Toward a Mechanism of Stressor Induced Alterations in Microflora

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It is tempting to speculate on the mechanisms through which the intestinal microflora could have been altered by stressful pregnancy conditions. For example, it is known that cortisol can affect many aspects of infant development, and many of the effects of prenatal stress on the immune system can be mimicked by administration of ACTH or the synthetic glucocorticoid, dexamethasone (Coe et al. 1996). And, others have found that giving corticosterone to pregnant rats significantly reduced the concentrations of total and Gram-negative aerobes and facultative anaerobes (Schiffrin et al. 1993). The mechanisms through which glucocorticoids might affect the microflora are not known, but fetal development of the gi tract is thought to be influenced by glucocorticoids. For example, maturation of the intestines occurs concomitantly with the prepartum surge in cortisol in pre-cocial species, such as pigs, sheep, and humans (Trahair and Sangild 1997). Moreover, very high levels of glucocorticoids adversely affect intestinal development, such as the ability to secrete gastric acid and the densitivity of villi and crypts (Sangild et al. 1994), thus changing the microenvironment in the intestines and opening the possibility of shifts in ecological competition.

Altering the microenvironment may also affect established microflora populations in older hosts. The complete set of factors controlling the types of bacteria that can reside as part of the intestinal microflora are not well understood, but it is thought that the host plays a role in "selecting" the microflora. This was elegantly demonstrated by Rawls et al. (2006), who reciprocally transplanted gut bacteria between mice and zebrafish. After transplantation, gut microbial populations shifted to reflect the proportions of bacteria found in the microflora of conventionally reared recipient animals, and no longer reflected the microflora of the original donor animal (Rawls et al. 2006). This may in part be due to the physiology of the host GI tract, since certain aspects of GI physiology are known to influence micro-bial populations in the GI tract. For example, it is well known that for bacteria to take up residence in the gi tract, they must first survive the low pH of the stomach. Therefore, it is not surprising that reduced production of gastric acid (as occurs with hypochlorhydria) results in overgrowth of bacteria in the gi tract (Drasar et al. 1969). Some species, however, such as members of the genera Lactobacillus and Bifidobacteria are acid tolerant and are able to grow in the low pH (Drasar et al. 1969). This acid tolerance gives the genera an ecological advantage over other species that compete to colonize the gi tract. Therefore, a logical hypothesis is that any stimulus that disrupts gastric acid production will in turn affect intestinal microflora levels.

The influences of emotional states on the secretion and motility of the GI system were documented as early as 1833, when the surgeon William Beaumont noted that the secretion of gastric juice was decreased or abolished during periods of anger or fear in his patient with a gastric fistula (Beaumont 1838). Experimental data has confirmed this observation, and it is now known that secretion of gastric acid can be suppressed by experimental stressors, such as the cold pressure task and mental arithmetic (Badgley et al. 1969; Holtmann et al. 1990). In animals, different stressors have differential effects on acid secretion, with restraint stress reported to significantly increase or decrease gastric acidity depending upon temperature (Murakami et al. 1985; Lenz et al. 1988). These differences are due to different levels of activation of the sympathetic and parasympathetic nervous systems; activating the SNS suppressed whereas activating the PNS enhanced acid secretion (Yang et al. 2000). Research is needed to determine whether gi acidity plays a role in stressor-induced alterations of microflora.

There are, of course, additional secretory products that can affect microflora levels and are themselves influenced by the stress response such as additional digestive products like bile, and immune products like secretory immunoglobulin A (sIgA) and antimicrobial peptides. The use of secretory immunoglobulin deficient mice has shown the importance of this immunoglobulin in influencing micro-bial populations; sIgA deficient mice have significantly increased populations of anaerobic microflora in the small intestine (Fagarasan et al. 2002). Moreover, antimicrobial peptides, such as the defensins, have been suggested to modify the types and numbers of bacteria colonizing the GI tract (Salzman et al. 2007). Because these molecules can be affected upon exposure to a stressor (Jarillo-Luna et al. 2007; Korneva et al. 1997), an additional plausible hypothesis is that stress-associated alterations of the microflora are dependent upon stressor-induced alterations in sIgA and/or defensins.

Perhaps the most well-studied effects of stress on the gi tract are the effects on GI motility. Animal models have established that stress reduces gastric emptying (Taché et al. 2001; Nakade et al. 2005) and slows transit in the small intestine (Lenz et al. 1988; Kellow et al. 1992) through stressor-induced elevations of corticotro-phin releasing hormone (Taché et al. 2001; Nakade et al. 2005). In contrast to the inhibitory effects in the stomach and small intestine, stress tends to enhance motil-ity in the colon due to increased sacral parasympathetic outflow to the large intestine through a CRH dependent circuit (Lenz et al. 1988; Martinez et al. 1997).

Gastrointestinal motility has long been thought to influence microbial populations in the GI tract. For example, slowing peristalsis, and thus motility, by administering high doses of morphine causes significant bacterial overgrowth in the small intestines of rats (MacFarlane et al. 2000; Scott and Cahall 1982). Moreover, data from humans show an association between surgical trauma, stagnation of intestinal motility, and bacterial overgrowth, thus supporting the notion that delayed intestinal motility can result in bacterial overgrowth (Marshall et al. 1988; Nieuwenhuijzen et al. 1996a, b). Interestingly, increased GI motility can also affect microflora levels, with some studies showing a direct correlation between small intestine microflora levels and the rate of peristalsis.

An equally likely explanation is that the intestinal microflora were directly affected by stressor-induced increases in intestinal hormones, such as NE. The primary focus of this book is the exciting finding that bacteria can change their growth characteristics when exposed to hormones. And, the growth of many types of microflora has been shown to be significantly enhanced upon culture with NE (Freestone et al. 2002). Despite the many studies showing bacterial growth enhancement by NE in vitro, demonstrating that these interactions occur in vivo has been challenging. Neuroendocrine-bacterial interactions, however, undoubtedly occur in vivo when NE levels reach high levels. This was evident with the use of the neurotoxin 6-hydroxydopamine, which lyses the nerve terminals of sympathetic neurons resulting in the release of NE that is stored in the nerve terminals (Lyte and Bailey 1997). Thus, even though 6-OHDA is a useful way to chemically sympath-ectomize laboratory rodents, its initial effect is the release of a large bolus of NE 24 h after injection (Porlier et al. 1977; De Champlain 1971). Interestingly, bacterial levels in the cecums of mice were found to be significantly increased 24 h after administration of 6-OHDA, with E. coli showing the greatest increase (Lyte and Bailey 1997). Since the growth of commensal E. coli is strongly affected by exposure to NE (Freestone et al. 2002), the data suggest that overgrowth of E. coli in the cecums of chemically sympathectomized mice results from direct enhancement of bacterial growth by NE.

Overgrowth of bacteria in the family Enterobacteriaceae is also evident in the intestines of mice exposed to psychological stressors. Our recent studies indicate that restraining mice for prolonged periods (i.e., 16 h per day for 7 days) result in an overgrowth of Enterobacteriaceae in both the small and large intestines (Bailey et al. manuscript under review) as well as in the cecum (Bailey et al. 2006). This overgrowth may have important health implications, since bacterial overgrowth is a precipitating factor in the translocation of bacteria from the gi tract to the rest of body. In fact, the translocation of some species in the family Enterobacteriaceae was found to be directly related to levels in the small intestine and cecum (Steffen and Berg 1983). The finding that exposing mice to psychological stressors can enhance E. coli levels in the intestines prompted the determination of the impact of psychological stressors on bacterial transloction.

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