Gut: first published as 10.1136/gut.30.11.1630 on 1 November 1989. Downloaded from Gut, 1989, 30, 1630-1640 Occasional report Growth and transformation of the small intestinal mucosa - importance of connective tissue, gut associated lymphoid tissue and gastrointestinal regulatory peptides E 0 RIECKEN, A STALLMACH, M ZEITZ, J D SCHULZKE, H MENGE, AND M GREGOR (This article is one ofa series linked with the Festschriftfor Christopher Booth. See Gut Festschrift 1989; 30.) Physiologically, the architecture of the small rather to focus on areas of our own interest in the intestinal mucosa is maintained by a delicate balance subject. between cell production in the crypt compartment, One of the prerequisites of the striking small enterocyte migration along the villi, and extrusion of intestinal mucosal potential to change its structure mature epithelial cells from the tip of the villi into the and function is the fact that each villus possesses lumen.' Migration and maturation of the lining cells numerous crypts with an enormous proliferative are affected in response to various types of stress and potential. The average number of crypts per villus in under conditions of mucosal damage and repair. This upper human jejunum amounts to 8&3 per villus.' In is also true for the tissue components beneath the man, 23 of 33 cell positions of the lower part of the lining cells. On the other hand, although the equi- crypt cell column belong to the proliferative compart- librium of the lining cells may be disturbed by a great ment, whereas the upper third represents the matura- variety of various types of stress, the response of the tion area in which the crypt cells obtain their mucosa is rather uniform and restricted to three functional competence.7 The crypt is able to enlarge http://gut.bmj.com/ distinct mucosal patterns only - namely, hyper- and to decrease its size in diameter and depth as a trophy, hypotrophy, and mucosal transformation of consequence of changes in its proliferative capacity. the hyperregenerative type (Fig. 1).' In these In this respect, it is of interest that the crypts of mucosal patterns alterations of the absorptive cells and the zonation of villi and crypts have been studied extensively. The regulation of cell proliferation and differentiation in this system is, however, still not well understood although the importance of some on September 24, 2021 by guest. Protected copyright. factors such as luminal nutrition and the ornithine decarboxylase system have been recognised.'4 Furthermore, the role of regulatory peptides has attracted much attention, though with few concrete results, and the implications of the interaction Mucosal between the lining cells, the mesenchyme, and the hypertrophy gut associated lymphoid tissue with respect to cell proliferation and maturation have only recently Mucosal Normal gained interest.' atroph ie mucosa It is the purpose of this contribution to briefly describe the three principal mucosal responses to various types of stress and also to discuss some aspects of the connective tissue, the gut associated tissue and the in the lymphoid regulatory peptides Mucosal control of intestinal mucosal growth and their transformation of the perspectives in future research as far as the regulation hyperregenerative type of mucosal growth is concerned. It is not intended, Fig. 1 Principalforms into which the small intestinal however, to be complete within the frame given, but mucosa may be transformed. 1630 Gut: first published as 10.1136/gut.30.11.1630 on 1 November 1989. Downloaded from Growth and transformation ofthe small intestinal mucosa 1631 Functional c compartment 0 4._ cc c ._.a1) L- c 0)0 4._ Proliferative CO compartment Fig. 2 Sclheme ofmigration and differentiation ofepithielial cells and subepithlelial myofibroblasts along tlie crypt-lillus axis in tle adult small intestine. Left panel sliows postulated interrelationslip between stem cells and connective tissues into differ-ent surface cells. the small intestine are surrounded by a prominent diameter, whereby the number of crypts per mucosal sheath of fibroblasts within the lamina propria of the area is reduced. Concomitantly, there is a propor- http://gut.bmj.com/ bowel Fig. 2. It has been assumed that in the adult tional increase in villus size, which again leads to a small intestine, this specialised mesenchymal cell reduction in the number of villi per unit area. Thus, type, the 'pericryptal myofibroblast' undergoes a there is a largely proportional enlargement of villi rapid turnover similar to that of the epithelial cell.' and crypts which contain an increased number of Synchronous division and parallel migration of lining cells, which may undergo distinct changes in epithelial and subepithelial mesenchymal cells may size and function."1' Thus, the number of cells per form a 'unit' of both cell populations. Zajicek has unit length may increase,' and microvilli of absorp- on September 24, 2021 by guest. Protected copyright. proposed the concept of an 'intestinal proliferon', tive cells after intestinal resection are shortened.'3 In consisting of epithelial, mesenchymal, neural, and addition, specific brush border enzyme activities vascular elements, in which a turnover of the differ- have been shown to be decreased and in v,itro ent cell populations is closely coordinated.' Other absorption of non-electrolytes in the hyperplastic findings, however, indicate that the division rate of mucosa is reduced. These findings have led to pericryptal myofibroblasts is lower than the division the concept that there are functionally immature rate of epithelial cells, some 3H-thymidine labelled enterocytes after intestinal resection, which is in myofibroblasts remain at the basis of the crypt for a accordance with the fact that cell migration time after long time and also become polyploid."' intestinal resection is increased and the cell life span of the enterocytes is shortened. None the less, Mucosal hypertrophy Menge et al could show that in the hypertrophic mucosa brush border vesicle transport was not Mucosal hypertrophy with hyperplasia of the cells is altered after proximal resection, as judged by studies one condition in which the crypt cell compartment of the accumulation of D-glucose.'4 Furthermore, has altered its geometry. The model in which this when using more sophisticated enzymatic in situ mucosal pattern can be studied best is the ileal studies, a differential enzyme response has been remnant after proximal small intestinal resection in observed at the cellular level'3: a significant decrease the animal." The mitotic activity increases first and is in both Vmax and Km values of neutral a-glucosidase followed by an increase in crypt depth and in crypt were already expressed four days after resection and Gut: first published as 10.1136/gut.30.11.1630 on 1 November 1989. Downloaded from 1632 Riecken, Stallmach, Zeitz, Schulzke, Menge, and Gregor confined to the apical villus while no changes in the accumulation studies also remains unaltered.'4 Thus, kinetics of the lactase/4-glucosidase occurred. in mucosal atrophy as in mucosal hypertrophy, the Similarly, Chavez et al showed selective increments initial step of non-electrolyte absorption is not in enzyme expression in ileal enterocytes after dependent on the proliferative state of the mucosa, proximal small bowel resection.'` Therefore, a thereby signalling that the absorptive function of the complex pattern of cellular enzymatic and morpho- individual enterocyte remains unaltered. logical adaptation to proximal resection ensues in Similar changes of the mucosa as in the bypassed the otherwise rather uniform pattern of hyperplastic intestine do occur in longterm parenteral nutrition" ileal mucosa with increased zonation of villi and and in the starved animal in which diameter and crypts.`' 7 depth of crypts decrease, as does eventually the Because in the hypertrophic mucosa the absorptive number of villi and crypts. Mucosal atrophy may be capacity is mainly restricted to the upper third of the altered further in a number of conditions such as villi as in the normal intestine the main increase in cytostatic treatment and irradiation, the damage function per centimetre intestine is achieved by an thereby depending on dose, time course, and action increase in diameter of the small intestine.'8 This has of the drug.' 7 been experimentally proven: a 45% proximal small intestinal resection leads to an increase in villus Mucosal transformation height, mucosal circumference and glucose absorp- tion in vivo when the substrate disappearance rate is The third mucosal pattern which represents the most expressed in terms of unit serosal length. A 70% striking alteration of the mucosal geometry is resection induces a further increase in mucosal .mucosal transformation of the hyper-regenerative circumference and glucose absorption, while villus type'. It is characterised by hyperproliferation height remains unchanged.'` and mucosal growth as is the case in mucosal Intestinal mucosal hyperplasia in man largely hypertrophy. It differs, however, from mucosal corresponds to the findings in the experimental hypertrophy in that it is characterised by the trans- animal, although it has been investigated less syste- formation of the normal zonation with reduced villi matically and less completely. Booth and coworkers and enlarged crypts, the reason why we have chosen had already shown in 1961 that the functional reserve this term.'8 In addition, it is associated with damage after proximal intestinal resection is so effective that to the surface cells and the underlying connective malabsorption is not a problem even if 250 cm of tissue. A suitable model to study this form of mucosal http://gut.bmj.com/ intestine have been removed." In this context two response to stress is the self-filling small intestinal additional phenomena have been recognised to be blind loop in the experimental animal in which stasis, important in man. First, the intestinal remnant may bacterial overgrowth and increased concentrations of also grow in length after resection and thereby toxic deconjugated bile acids are the stressors to the enforce function of mucosal hyperplasia.' Second, surface epithelium.