of Crohn’s disease [CD] and ulcerative colitis [UC] patients. Adapted from:
Kiernan, M.G. et al., Journal of Crohn’s and Colitis 2019;13(1): 58–66. Copyright © Oxford
University Press
Fig. 6.2 Mesenteric lymph node [MLN] mapping. Proportions of 16S PCR–positive MLNs taken
from each location of UC or Crohn’s disease-associated mesentery. Adapted from: Kiernan, M.G.
et al., Journal of Crohn’s and Colitis 2019;13(1): 58–66. Copyright © Oxford University Press
48 M. G. Kiernan et al.
Fig. 6.3 Abundance of phyla in pooled mesenteric lymph nodes [MLNs] of Crohn’s disease [CD]
and ulcerative colitis [UC] patients. Abundance [%] of major bacterial phyla Firmicutes (52.8%/
18.6%), Bacteroides (30.6%/32%), Proteobacteria (11.8%/36.1%), and Actinobacteria (4.6%/
6.1%)in pooled MLNs of UC and CD patients, respectively Adapted from: Kiernan, M.G. et al.,
Journal of Crohn’s and Colitis 2019;13(1): 58–66. Copyright © Oxford University Press
The Mesentery—A Reservoir for Pathogenic Bacteria?
Pathogenic bacteria, such as Salmonella or Campylobacter, have not been yet
identified in mesenteric fat in IBD. Although Escherichia/Shigella, Campylobacteraceae, Yersinia, and Helicobacteriaceae have been identified from MLNs in
Crohn’s disease, they have also been found in MLNs of non-IBD subjects. Yersinia,
Helicobacteriaceae and Listeria have been detected (in low numbers) in MLNs of
patients with Crohn’s disease, and warrant further investigation to determine
whether they play a role in IBD.
Mesenteric lymphadenitis raises interesting questions. Associated with gastroenteritis (and respiratory tract infections, appendicitis, diverticulitis, pancreatitis
and cholecystitis), mesenteric lymphadenitis during childhood or adolescence
results in reduced risk of developing ulcerative colitis. MLNs harvested from
patients with mesenteric lymphadenitis can contain E. coli, Salmonella, Shigella,
Yersinia enterocolittica, mycobacteria, Staphylococcus and beta-haemolytic
Streptococcus. This may point to an immunisation effect and perhaps represent
an opportunity to identify microbial agents associated with ulcerative colitis onset.
6 Emergence of the Human Gut Microbiota … 49
Mesenteric Abscess—A Special Microenvironment for Pathogenic Bacteria in Inflammatory Bowel Disease?
Crohn’s disease is commonly complicated by the development of intra-peritoneal
abscesses. These can be located between different regions of mesentery (so-called
inter-loop abscesses), in the pelvis, or in the flanks. They usually occur following
bowel perforation, when a collection of infected fluid forms. Such fluid will most
likely contain multiple bacteria, and these are frequently pathogenic. Gram negative
bacilli, Gram positive cocci and anaerobic bacteria are typically detected from
abscesses in Crohn’s disease. E. coli and B. fragilis are the most common species
identified. Mycobacterium spp have been detected in a mesenteric abscess in a
patient with HIV, indicating at least potential as a reservoir for Mycobacterium
avium spp. paratuberculosis. It is feasible that further characterisation of microbial
ecology associated with mesenteric abscesses could yield important information
related to IBD.
Conclusion
It seems reasonable to conclude that given the abundance and diversity of microbes
borne in the human intestine that these cells may infl uence health and disease.
Molecular technologies enable better insight into microbial community profiles
characteristic of specific disease; and understanding of how such microbes penetrate
and influence the mesentery and its component parts are likely to develop in tandem. Although entirely conjecture, it seems rational to suggest that microbial
interaction with mesenteric adipocytes and MLNs may prove influential in disease
initiation and progression. Elucidating the mechanisms that mediate these processes
will involve research with sufficient scale to credibly determine definitive mesenteric microbiome profiles in each discrete disease setting. Accepting the confounding factors associated with geography and diet, among other factors, such
scale will require collaboration of international investigators in multicentre studies.
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Cellular Anatomy of the Mesentery
Miranda G. Kiernan and J. Calvin Coffey
Introduction
There has been relatively little focus in the histological composition of the
mesentery. The mesentery is now defined as the collection of tissues that maintains
all abdominal digestive organs in position and in continuity with other systems.
Given this definition, it is important to describe the tissues that make up the
mesentery. Any such description should also include a description of the histology
of associated structures. These include the peritoneal reflection a Toldt’ s fascia,
both of which maintain the mesentery in position.
Mesenteric Histology
7
The following description focuses on the detached and mobilized adult mesentery.
The first study to characterize the histological appearance of the mesentery at
multiple levels was conducted by Culligan et al. In this study, full thickness
biopsies were taken at multiple points, through cadaveric mesentery. The overall
histological components and organization, is similar at all points in the mesentery
from duodenojejunal flexure to anorectal junction. Both surfaces of the mesentery
are lined with a sheet of elongated mesothelial cells. The surface of the mesentery
(as seen on scanning electron microscopy) is remarkably smooth for the most part
but is occasionally interrupted by grooves (Fig. 7.1). The surface is markedly
different in disease states such as Crohn’s disease.
M. G. Kiernan J. C. Coffey (& )
School of Medicine and Department of Surgery, University of Limerick Hospital Group, Raheen,
Dooradoyle, Limerick, Ireland
e-mail: Calvin.coffey@ul.ie
© Springer Nature Switzerland AG 2021
E. D. Ehrenpreis et al. (eds.), The Mesenteric Organ in Health and Disease,
https://doi.org/10.1007/978-3-030-71963-0_7
53
54 M. G. Kiernan and J. C. Coffey
Fig. 7.1 Light microscopy of the mesentery. Elastic fibers (arrows) stain selectively as dark think
branching fibers in loose connective tissue. Fibroblast nuclei (Fi) and a capillary (Cap) with
erythrocytes are also seen
A connective tissue layer occurs immediately under surface mesothelium of the
mesentery. This is variable in thickness and in some regions, it appears absent
whilst in others it is well formed. Clusters of mesenchymal cells are intermittently
observed within the connective tissue layer. On occasion these clusters are seen in
association with connective tissue septations in the mesentery. On other occasions
they appear entirely separate, based on examination of serial sections. The nature
and function of the cells located in these clusters remains to be characterized.
Lymphatic channels occur in the submesothelial connective tissue. It has been
suggested that stomata (openings between surface mesothelial cells) expose these
lymphatics to peritoneal fluid and thereby facilitate the absorption of the latter. The
channels are in turn continuous with lymphatic channels in mesenteric connective
tissue septations. Collectively, these comprise a lymphatic network.
Gene Expression and Protein Synthesis in the Mesentery
These above are qualitative studies and functional studies are required to compare
different regions of the mesentery. There are some suggestions, based on gene
expression profiles, that regions of mesentery behave in different manners. For
example, gene expression profiles from the small bowel regio n of mesentery differ
from those in the mesogastric region of the mesentery. Histology is reflected in
functionality and it has been suggested that the mesentery is a site of CRP
7 Cellular Anatomy of the Mesentery 55
production. Whilst CRP production was historically thought limited to the liver,
emerging data point to mese nteric production and relate this to the control of
systemic glucose levels.
Mesenteric Derived Mesothelial Cells
In separate studies, we generated mesenteric cells, cultured these in vitro and
characterized the resultant cell types. When this is done they express—after—in
culture. These studies were the first to generate and characterize mesenteric derived
mesenchymal cells. They proliferate adhere and migrate in a manner that is similar
to murine fibroblasts. We also compared these properties with mesenteric mesenchymal cells derived from patients with Crohn’s disease. Interestingly, marked
differences emerged indicating that each of these properties was increased in
mesentery derived mesenchymal cells. Preliminary data also incase that some
characteristics may be attenuated through ambition of TGF-beta.
Connective Tissue Continuity
Characterization of the mesentery demonstrated a distinct connective tissue lattice.
This is continuous with submesothelial connective tissue. It is also continuous, at
the surface of the intestine, with connective tissue septations in the intestinal wall.
In addition, mesenteric connective tissue coalesces around intra-mesenteric blood
vessels. This means there is continuous network of connective tissue extending
from the submucosa of the intestine to contiguous mesentery and thereafter to
vessels within it.
Mesenteric Adipocytes
Adipocytes are the main cellular contributor to the mesentery. Importantly, they are
organised in a honeycomb-like distribution. It is not possi ble to distinguish individual adipocytes as their lipid surfaces are closely apposed within the mesentery.
The overall appearance of the mesenteric adipocyte fraction, is that of an extensive
system of cells. At the surface of intra-mesenteric blood vessels, this system is
contiguous with surface connective tissue. This could be of considerable importance as the metabolic activity of the adipose system may be conducted to that of
adjacent vessels, and thereafter to blood, thus providing mammals when an
excellent mechanism of heat regulation.
Adipocytes within the mesentery are highly active. This is reflected in multiple
studies comparing gene expression studies as well as studies examining individual
cytokine production.
.
56 M. G. Kiernan and J. C. Coffey
Fibrocytes
Mesenteric fibrocytes have received little overall attention to date. These are generally described as blood-borne and derived from hematopoietic progenitors. In a
study of patients with Crohn’s disease, we noted these cells were present in
increased numbers in blood vessels in the mesentery, and in the tissue surrounding
vessels. We also noted they were present in clusters at the surface of the intestine.
This led our group to suggest the mesentery may provide a platform into which
fibrocytes may migrate, from blood vessels, and within which they could exploit the
connective tissue continuity of the mesentery and intestine, to access the surface of
the intestine.
Fibrocytes are not the only cells to utilize the mesentery as a platform for
migration. As mentioned in the section on the embryological development of the
mesentery, primordial germ cells use the mesentery to migrate to the genital ridge.
In addition, neural crest cells migrate across the mesentery from the neural crest.
Findings related to fibrocytes are particularly relevant as these cells can differentiate
into either fibroblasts or adipocytes. In Crohn’s disease, the mesentery advances
over the surface of the intestine as fat wrapping. The cellular basis of fat wrapping
in unknown but it is tempting to think that fibrocyte exploit and migrate along
mesentery, access the surface of the intestine and migrate to give rise to fat
wrapping.
The Peritoneal Reflection
The peritoneal reflection must be incised in order to access the plane where the
mesentery is attached to Toldt’s fascia. Separation of the mesentery and Toldt’s
fascia is an essential compo nent of mesenteric detachment.
The reflection is the region of peritoneum where p arietal peritoneum is continuous with visceral peritoneum. An excellent example of this occurs where the small
intestinal region of mesentery continues as the right mesocolon. This anatomical
region is not directly apparent when one enter s the abdomen, as it is obscured from
view by the reflection in this region. Here, perit oneum leaves the posterior
abdominal wall and reaches across to seamlessly continue as the visceral
peritoneum.
Numerous terms have been applied to the reflection including ligaments (coronary and triangular ligament), folds (bloodless fold of Treves), and membranes (i.e.
Jackson’s membrane). These are all examples of where the parietal and visceral
peritoneum are continuous.
Histological examination of the reflection demonstrates that it comprises two
continuous layers of mesothelial cells with variable amounts of connective tissue
located between both. Scanning electron microscopy (SEM) demonstrates that the
surface facing the peritoneal cavity is smooth in normality, but disrupted and
irregular in disease settings (i.e. Crohn’s disease). SEM studies also demonstrate the