The influence of the gut microflora on food toxicity.

The impressive variety of reactions that can be performed by the gut flora on both exogenous and endogenously-produced compounds justifies its status as a major site of metabolism, comparable to the liver (Drasar et al. 1970; Scheline, 1973; Walker, 1973; Drasar & Hill, 1974). Furthermore, one might expect that the capacity of the flora to adapt to metabolic pressure by altering its component organisms as well as by induction of enzymes, would exceed that of the liver. Surprisingly, however, although hepatic enzyme induction has been extensively studied, metabolic adaptation by the gut flora remains a largely unproven theory, with the notable exception of cyclamate metabolism (Drasar et al. 1972). If the metabolic activity of the intestinal bacteria is compared to that of the liver it is apparent that the bacterial biotransformations both complement and antagonize hepatic metabolism. Whereas reactions in the liver are mainly oxidative in character and syntheses are common (for example, production of glucuronides and sulphate conjugates) the lack of molecular oxygen in the intestinal lumen limits the number of oxidations that can take place and hence reductive and degradative metabolism predominates. Synthesis by the gut flora is rare with the notable exceptions of nitrosamine formation (Sander, 1968; Hawksworth & Hill, 1971) and alkylation of metals (Rowland et al. 1977~). The reactions of the intestinal bacteria therefore complement those of the liver and the net result is an expansion of the range of possible biotransformations to which an ingested compound can be subjected. The gut flora antagonizes hepatic metabolism by hydrolysing the biliary conjugates (such as glucuronides, sulphates and amides) synthesized by the liver in an attempt to excrete toxic non-polar drugs and anutrients. Hydrolysis of the conjugates can lead to an enterohepatic circulation (Williams et al. 1965) which not only delays excretion due to reabsorption of the parent compound into the portal system, but also permits further metabolism of the substance due to its subsequent passage through the liver. Some of the toxicological consequences of gut flora metabolism have been discussed by Drasar et al. (1970), Scheline (1972, 1973) and Walker (1973) and are summarized in Table I. In the present paper, rather than giving a series of brief examples to illustrate the points in Table I, I shall confine the discussion to two classes of compound (azo dyes and heavy metals) which have been extensively studied with respect to their bacterial metabolism.