1. 42. A. Criticims are offered upon theories previously enunciated concerning the causation of sprue and upon some of the observations upon which they are founded. 2. B. An attempt is made to suggest the lines along which a solution of the problem may lie. 3. C. Evidence is adduced in favour of a theory based upon the “partition” hypothesis which predicates for unsplit (neutral) fat and for fatty acids a different mode of absorption from the intestine, a different route after absorption, a different composition during transport, a different destination and a different rôle in the bodily metabolism. 4. D. The theory now tentatively put forward regarding the pathogeny of sprue enlists the following considerations:— 5. (1) The deficient absorption of fat is limited primarily to loss of power to absorb the fatty acid moiety and cholesterol. 6. (2) There is no loss of power to absorb neutral fat (glyceride) but there is a deficiency of neutral fat absorption due, secondarily, to non-absorption of fatty acid. 7. (3) There is also a primary loss of power to absorb glucose which results in a low flat oral blood sugar tolerance curve, glucose no longer being selectively absorbed by an active process but only by diffusion. 8. (4) The same is true of glycerol formed by the splitting of neutral fat. 9. (5) The loss of power to absorb fatty acid, glycerol and glucose is due probably to failure of phosphorylation. They are all substances, as opposed to many others, which require to be phosphorylated on absorption by the intestinal mucosa. 10. (6) Neutral fat is normally absorbed as a finely dispersed emulsion and does not require to be phosphorylated. Failure of absorption is secondary to non-absorption of fatty acid. 11. (7) Fructose (laevulose) is normally absorbed without phosphorylation and utilized by the sprue patient as by the normal subject. 12. (8) Loss of calcium to the body is due to “fixation” by fatty acid in the bowel with the formation of insoluble soaps. 13. (9) Loss of phosphorus is due to defect in phospholipid formation resulting from failure of phosphorylation. 14. (10) The effect of the mass of unabsorbed fatty acid and collection of gas due to the fermentation of unabsorbed glucose upon the small bowel is to produce intestinal delay in the small bowel and a passive distension, together with the other signs commonly demonstrated by radiographic examination. 15. (11) The primary failure in sprue, as above stated, is one of phosphorylation, not due, as suggested by Verzár, to lack of adrenal hormonal control, but the result of defective enzymic action. 16. (12) The enzyme or enzymes which catalyse phosphorylation—the “carriers” of phosphoric acid—probably have as the active part of the molecule coenzymes embodying some member or members (identified or unidentified) of the vitamin B 2 complex—all present in crude liver extracts. These may include riboflavin, nicotinic acid and pyridoxin. It may be remembered that choline is sometimes now included in the B 2 complex. 17. (13) Whether the same enzyme catalyses the phosphorylation of all of the several substances is uncertain. 18. (14) Since normally the phospholipids (lecithins) synthesized by the intestinal mucosa from fatty acid, glycerol, phosphoric acid and choline contain unsaturated fatty acids it is possible that desaturation occurs at the same time as phospholipid synthesis. In view of the close association of pyridoxin with unsaturated fatty acids, it seems possible it may here be at fault in sprue. 19. (15) The nature of the fatty acids in the diet may be a factor in determining the geographical distribution of the disease. 20. (16) The loss to the body of certain phospholipids containing highly unsaturated fatty acids may be a factor in the causation of the anaemia in sprue and of other nutritional anaemias. 21. (17) There are no pathological changes in sprue. There is no secretory failure and no failure of absorption except that resulting from defect in phosphorylation. 22. (18) Sprue is properly placed among the diseases of malnutrition.