Neonatal abstinence syndrome and the gastrointestinal tract

Medical Hypotheses 97 (2016) 11–15

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Neonatal abstinence syndrome and the gastrointestinal tract Denise Maguire PhD, RN, CNL ⇑, Maureen Gröer PhD, RN, FAAN University of South Florida College of Nursing, 12901 Bruce B. Downs Blvd., MDC 22, Tampa, FL, United States

a r t i c l e

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Article history: Received 31 August 2016 Accepted 18 October 2016

a b s t r a c t Development of a healthy gut microbiome is essential in newborns to establish immunity and protection from pathogens. Recent studies suggest that infants who develop dysbiosis may be at risk for lifelong adverse health consequences. Exposure to opioid drugs during pregnancy is a factor of potential importance for microbiome health that has not yet been investigated. Since these infants are born after an entire gestation exposed to mu opioid receptor agonists and have severe gastrointestinal and neurological symptoms, we hypothesize that these infants are at risk for dysbiosis. We speculate that opioid exposure during gestation and development of NAS at birth may lead to a dysbiotic gut microbiome, which may impair normal microbiome succession and development, and impact future health of these children. Ó 2016 Elsevier Ltd. All rights reserved.

Introduction Development of a healthy gut microbiome is essential in newborns to establish immunity and protection from pathogens [1]. Conditions known to impact the developing microbiota in infants include birth delivery method [2], diet [3,4], early hospitalization [5], antibiotic use, and country of origin [6]. Recent studies suggest that infants who develop dysbiosis may be at risk for lifelong adverse health consequences [7–9]. Much work has been completed to describe the microbiome of the healthy, term infant. The early studies were limited by sample size and diverse characteristics, but consistently reported Bifidobacterium as the dominant organism [4,10–12]. Eggesbo and colleagues [13] optimized design in a study of 85 infants delivered vaginally during the first 4 months of life, providing an excellent reference for the colonization process. Infants were exclusively breast fed for the first month, and were partially or exclusively breastfeeding at 4 months in their native Norway. Bifidobacterium was confirmed to be the most prevalent constituent, findings which have been replicated in more recent investigations [14,15]. Although microbiome characteristics have been generally described in the healthy newborn, there is some evidence that differences exist among different countries [6], illustrating the gut sensitivity to the environment. There is also new concern that the built environment (that in which we live) greatly influences the human microenvironment in ways not fully understood [16]. Many people live in a structure that has limited air circulation with the outdoors, and often air conditioning that

⇑ Corresponding author at: University of South Florida College of Nursing, MDC 22, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, United States E-mail address: [email protected] (D. Maguire). http://dx.doi.org/10.1016/j.mehy.2016.10.006 0306-9877/Ó 2016 Elsevier Ltd. All rights reserved.

probably limits the types of microbiota that can thrive in them [16]. Given the extreme sensitivity of microbiome development to external factors, it is logical to suggest that a fetal gut chronically exposed to opioids during gestation will be negatively impacted after birth. This is supported by the finding that opioids are associated with both decreased diversity and increased numbers of virulent and antibiotic resistant pathogens in the adult gut microbiome [17]. Untreated pregnant women who are opiate-dependent are at great risk for numerous pregnancy complications (low birth weight, preeclampsia, bleeding, malpresentation, fetal distress and meconium aspiration). These pregnancy effects are combined with serious infant morbidity and a 74-fold increase in sudden infant death syndrome [18]. Pregnant women addicted to opioids are treated with methadone because it improves important perinatal outcomes such as birth weight [19]. Pregnant women are administered methadone or buprenorphine, long acting l opioid agonists, as a mechanism to reduce exposure of the fetus to repeated cycles of opioid exposure. These opiates, however, are not innocuous and have short term effects on infant’s nervous system and neurobehavior [18] and put the infant at risk for withdrawal symptoms after birth. Withdrawal from methadone causes neonatal abstinence syndrome (NAS) [20–22], and infants suffer from inconsolable crying and gastrointestinal (GI) distress [23]. This distress is manifested as diarrhea, cramping, and poor feeding, suggesting alterations in normal gastrointestinal function. Long term effects of prenatal opioid exposure include developmental delays, poor fine motor coordination [24], and attention deficit hyperactivity disorder [25,26]. Although the literature is silent on any associations of prenatal opioid exposures with physical health problems, it has been postu-

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lated that prenatal exposure could affect gut development, immune function, and neurobehavior [27]. NAS affects more than 10,000 infants annually, and the rate has increased significantly since 2004 (p < 0.001) [28]. The costs of hospitalization for NAS have been estimated to have increased from $190 million to $720 million between 2000 and 2009 [28], increasing again in 2013 to $1.5 billion with 80% paid by Medicare [29]. The most well-known outcome of any opioid exposure is NAS, reported to occur in 75–90% of exposed infants [30]. The hypothesis A factor of potential importance for microbiome health that has not yet been investigated is exposure to opioid drugs during pregnancy. Since these infants are born after an entire gestation exposed to mu opioid receptor agonists and have severe gastrointestinal and neurological symptoms, we hypothesize that these infants are at risk for dysbiosis. We speculate that opioid exposure during gestation and development of NAS at birth may lead to a dysbiotic gut microbiome, which may impair normal microbiome succession and development, and impact future health of these children. Our model of the proposed mechanism of action is illustrated in Fig. 1. The maternal opioid abuse (or treatment with methadone/buprenorphine) activates the fetal gut mu receptors, which results in altered (decreased) gut motility and presumed effects on transcription pathways across time. The decreased gut motility is expected to alter development of a normal microbiome. Once withdrawal symptoms appear as a newborn, gut motility drastically increases, causing pain, distention, and behavioral stress in the newborn. The effects on transcription pathways across time may also alter the responsiveness of the gut to opioids, resulting in altered gut motility, as well as contributing to an altered microbiome. There is emerging evidence that genetic and/or epigenetic factors may provide some protection against NAS [31,32]. The impact of prolonged prenatal exposure to opioids during embryogenesis on MORs and gut physiology/motility and the potential impact on the microbiome are unknown. The MORs in the gut are involved in physiological and pathophysiological phenomena such as feeding [33], obesity [34], and immunosuppression [35]. These receptors are widely dispersed in the gut during gestation [36–38] and play an important role in motility and secretion. Gut motility then plays an important role in the determination of number and diversity of bacteria [39]. Motility has a bidirectional relationship with the commensal microbiome [40], in that microflora exerts an effect on motility, and motility impacts diversity. Gut motility is decreased by activation of MORs, and increases beyond normal rates during withdrawal. Since gut motility has a bidirectional relationship with the microbiome [39], it is unclear if motility changes are due to decreased MOR binding,

changes in the microbiome, or a combination of both. Activation of MORs in the gut decreases motility by slowing peristalsis [36], potentially impacting or altering the microbiota. Normally, anaerobic organisms thrive in the distal gut with slow peristalsis, while aerobic organisms are more commonly found in the proximal gut where peristalsis is more rapid [39], but with motility changes, this balance is likely to be disrupted. The common symptom of abdominal cramping experienced by adults in withdrawal are likely to manifest as irritability and distress in newborns with NAS. We have reported signs of infant distress that interrupted feeding in infants with NAS, and many times accounted for more than half of the feeding session [41]. The gut has more neurons than any organ other than the central nervous system, and is considered by many to be a neurological organ (a ‘‘second brain”). The enteric nervous system (ENS) supplies all layers of the gut, and thus autonomously regulates virtually every aspect of digestion, including secretion and motility. Motility, secretion and absorption are largely mediated by transmembrane G protein-coupled receptors in the gastrointestinal tract which are responsive to many different messenger molecules, including opiates such as methadone. MOR agonist binding results in receptor endocytosis, and pre- and post-synaptic effects, including potassium channel activation, membrane hyperpolarization, calcium channel inhibition and decreased cyclic adenosine monophosphate. These effects interrupt normal enteric propulsion and water and electrolyte secretion, leading to chronic constipation, bloating and pain. Like many receptors, MORs respond by desensitization and resensitization [42]. Genes involved in coding MORs are subject to epigenetic influences such as methylation, which has been observed in infants with NAS [32]. The gene promoter coding for MOR is methylated (and thus silenced to some degree) in heroin addicts [43] and in addicts maintained on methadone [44]. MORs can become desensitized when chronically exposed to opioids, and signaling is decreased [45]. Yet, with chronic use of MOR agonists, while receptors may be desensitized, there is still often a significant inhibitory effect of opioids on gut motility and secretion. This may be related to refractoriness of the colon to MOR desensitization. The interactions between gut microbiome and motility are bidirectional [40]. Disruption of the delicate balance leads to local and systemic consequences such as diarrhea or constipation [40]. The mechanisms that have been implicated from the microbiota side are release of end products of bacterial fermentation, intestinal neuroendocrine factors, and release of GI immune system mediators [40]. These products can reach and affect many tissues, including the brain. Dysbiosis in mice has been reported to be associated with down regulated MORs, and increased colonic contractility [46]. The modulatory mechanism of action through which MORs affects gut motility and secretion involves inhibition of acetyl-

Fig. 1. Model of the proposed mechanism of action.

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choline release from myenteric neurons that innervate the gatrointestinal tract smooth muscle or goblet cells involved in mucin secretion. There is also evidence for inhibition by opioids on release of vasoactive inhibitory peptide (VIP) and nitrous oxide [42]. These effects results in disrupted peristalsis. Gastrointestinal peristalsis is coordinated by interneurons in the enteric nervous system that involve transmission by opioids or somatostatin [47]. The ileocecal valve marks the transitional gradient between the small and large intestine in terms of the microbial flora and motility patterns. The colon contains the heaviest concentration of microbes, and with low motility and low oxygenation, the anaerobes thrive in this environment [39]. There are regional differences in actions of opioids, and tolerance does not occur in the colon, leading to chronic constipation in users of opioid derivative drugs [48]. Considering the multiple ways in which MORs might be involved in gut function, it is reasonable to include that risk for dysbiosis is present in infants chronically exposed to opioids during gestation.

Signs of NAS Neonatal abstinence syndrome is the most common outcome of gestational opioid exposure, occurring in 75–90% of exposed infants [30]. Symptom severity does not seem to be associated with maternal methadone dose or length of treatment [49]. Withdrawal usually becomes evident 24–48 h after birth, but can be earlier in those exposed to poly drug abuse [50]. Signs of withdrawal peak between 34 and 50 h of life [51], as measured by one of many assessment scales. Most infants (95%) with NAS demonstrate signs by day 5 of life [50]. The most prominent signs of NAS have been described as disturbed sleep (77%), excessive sucking (57%), tachypnea (56%), loose stools (53%), tremors (48%), and increased tone (41%) [52]. The range of symptoms also includes excessive, high pitched crying, hyperactive reflexes, seizures, sweating, fever, mottling, nasal flaring, poor feeding, and vomiting and regurgitation [53]. Minor withdrawal signs are managed with non-pharmacologic interventions such as swaddling and decreased external stimulation, while more severe signs are treated with scheduled opioids until they are well controlled, and then slowly tapered [30]. Depending upon the severity of withdrawal and use of standardized treatment plans, treatment can be expected to last 4–6 weeks [30]. Buprenorphine is associated with a later onset of symptoms, use of less opioid to treat NAS, and shorter duration of treatment than those exposed to methadone [54]. We reported the predominance of ‘fussing’ behaviors in bottle fed infants with NAS that included averting face, turning away, and resisting; grimacing or frowning; hyper-extending arms or legs; flailing arms; splaying fingers; pushing or spitting out the nipple; and vocal objections like whimpering [41]. These fussing behaviors accounted for 40% of the feeding time, nearly twice as long as the time infants spent feeding (24%) during a feeding episode. As a result, infants with NAS are extremely irritable, sleep poorly, and are difficult to feed. Many of their symptoms seem to be associated with abdominal pain or cramping, as reported by adults in opioid withdrawal [55]. Feeding patterns and/or the mechanics of sucking may also be different in infants with NAS [56–59]. Infants exposed to opiates have been found to be less efficient feeders and had more apneic swallows than healthy infants in the first three days of life [56]. Others have reported poor sucking performance in infants exposed to methadone [58] and more feeding problems (rejecting the nipple, dribbling milk, hiccoughing, spitting up, and coughing) than non-drug exposed infants or those exposed to cocaine [59].

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Recovery from NAS and long term effects There is growing evidence that opioid exposure during gestation has adverse effects on long term outcomes of infants, particularly those who require treatment for NAS. Significant differences were found between methadone-exposed infants and normal controls at 18 months of age for dystonia, fine motor coordination, language, and vision problems [24]. The Bailey mental and motor scores were significantly lower on the infants with NAS, but still within the normal range [24], although others report significant impairment in opiate-exposed children [60]. Height, weight and head circumference were significantly lower in children between 3 and 6 years who were born to heroin addicts, and they performed significantly poorer on the Columbia Mental Maturity Scale than matched controls [61]. Other investigators have reported impaired verbal and performance skills [62], as well as visual-motor weakness and perceptual abilities [63]. Buprenorphine exposure during gestation is also associated with poor outcomes in children ages 5– 6, including significant hyperactivity, impulsivity, and attention problems [26]. Animal models have suggested that heroin exposure decreases neuronal dendrite length and branching in the brain [64]. Animal models also indicate that adult male rats whose mothers were exposed to morphine as adolescents develop increased sensitivity to analgesic effects, and develop tolerance more rapidly [65]. Vision is also affected by prolonged opioid exposure [66–69]. Deficits include strabismus [67,70], reduced visual acuity, nystagmus, refractive errors, and cerebral visual impairment [67]. Others have reported that visual evoked potential peak times were significantly slower (p = 0.02) with smaller amplitudes in a comparison study [68]. Considering the neurological effects, and the gastrointestinal tract’s enteric innervation as well as the gut-brain axis, it is reasonable to suggest that gastrointestinal impairments and dysbiosis may occur as the result of opioid exposures during fetal life and could contribute to later neurobehavioral and gastrointestinal abnormalities in children. Effects of dysbiosis Evidence that the initial gut microbiome has a significant impact on the future health of the individual has been mounting for 10 years. Evidence has shown that gut microbiota play a major role in obesity and insulin resistance in both animal models and humans [71]. The microbiome has been implicated with the development of childhood allergies: decreased colonization with lactobacilli, Bifidobacterium, and C. difficile have been reported in children who developed allergies by age five [9]. Similarly, altered gut microbiota (elevated Firmicutes-to-Bacteroidetes ratio) have been reported in obese children [72]. Gilbert and colleagues [73] postulate that the rapid increase in autism spectrum disorders (ASD) may be due to a microbiome dysbiosis, since people with ASD have been shown to lack Prevotella [7]. Zaborin and colleagues [17] recently demonstrated that exposure to opioids decreased the commensal diversity in the gut of adults, but nothing is known about this relationship in infants. Mechanisms by which the gut microbial balance and diversity can affect diverse physiological processes are being studied. There appears to be a critical window in time during which development of dysbiosis can profoundly alter immunity [74,75]. Development and maturation of immune function may also be altered by many perinatal factors such as antibiotic use in early life [76]. Immunological alterations resulting from early life dysbiosis may program the child towards a particular disease phenotype such as allergy and asthma, or Crohn’s disease. Other effects of dysbiosis may be the result of inflammation, opening of gut epithelial cell gap junctions, and ‘‘leakage” of gut microbes, microbial metabolic products, and toxins (LPS) into the circulation. Some of these metabolites can

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interact with the immune system (short chain fatty acids). Others have neurochemical effects (tryptophan). There is a gut-brain axis that is implicated in behavioral effects of abnormal gut microbiota. This is a bidirectional communication that includes include neural, humoral, immune, and metabolic pathways [77]. The gut provided information to the brain both through metabolic products, immune molecules such as cytokines, and the afferent vagal fibers influential while the hypothalamic-pituitary-adrenal axis (HPA), neuroendocrine factors and neuropeptides affect the gut microbiota composition. Theses axes are thought to be involved in the pathogenesis of mood disorders, autism-spectrum disorders, attention-deficit hypersensitivity disorder, multiple sclerosis, and obesity [78]. Children who have experienced NAS and develop dysbiosis may be at later risk for these types of problems. Conclusion This paper speculates that opioid exposure during gestation and development of NAS at birth, which is well known to be associated with gastrointestinal distress, may lead to a dysbiotic gut microbiome. This dysbiosis may impair normal microbiome succession and development, and impact later health of these children. This deserves careful study at several layers of investigation, from the molecular to the clinical to the epidemiological level. Funding None. References [1] Weng M, Walker WA. The role of gut microbiota in programming the immune phenotype. J Dev Origins Health Dis 2013;4(3):203–14. [2] Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci USA 2010;107(26):11971–5. [3] Jeurink PV, van Bergenhenegouwen J, Jimenez E, Knippels LM, Fernandez L, Garssen J, et al. Human milk: a source of more life than we imagine. Beneficial Microbes 2013;4(1):17–30. [4] Yoshioka H, Iseki K, Fujita K. Development and differences of intestinal flora in the neonatal period in breast-fed and bottle-fed infants. Pediatrics 1983;72 (3):317–21. [5] Brooks B, Firek BA, Miller CS, Sharon I, Thomas BC, Baker R, et al. Microbes in the neonatal intensive care unit resemble those found in the gut of premature infants. Microbiome 2014;2(1):1. [6] Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, et al. Human gut microbiome viewed across age and geography. Nature 2012;486(7402):222–7. [7] Kang DW, Park JG, Ilhan ZE, Wallstrom G, Labaer J, Adams JB, et al. Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children. PLoS ONE 2013;8(7):e68322. [8] Shaw SY, Blanchard JF, Bernstein CN. Association between the use of antibiotics in the first year of life and pediatric inflammatory bowel disease. Am J Gastroenterol 2010;105(12):2687–92. [9] Sjogren YM, Jenmalm MC, Bottcher MF, Bjorksten B, Sverremark-Ekstrom E. Altered early infant gut microbiota in children developing allergy up to 5 years of age. Clin Exp Allergy 2009;39(4):518–26. [10] Benno Y, Sawada K, Mitsuoka T. The intestinal microflora of infants: composition of fecal flora in breast-fed and bottle-fed infants. Microbiol Immunol 1984;28(9):975–86. [11] Palmer C, Bik EM, DiGiulio DB, Relman DA, Brown PO. Development of the human infant intestinal microbiota. PLoS Biol 2007;5(7):e177. [12] Rotimi VO, Duerden BI. The development of the bacterial flora in normal neonates. J Med Microbiol 1981;14(1):51–62. [13] Eggesbo M, Moen B, Peddada S, Baird D, Rugtveit J, Midtvedt T, et al. Development of gut microbiota in infants not exposed to medical interventions. APMIS 2011;119(1):17–35. [14] Guaraldi F, Salvatori G. Effect of breast and formula feeding on gut microbiota shaping in newborns. Front Cell Infect Microbiol 2012;2:94. [15] St James-Roberts I, Conroy S. Do pregnancy and childbirth adversities predict infant crying and colic? Findings and recommendations. Neurosci Biobehav Rev 2005;29(2):313–20. [16] Lax S, Smith DP, Hampton-Marcell J, Owens SM, Handley KM, Scott NM, et al. Longitudinal analysis of microbial interaction between humans and the indoor environment. Science 2014;345(6200):1048–52.

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