Adult male rats were fasted for 0 (controls), three, five and seven days; a group was refed for one day after six days of starvation. Histological samples were taken from five regions along the length of the small intestine. The sizes of the villi, crypts and mitotic pool were estimated by measuring the number of epithelial cells per villus and crypt section and the number of mitotic figures per crypt section. Additional studies were carried out using colchicine for estimating mitotic time and methotrexate for inhibiting mitosis.



All three parameters decreased progressively during starvation; the decrease in villus size was most pronounced in the duodenum and gradually less distalward. Refeeding increased the mitotic pool in every region; crypt size did not increase and villus size increased slightly in duodenum and jejunum only. When refeeding was combined with mitotic inhibition, the cell population of the crypts became depleted by 30–40% without change in villus size; thus, renewal appeared to continue by crypt cells migrating to the villi.



Mitosis in the crypts is used for epithelial renewal in the adult intestine. The calculated turnover time of the epithelium was longer than normal and similar in every stage of starvation. Refeeding appeared to stimulate renewal. Since villus size changed somewhat independently from mitotic activity, the involvement of a separate mechanism controlling villus size was indicated.

Influence of starvation and refeeding on mucosal size and epithelial renewal in the rat small intestine

Effect of fasting versus feeding on the rat small intestine. Morphological, biochemical, and functional differences.

Male rats were starved for a period of 96 hours Measurements of crypt cell population showed a small reduction during starvation The growth fraction remained constant, but the total number of proliferating cells per crypt fell as a consequence of the reduction in crypt population Both labelling and mitotic indices fell throughout the starvation period The cell cycle time (Tc), measured by a stathmokinetic technique using vincristine, was increased from 10-4 hours in control rats to 14-7 hours after 96 hours' starvation Upon refeeding, the proliferative indices were observed to rise After a small initial fluctuation, the growth fraction remained constant The crypt population remained substantially unchanged Sixteen hours after refeeding, the cell cycle time was reduced to 6-5 hours The hypoproliferative response to starvation is mediated solely by an increase in cell cycle time, and the response to refeeding is interpreted in terms of a reduction in Tc Changes in the size of the proliferating population are considered not to play an important role in either response, although it is not possible to exclude entirely the presence of resting cells in the proliferative compartment itself

The effect of starvation and refeeding on cell population kinetics in the rat small bowel mucosa.

Marshall D. McCue: An introduction.- Jean-Herve Lignot, Yvon LeMaho: A history of modern research into fasting, starvation, and inanition.- Kevin L. Kirk: Starvation in rotifers: physiology in an ecological context.- Allen G. Gibbs, Lauren A. Reynolds: Drosophila as a model for starvation.- Johannes Overgaard, Tobias Wang: Metabolic transitions during feast and famine in spiders.- Nadav Bar, Helene Volkoff: Adaption of the physiological, endocrine and the digestive system functions to prolonged food deprivation in fish.- Frederic Hervant: Starvation in subterranean species versus surface-dwelling species: crustaceans, fish, and salamanders.- Marshall D. McCue, Harvey B. Lillywhite, Steven J. Beaupre: Physiological responses to starvation in snakes.- Rike Campen, Matthias Starck: Cardiovascular circuits and digestive function of intermittent-feeding sauropsids.- Esa Hohtola: Thermoregulatory adaptations to starvation in birds.- Susanne Jenni-Eiermann and Lukas Jenni: Fasting in birds: general patterns and the special case of endurance flight.- Ulf Bauchinger, Scott R. McWilliams: Tissue-specific mass changes during fasting: the protein turnover hypothesis.- Xueying Zhang et al: Seasonal changes in body mass and energy balance in wild small mammals.- Jehan-Herve Lignot: Changes in form and function of the gastrointestinal tract during starvation: from pythons to rats.- Edwin R. Price, Teresa G. Valencak: Changes in fatty acid composition during starvation in vertebrates.- Miriam Ben-Hamo et al.: Physiological Responses to Fasting in Bats.- Hank Harlow: Muscle protein and strength retention by bears during winter fasting and starvation.- Duane E. Ullrey: Seasonal starvation in northern white-tailed deer.- Cory Champagne et al: Fasting physiology of the pinnipeds.- Kent A. Hatch: The use and application of stable isotope analysis to the study of starvation, fasting, and nutritional stress.- Kevin Grant: Study and treatment of human starvation in the United Kingdom and India.- Kevin D. Hall: Quantitative physiology of human starvation: adaptations of energy expenditure, macronutrient metabolism and body composition.- Krista A. Varady: Alternate day fasting: effects on body weight and chronic disease risk in humans and animals.- Marshall D. McCue: Horizons in starvation research.

Comparative physiology of fasting, starvation, and food limitation

Following a period of fasting, feeding a normal diet results in a burst of DNA synthesis in the crypts of the colonic epithelium. This is due largely to a prompt entry of cells, blocked in G1, into S. Peak levels of S cellularity exceed 4 times the fasting, and 2 times the normal fed, control values. Refeeding a low residue diet (soluble casein, glucose and corn oil) results in a return to control levels of proliferative activity, but no hyperplasia.



However, in jejunum and ileum, refeeding is followed by a return to near control levels of proliferation with only a slight overshoot in S phase cellularity.



During the fasting period, the ileal crypt proliferative compartment (Pc-zone) and total crypt cellularity decline significantly. These changes are accompanied by an increase in the total cycle time, due to an equivalent lengthening of the G1 and S phases. Following refeeding, there is a reduction in the cycle time and a gradual return to the control values for the Pc-zone size and cellularity.



In the colon, fasting has no effect on the Pc-zone size or total crypt cellularity. There is an approximate doubling of the cycle time due solely to an increase in G1. Following refeeding there is an increase in the Pc-zone size and crypt cellularity and a marked shortening of the cycle time.



Evidence that a G1 cycle blockade is induced in the colon by fasting is given by a lengthening of the G1 period and by stathmokinetic studies employing vincristine.

Fasting and refeeding: cell kinetic response of jejunum, ileum and colon

SummaryIn rats starved for periods up to 10 days or fed a protein-free diet for periods up to 11 weeks, the number of cells per crypt of the small intestine declined steadily. During this time, however, with the exception of the rats kept on a protein-free diet for 11 weeks, the number of cells per crypt synthesizing DNA and dividing remained the same as in the control crypts, thus resulting in an increase in the labeling and mitotic indices in the experimental animals. The hypoplasia in the crypts, despite the fact that there were a constant number of cells per crypt undergoing proliferative activity was due to the inhibitory effect of the dietary regimes on the generation cycle time. The synthetic and the mitotic phases of the cycle are inhibited to the greatest extent.

A. F. Hopper

Papers

Cell Population Changes in the Intestinal Epithelium of the Rat following Starvation and Protein-Depletion∗: