Year: 2015
Type: article
Abstract: How does maternal stress during pregnancy affect postpartum development? How and when do we acquire our gastrointestinal (GI) microbiota? Does psychological stress affect our microbiota? Can changes in maternal microbiota be vertically transmitted to offspring and can those changes influence brain development? These are questions that Jasarevic et al raise and begin to answer (1). In brief, Jasarevic et al propose the following scenario. The neonate swallows vaginal fluids during birth that contain some of the bacteria that will constitute the baby's future GI microbiota. Stress to Mom during pregnancy alters the vaginal microflora as evidenced by a decrease in Lactobacillus both in number and as a percent of total microflora. Thus, the neonate during birth receives a different mix of microflora if being birthed by a stressed mother than if birthed by one that has not been stressed. Although the vaginal flora is largely derived from the maternal GI tract, the offspring's GI flora more clearly reflects the maternal vaginal flora than the maternal GI flora. Also found were changes in the offspring's neurochemistry (eg, differences in the brain levels of some amino acids) that Jasarevic et al argue are caused by the neonate's differing GI flora and so, indirectly caused by maternal stress. Thus, this article suggests an exponential growth in the importance of the microbiota from one of simply maintaining a healthy gut to one involved in intergenerational gut-brain communication. This fascinating vision linking Guts, Germs, and Stress still requires much work to confirm its tenets, determine its mechanisms, and explore its implications. Some of the ideas are well implanted: the vaginal fluids, along with colostrum (2), contribute to the neonatal microbiota; maternal stress alters the vaginal microbiota; the neonatal GI microbiota and brain amino acid composition is different in males whose mothers were stressed in comparison with male neonates from unstressed dams. Other ideas, mostly mechanistic and the implications of vertical transmission of gut flora via the vagina, are in their infancy. We explore 3 ideas below. Many of the principles of neuroimmunology that have been elucidated in the last 20 years directly relate to the mechanisms by which gut flora affect brain function, both physiologically and in disease states. Many of these principals have been elucidated using lipopolysaccharides (LPSs), small fragments derived from the cell wall of Gram-negative bacteria that activate the innate immune system. Treating animals with LPSs alters many behaviors, including sickness behavior, through the release of cytokines and other neuroimmuno-active substances (3). Both the brain and blood levels of these neuroimmuno-active substances are altered with LPS treatment. LPS, which crosses the blood-brain barrier poorly (4), affects brain levels of neuroimmuno-active substances through a variety of mechanisms that include mediation through the vagal and other nerve afferents, acting at the circumventricular organs, inducing cytokine elevations in the blood that then cross the blood-brain barrier, increasing immune cell trafficking into the central nervous system, and inducing the cells that form the blood-brain barriers to themselves secret neuroimmune substances (5). By these mechanisms, LPS can activate the neuroimmune axes. Increasingly, these neuroimmune axes are found to be fundamentally important in physiological phenomena, not just those related to illness. For example, the cytokine TNF-α, initially shown to be important to pathological sleep as induced by LPS, is now known to be important in regulating physiological sleep as well (6). Likewise, LPS is found in serum in many conditions, not just in sepsis. Although many of the conditions associated with the detection of LPS in the blood stream, such as the gastroenteropathy of AIDS, are clearly pathologic, others, such as intense running and ingestion of a high fat meal, seem to relate more to physiologic functioning (7–9). This raises the question of whether low levels of LPS could be part of the physiologic neuroimmune axes, perhaps acting to incorporate elements of the immune system into one of the various gut-brain axes. This, in turn, raises the question of whether all LPSs are equal; for example, might those from pathogenic bacteria be more potent activators of the immune system or activate the immune system in different ways than those from nonpathogenic bacteria. In other words, might there be “good” LPSs and “bad” LPSs? Lactobacillus being a Gram-positive bacterium does not give rise to LPS, but instead contains lipoteichoic acid (LTA). Like LPS, LTA can active the innate immune system, releasing cytokines and inducing a septic-shock like picture with multiorgan failure (10). However, LPS and LTA are not interchangeable, but work through different receptors, have different profiles of cytokine and chemokine release, and interact to modulate one another's activities (11, 12). Thus, similar questions can be asked about physiologic modifications of the immune, neuroimmune, and nervous systems by LTA and, additionally, how LTA interacts with LPS. Viewing a phenomenon such as maternal-infant GI microbiota transmission with an evolutionary perspective rather than a disease model perspective yields a different set of future questions. The disease model view would raise questions such as what are the consequences of delivery by Caesarian section, of altering the microbiota with antibiotics, or of urinary tract infections. In the evolutionary model, the prime consideration is the impact on reproductive success (RS). Animals born into a stressful world may have better chances to reproduce if they can be adapted early on to the stresses of that world. By affecting adaption during the critical periods of development, vertical transmission by any means can allow offspring a better chance at survival, reproduction, and effective parenting, all of which can improve RS. This raises the question of whether all stresses would have the same effects as the stresses used here. The stresses used in the current study were mainly “psychological” such as threatening odors, physical restraint, and novel noises. Would a different set of stresses indicating a world with a different set of challenges and requiring a different set of adaptions to maximize RS produce a different pattern of changes in brain neurochemistry? Would, for example, stressors such as maternal starvation or food deprivation, increased maternal physical activity, or excess temperatures produce different shifts in the microflora than those used here and would those changes result in different changes in the neonates? The current set of stressors produced changes primarily in males. Is this because this particular set of stressors requires male adaption primarily to improve RS? Or are only males susceptible to changes in vertical transmission of the gut microbiota? Would any set of stressors produce the same pattern of change see here? To be more concrete with an example, it might be advantageous for a breeding population in a resource poor environment if more offspring developed into k strategists that maximize the use of a habitat rather than into r strategists that have a high reproductive potential and are better at exploiting new environments (13). Could maternal perception of resource availability be transmitted to offspring through a microbiota adapted to take advantage of those resources? Many of the adaptions made to increase RS can have long-term detrimental effects during advanced aging. Alternatively, adaptions which may be detrimental during younger years may be beneficial for prolonging survival as one grows older, a concept known as adaptive senectitude (14). These concepts are especially popular at this time in regards to early neuroinflammation and the development of the neurodegenerative diseases of aging. Neonatal hypoxia, for example, sets up a neuroinflammatory cascade that can produce changes in brain weight and behavior that can last into adulthood (15). Prenatal exposure to LPS results in offspring born with a great reduction in dopamine neurons, predisposing them to the development of Parkinson's disease later in life (16). Interestingly, bacterial vaginosis, an overgrowth of the vaginal flora most typically by Gardnerella vaginalis, has been suggested as a potential source of LPS during pregnancy. Thus, the vagina and the conversations it has with the gut and brain could literally affect us from cradle to grave. Possible mediators of these messages may be the LTAs and LPSs derived from a mix of friendly and foul bacteria, secreted primarily from the gut to act in a hormone-like fashion to influence brain function through immune and neuroimmune mechanisms. This work was supported by Veterans Affairs and by National Institute on Aging Grant R01 AG046619. Disclosure Summary: The author has nothing to disclose. gastrointestinal lipopolysaccharide lipoteichoic acid reproductive success.
Source: Endocrinology
DOI: 10.1210/en.2015-1590
Author: William A. Banks
Institutions: University of Washington, VA Puget Sound Health Care System
Language: English
Topic: Gut microbiota and health
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W1929029870