Show Summary Details

Page of

PRINTED FROM the OXFORD RESEARCH ENCYCLOPEDIA, NEUROSCIENCE (oxfordre.com/neuroscience). (c) Oxford University Press USA, 2019. All Rights Reserved. Personal use only; commercial use is strictly prohibited (for details see Privacy Policy and Legal Notice).

date: 19 October 2019

Gut Dysbiosis and Recovery of Function After Spinal Cord Injury

Summary and Keywords

Spinal cord injury (SCI) disrupts the autonomic nervous system (ANS) and impairs communication with organ systems throughout the body, resulting in chronic multi-organ pathology and dysfunction. This dysautonomia contributes to the pronounced immunosuppression and gastrointestinal dysfunction seen after SCI. All of these factors likely contribute to the development of gut dysbiosis after SCI—an imbalance in the composition of the gut microbiota that can impact the development and progression of numerous pathological conditions, including SCI. The gut microbiota are the community of microbes (bacteria, viruses, fungi) that live in the GI tract and are critical for nutrient absorption, digestion, and immune system development. These microbes also communicate with the CNS through modulation of the immune system, production of neuroactive metabolites and neurotransmitters, and activation of the vagus nerve.

After SCI, gut dysbiosis develops and persists for more than one year from the time of injury. In experimental models of SCI, gut dysbiosis is correlated with changes in inflammation and functional recovery. Moreover, probiotic treatment can improve locomotor recovery and immune function in the gut-associated lymphoid tissue (GALT). Since different types of bacteria produce different metabolites with unique physiological and pathological effects throughout the body, it may be possible to predict the prevalence or severity of post-injury immune dysfunction and other related comorbidities (e.g., metabolic disease, fatigue, anxiety) using microbiome sequencing data. As research identifies microbial-derived small molecules and the genes responsible for their production, it is likely that it will become feasible to manipulate these molecules to affect human biology and disease.

Keywords: neuroinflammation, microbiome, spinal cord injury, probiotics, intestinal dysbiosis

Spinal Cord Injury Causes Dysautonomia

Traumatic spinal cord injury (SCI) results in loss of motor and sensory function below the level of the injury. SCI also causes permanent damage to the sympathetic branch of the autonomic nervous system. The resultant dysautonomia contributes to chronic multi-organ pathology and dysfunction.

Sympathetic preganglionic neurons (SPNs) that reside in thoracic and upper lumbar spinal cord are either directly injured by SCI or their function is disrupted due to loss of interneuronal connections that regulate intersegmental spinal reflexes. SPNs are cholinergic neurons that innervate adrenergic neurons within pre-/post-vertebral ganglia located outside the spinal cord. Post-ganglionic adrenergic sympathetic neurons release norepinephrine (NE) in target organs including (but not limited to) the immune system, liver, cardiovascular system, and the gastrointestinal (GI) tract (hereafter referred to as the “gut”) (Felten, Ackerman, Wiegand, & Felten, 1987; Felten & Olschowka, 1987).

In the gut, sympathetic post-ganglionic innervation controls motility, mucosal secretions, vascular tone, and immune function (Cervi, Lukewich, & Lomax, 2014; Elenkov, Wilder, Chrousos, & Vizi, 2000). SPNs controlling the small and large intestines are located primarily in the intermediolateral cell column in thoracic segments T5-10 and T10-S4, respectively (Browning & Travagli, 2014; Levatte, Mabon, Weaver, & Dekaban, 1998; Mabon, LeVatted, Dekaban, & Weaver, 1997). Therefore, an injury at any spinal level will adversely affect autonomic control of the gut to some degree, although high-level SCI (above T5) will remove most/all bulbospinal control over spinal autonomic networks innervating the gut. Common GI complications after SCI include constipation, fecal incontinence, and decreased colonic transit time (Hou & Rabchevsky, 2014; Qualls-Creekmore, Tong, & Holmes, 2010; Tate et al., 2016).

Sympathetic post-ganglionic neurons also innervate primary and secondary lymphoid tissues including bone marrow, spleen, and lymph nodes (Bellinger & Lorton, 2014; Mignini, Streccioni, & Amenta, 2003). Thus, like the gut, peripheral immune organs are directly connected to and receive information from the spinal cord via the sympathetic nervous system (SNS). After SCI, a dysfunctional SNS profoundly impairs function in the gut and the immune system (Inskip, Ramer, Ramer, & Krassioukov, 2009; Kabatas et al., 2008; Zhang et al., 2013).

Gut Microbiome

The gut microbiota is the community of microbes (bacteria, viruses, fungi) that live in the gut, specifically within the small and large intestines. These microbes are at least as numerous as mammalian cells (Sender, Fuchs, & Milo, 2016) and may outnumber mammalian cells by ~10:1 (Gill et al., 2006; Hollister, Gao, & Versalovic, 2014). This diverse ecosystem, and associated genome, is critical for and can regulate numerous functions in the host, including metabolism, digestion, nutrient absorption, and immune system development and function (Hooper, Littman, & Macpherson, 2012; Nicholson et al., 2012; Round & Mazmanian, 2009). The types and diversity of microbiota vary as a function of location in the gut. High acidity and oxygen content limit the growth of many types of bacteria in the small intestine (Donaldson, Lee, & Mazmanian, 2016); Lactobacillaceae and Enterobacteriaceae are enriched in the small intestine (Gu et al., 2013). A more diverse and abundant microbiome exists in the colon, and because there is lower oxygen tension, the colon is enriched in anaerobic microbiota (Donaldson et al., 2016; Gu et al., 2013). In addition to regulating inflammation and function of the gut, the intestinal microbiota can influence disease development throughout the host, including in the CNS (Collins, Surette, & Bercik, 2012; Wang & Kasper, 2014).

Bidirectional communication between the gut and the CNS occurs via several routes. Gut microbes, through activation of immune cells in the gut-associated lymphoid tissues (GALT) and subsequent release of cytokines, affect CNS function (Bercik et al., 2010). Given that most (~80%) of the body’s immune cells are found in GALT, this is a profound yet poorly recognized route of communication between the gut and brain. Gut microbes also affect post-natal development of the hypothalamic-pituitary-adrenal (HPA) axis and therefore play a critical role in regulating the body’s response to stress, including cortisol release (Crumeyrolle-Arias et al., 2014; Sudo et al., 2004). In a landmark study, Sudo et al. (2004) defined a post-natal “window” during which gut microbiota program the responsiveness of the HPA axis. Adult germ-free mice develop an exaggerated HPA response to stress, which can be completely or partially reversed with a fecal transplant from a conventional mouse. The degree of reversal depends on the age at which the germ-free mice receive the fecal transplant (i.e., complete reversal can occur if colonization occurs at 6 weeks age; there is no effect when waiting until 14 weeks of age) (Sudo et al., 2004). A similar exaggeration in HPA response to stress has been seen in germ-free rats (Crumeyrolle-Arias et al., 2014), suggesting that the ability of gut microbiota to regulate the stress response is conserved across species.

Gut microbiota produce their own payload of neuroactive metabolites (i.e., short-chain fatty acids, choline) and neurotransmitters (GABA, noradrenaline, serotonin, dopamine, acetylcholine). These metabolites can act locally on neurons and glia that make up the enteric nervous system (Clarke et al., 2014; Tillisch, 2014), but they also accumulate in the bloodstream. Circulating metabolites can influence CNS structure/function after bypassing the blood-brain barrier or by modulating signaling of the afferent vagus nerve in the periphery (Clarke et al., 2014; Forsythe, Bienenstock, & Kunze, 2014; Wikoff et al., 2009).

Gut Dysbiosis After SCI

Altering the composition of the gut microbiota creates a state of “dysbiosis” where the balance between beneficial and inflammatory bacteria becomes skewed, usually favoring the latter. Common causes of gut dysbiosis include antibiotic use, stress, and gut dysfunction (Bailey et al., 2010, 2011; El Aidy, Dinan, & Cryan, 2015; Hawrelak & Myers, 2004; Hill & Artis, 2010; Hooper et al., 2012; Round & Mazmanian, 2009). Many of these dysbiosis triggers also compromise the mucosal barrier, leading to bacterial translocation, a process whereby gut bacteria migrate from the intestinal lumen into mesenteric lymph nodes and other extraintestinal tissues (Balmer et al., 2014; Balzan, de Almeida Quadros, deCleva, Zilberstein, & Cecconello, 2007; Macpherson & Smith, 2006). After SCI, impaired autonomic control of the gut likely triggers dysbiosis, which is then exacerbated by (physical and psychological) stress and the need for repeat or prolonged antibiotic use in this patient population.

SCI-induced intestinal dysbiosis has now been documented in multiple species, including human, rat, and mouse (Gungor, Adiguzel, Gursel, Yilmaz, & Gursel, 2016; Kigerl et al., 2016; O’Connor et al., 2018). In mice (C57BL/6 strain), 16s rRNA sequencing was used to determine the identity and relative abundance of bacteria in fecal samples. When data were compared between control (naive, sham-injured) mice and mice that received a mid-thoracic SCI, robust and lasting gut dysbiosis was detected in SCI mice. Specifically, Bacteroidales and Clostridiales, the two most prevalent bacterial taxa in mouse gut (Eckburg et al., 2005; Krych, Hansen, Hansen, van den Berg, & Nielsen, 2013), were inversely regulated by SCI: Bacteroidales decreased while Clostridiales increased. Lesser but consistent changes in minor taxa including Anaeroplasmatales, Turicibacterales, and Lactobacillales also were detected. Chronic dysbiosis also was described in SCI rats using slightly different techniques for sample collection and data analysis (O’Connor et al., 2018). In humans, the abundance of butyrate-producing gut bacteria was reduced for at least 1 year post-SCI (Gungor et al., 2016).

Although the functional consequences of SCI-induced dysbiosis are unknown, the relative abundance of some gut bacteria correlate with locomotor recovery in SCI mice (Kigerl et al., 2016). In these same mice, the composition of leukocytes changes in the Peyer’s patches and mesenteric lymph nodes for up to one month post-injury, and these changes are associated with increased cytokine production (TNFα‎, IL-1β‎, TGF-β‎, IL-10) (Kigerl et al., 2016). Similarly, in SCI rats at 8 weeks post-injury, increased concentrations of inflammatory cytokines in the intestines correlate with the relative abundance of distinct species of gut bacteria (O’Connor et al., 2018).

Significance of Gut Dysbiosis in Health and Disease After SCI

The onset of gut dysbiosis could be the cause or result of SCI-induced changes in gut-immune homeostasis. Moreover, SCI-induced changes in autonomic control of the gut could alter gut physiology and epithelial function, which would facilitate bacterial translocation and the development of dysbiosis (Figure 1).

Gut Dysbiosis and Recovery of Function After Spinal Cord InjuryClick to view larger

Figure 1. Gut dysbiosis is a disease-modifying factor after SCI. SCI triggers the development of gut dysbiosis, likely via several mechanisms including dysautonomia, immune suppression, and antibiotic use. This dysbiosis then contributes to the onset or maintenance of SCI-associated comorbidities, such as chronic immune dysfunction, metabolic disease, and mood disorders.

Bacterial Translocation

Bacterial translocation occurs when gut commensal bacteria move from the gut lumen into GALT or beyond into the systemic circulation (Gatt, Reddy, & MacFie, 2007; Liu et al., 2004; MacFie, 2004; Magnotti & Deitch, 2005). Chronic immune suppression, intestinal obstruction, impaired intestinal motility, and frequent use of antibiotics, all complications of experimental and clinical SCI, can independently cause bacterial translocation.

In mice, prevalent bacterial translocation occurs to the lung, liver, and mesenteric lymph nodes within 1 week after SCI (Kigerl et al., 2016). Similar results have been described in other models of experimental SCI (Bai et al., 2011; Liu et al., 2004). Bacterial translocation may be a mechanism to explain the onset of spontaneous pneumonia and systemic inflammation after SCI and the subsequent development of multi-organ dysfunction that plagues SCI individuals (Bao, Omana, Brown, & Weaver, 2012; Brommer et al., 2016; Gris, Hamilton, & Weaver, 2008; Sauerbeck et al., 2015).

Immune Function

Infections are more prevalent in people with SCI and are a leading cause of morbidity and mortality (Failli et al., 2012; Kopp et al., 2017). The enhanced susceptibility to infection in this patient population is likely caused by a profound and persistent immune suppression that develops after SCI. The mechanisms responsible for a decrease in cellular and humoral immune function are also similar to those contributing to gut dysbiosis, i.e., post-injury dysautonomia. Indeed, within the injured spinal cord, aberrant plasticity and hyperactivity within intraspinal autonomic circuitry create abnormal neural-immune reflexes that impair the survival and function of immune cells (Lucin, Sanders, Jones, Malarkey, & Popovich, 2007; Lucin, Sanders, & Popovich, 2009; Prüss et al., 2017; Riegger et al., 2007, 2009; Ueno, Ueno-Nakamura, Niehaus, Popovich, &Yoshida, 2016; Zhang et al., 2013). Although not well studied in the context of SCI, gut dysbiosis may also contribute to immunological dysfunction after SCI.

The gut microbiota play a pivotal role in the development and regulation of the immune system (Belkaid & Hand, 2014). Not only do gut microbiota coordinate the local intestinal immune response, they also can influence how immune cells in secondary lymphoid tissues (e.g., lymph nodes, spleen) respond to peripheral challenges (Molloy, Bouladoux, & Belkaid, 2012). Gut microbiota can regulate monocyte egress from the bone marrow, modulate the immune response to respiratory infection, and affect the development of atopy and autoimmune disease (Hill & Artis, 2010; Ichinohe et al., 2011; Ochoa-Repáraz, Mielcarz, Begum-Haque, & Kasper, 2011; Shi et al., 2011; Wu et al., 2010). Thus, gut microbiota may be an underappreciated therapeutic target for boosting immune function and preventing infection after SCI. Indeed, oral probiotic treatments can prevent post-surgical infections and respiratory infections (Kasatpibal et al., 2017; Manzanares, Lemieux, Langlois, & Wischmeyer, 2016; Sawas, Al Halabi, Hernaez, Carey, & Cho, 2015). In able-bodied critically ill patients, ventilator-associated pneumomia (VAP) is reduced by prophylactic probiotic therapy (Manzanares et al., 2016; Morrow, Gogineni, & Malesker, 2012; Morrow, Kollef, & Casale, 2010). A similar approach may prove beneficial for SCI patients since they frequently develop VAP (Kornblith et al., 2013). Clinical trials are underway to assess whether probiotics also can limit urinary tract infections after SCI (Lee et al., 2016; Toh, Boswell-Ruys, Lee, Simpson, & Clezy, 2017).

Previously, Kigerl et al. (2016) discovered that daily treatment with VSL#3, a commercially available medical-grade probiotic, improves locomotor recovery, reduces lesion pathology, and boosts numbers of CD4+C25+FoxP3+ regulatory T cells (Tregs) in the mesenteric lymph nodes of SCI mice. Whether Tregs are causal in improving function/reducing pathology in SCI mice is not known; however, these cells play a crucial role in immune homeostasis by actively suppressing auto-reactive and other potentially deleterious effects of activated T cells (Bilate & Lafaille, 2012). Loss of Treg function is implicated in the onset or progression of multiple sclerosis, rheumatoid arthritis, graft vs. host disease, and irritable bowel disease (IBD). Probiotics, especially those like VSL#3 that contain Lactobacillus and Bifidobacterium, significantly enhance Treg activity in vivo (Dwivedi, Kumar, Ladha, & Kemp, 2016) and can ameliorate disease in models of multiple sclerosis by inducing Tregs (Kwon et al., 2013; Lavasani et al., 2010).

Metabolic Function

Bacteroidetes and Firmicutes are the two major bacterial phyla found in the microbiota of both mice and humans (Eckburg et al., 2005; Krych et al., 2013). We reported that in SCI mice, the relative abundance of Bacteroidales (phylum Bacteroidetes) and Clostridiales (phylum Firmicutes) change inversely as a function of time post-injury; Bacteroidales decreases while Clostridiales increases after SCI. Such changes in large bacterial populations can significantly affect host metabolism. Indeed, a similar reciprocal change in the Bacteroidetes:Firmicutes ratio occurs in obese humans and rodents, and lean mice can be made obese simply by colonizing their gut with microbiota from obese donors (Ley, Turnbaugh, Klein, & Gordon, 2006; Turnbaugh, Bäckhed, Fulton, & Gordon, 2008; Turnbaugh et al., 2006). Thus, gut microbiota may contribute to the pathophysiology of obesity (Baothman, Zamzami, Taher, Abubaker, & Abu-Farha, 2016; Tilg & Kaser, 2011; Turnbaugh & Gordon, 2009). Precisely how dysbiosis causes or exacerbates adiposity is not known, but a high Firmicutes:Bacteroidetes ratio increases energy harvest from diet (Bäckhed et al., 2004; Bäckhed, Manchester, Semenkovich, & Gordon, 2007; Turnbaugh et al., 2006).

Gut microbiota also contribute to the development of non-alcoholic fatty liver disease (NAFLD) (Saltzman, Palacios, Thomsen, & Vitetta, 2018). Blood flow to the liver is primarily supplied via the portal vein, which drains blood from the intestines. Therefore, bacterial-derived factors in the circulation that drain from the gut will first impact the liver. Development of NAFLD is thought to occur from a “two-hit” hypothesis. The first is the persistence of steatosis—accumulation of lipid droplets in the liver exceeding 5% of liver weight. The second hit is thought to be an inflammatory insult, possibly resulting from intestinal-derived factors (Saltzman et al., 2018; Tilg & Moschen, 2010). Data in rats indicate that SCI causes liver pathology consistent with NAFLD and non-alcoholic steatohepatitis (NASH) (Sauerbeck et al., 2015). NAFLD can increase the likelihood of developing type 2 diabetes and cardiovascular disease, as well as damaging liver function (Anstee, Targher, & Day, 2013; Perry, Samuel, Petersen, & Shulman, 2014). Probiotics have emerged as a promising tool to treat NAFLD (Famouri, Shariat, Hashemipour, Keikha, & Kelishadi, 2017; Kobyliak et al., 2018; Lavekar, Raje, Manohar, & Lavekar, 2017), suggesting a role for the gut microbiota in the development and maintenance of this disease. Future studies are needed to determine if gut dysbiosis after SCI contributes to the high incidence of metabolic disease and increased adiposity in SCI individuals (Gater, 2007; Gorgey et al., 2014; Gorgey, Mather, & Gater, 2011; Manns, McCubbin, & Williams, 2005; Maruyama et al., 2008; Nelson et al., 2007).

Mental Health

Depression and anxiety are prevalent after SCI (Craig et al., 2015; Craig, Tran, & Middleton, 2009; Fann et al., 2011). Many factors, including psychosocial stress, repeat hospitalization, and chronic pain, likely contribute to poor mental health after SCI; however, the onset of gut dysbiosis and the development of systemic inflammation also could contribute to or exacerbate these mood disorders after SCI. Indeed, gut microbiota regulate the ability of the HPA axis to respond to stress (Sudo et al., 2004) and also the availability of neuroactive peptides (NPY, PYY, PP) and neurotransmitters (5HT) that have been implicated in the development of depression and anxiety (Cryan & Dinan, 2012; Foster & McVey Neufeld, 2013; Lach, Schellekens, Dinan, & Cryan, 2018).

Chronic inflammation is thought to cause or propagate depression and anxiety (Bauer & Teixeira, 2019; Fleshner, Frank, & Maier, 2017). Gut microbiota or microbial products (e.g., peptidoglycan, lipopolysaccharide) that “leak” from the inflamed or “dysbiotic” gut can elicit systemic inflammation, producing cytokines that can activate innate immune cells and microglia throughout the brain. Localized inflammation in the gut also can signal directly to the brain via the vagus nerve (Breit, Kupferberg, Rogler, & Hasler, 2018). Together, these gut-to-brain signaling mechanisms may explain why psychological comorbidities, such as depression and anxiety, are common in individuals with IBD (Bonaz & Bernstein, 2013). Currently, several clinical trials are underway or have been completed to test whether probiotics can reduce depression and anxiety (Kazemi, Noorbala, Azam, Eskandari, & Djafarian, 2019; Pinto-Sanchez et al., 2017; Slykerman et al., 2017; Wallace & Milev, 2017).

Future Directions

We have just begun to understand how changes in the gut microbiome may impact various outcomes after SCI. To date, all studies documenting SCI-induced changes in the composition of the gut microbiota have relied on 16S rRNA sequencing (Gungor et al., 2016; Kigerl et al., 2016; O’Connor et al., 2018). Using this approach, bacterial species are identified by sequencing a portion of the highly variable region of the 16S rRNA gene. 16S rRNA sequencing is a useful tool for documenting changes in the relative abundance of bacteria in the gut. However, this approach has limitations. The intestinal microbiome is not exclusively comprised of bacteria—fungi, archaea, and viruses are an important, yet understudied, component of this vast ecosystem. In fact, viruses and bacteriophage (viruses that infect bacteria) are likely as prevalent in the human gut as bacteria (Kim, Park, Roh, & Bae, 2011; Reyes et al., 2010; Reyes, Semenkovich, Whiteson, Rohwer, & Gordon, 2012). The use of whole metagenome shotgun (WMGS) sequencing is rapidly gaining popularity due to the ability to detect other microbial organisms using this technique. In addition to the identification of viral and fungal components, WMGS allows users to gain insight into the functional component of the microbiome. Because all genetic material is sequenced with WMGS, identified genes can be grouped into pathways using GO terms or KEGG pathways providing a framework to assess microbiome “function.”

Since different types of bacteria produce different metabolites with unique physiological and pathological effects throughout the body, it may be possible to predict the prevalence or severity of post-injury immune dysfunction and other related comorbidities (e.g., metabolic disease, fatigue, anxiety) by comparing the relative density and types of bacteria (and perhaps viruses) found in the gut of uninjured and SCI individuals, as a function of both injury level and time post-injury. The emergence or reduction in key microbial species after SCI also could represent novel therapeutic targets. For example, customized pre- or probiotic formulations could be matched to offset SCI-induced changes in core bacterial taxa or even specific genera or low-abundance species.

Using “multi-omic” approaches, it may be possible to understand how the gut microbiome regulates the function and phenotype of cells in the brain and spinal cord. For example, the gut microbiome is already known to shape the transcriptome of adult microglia (Thion et al., 2018), and gut microbiota can alter microglial structure and maturity (Erny et al., 2015). In germ-free mice, the addition of specific microbial-derived metabolites (i.e., short-chain fatty acids), even in the absence of the bacteria themselves, can reverse deficits in microglia function (Erny et al., 2015). The gut microbiome also regulates the metabolism of several key neurotransmitters that can alter CNS function. Most (~90%) of the body’s serotonin is produced in the gut (Gershon & Tack, 2007), and its synthesis is regulated by gut microbiota (Yano et al., 2015). Indeed, germ-free mice have lower levels of serum serotonin compared to conventional wild-type mice (Wikoff et al., 2009). In addition to their role in serotonin synthesis, microbiota-mediated metabolism of tryptophan produces small molecules that can directly influence astrocyte function and alter the glial response to inflammation in the CNS (Rothhammer et al., 2016). As research continues to identify small molecules produced by gut-associated bacteria and the genes responsible for their production, it is likely that it will become feasible to manipulate these drug-like molecules to affect human biology and disease.

References

Anstee, Q. M., Targher, G., & Day, C. P. (2013). Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nature Reviews Gastroenterology Hepatology, 10, 330–344.Find this resource:

Bäckhed, F., Ding, H., Wang, T., Hooper, L. V., Koh, G. Y., Nagy, A., . . . Gordon, J. I. (2004). The gut microbiota as an environmental factor that regulates fat storage. Proceedings of the National Academy of Sciences of the United States of America, 101(44), 15718–15723.Find this resource:

Bäckhed, F., Manchester, J. K., Semenkovich, C. F., & Gordon, J. I. (2007). Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proceedings of the National Academy of Sciences of the United States of America, 104, 979–984.Find this resource:

Bai, C., An, H., Wang, S., Jiang, D., Fan, W., & Nie, H. (2011). Treatment and prevention of bacterial translocation and endotoxemia with stimulation of the sacral nerve root in a rabbit model of spinal cord injury. Spine (Phila Pa 1976), 36, 363–371.Find this resource:

Bailey, M. T., Dowd, S. E., Galley, J. D., Hufnagle, A. R., Allen, R. G., & Lyte, M. (2011). Exposure to a social stressor alters the structure of the intestinal microbiota: Implications for stressor-induced immunomodulation. Brain, Behavior, and Immunity, 25, 397–407.Find this resource:

Bailey, M. T., Dowd, S. E., Parry, N. M., Galley, J. D., Schauer, D. B., & Lyte, M. (2010). Stressor exposure disrupts commensal microbial populations in the intestines and leads to increased colonization by Citrobacter rodentium. Infection and Immunity, 78, 1509–1519.Find this resource:

Balmer, M. L., Slack, E., de Gottardi, A., Lawson, M. A., Hapfelmeier, S., Miele, L., . . . Macpherson, A. J. (2014). The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota. Science Translational Medicine, 6, 237ra266.Find this resource:

Balzan, S., de Almeida Quadros, C., de Cleva, R., Zilberstein, B., & Cecconello, I. (2007). Bacterial translocation: Overview of mechanisms and clinical impact. Journal of Gastroenterology and Hepatology, 22, 464–471.Find this resource:

Bao, F., Omana, V., Brown, A., & Weaver, L. C. (2012). The systemic inflammatory response after spinal cord injury in the rat is decreased by α‎4β‎1 integrin blockade. Journal of Neurotrauma, 29, 1626–1637.Find this resource:

Baothman, O. A., Zamzami, M. A., Taher, I., Abubaker, J., & Abu-Farha, M. (2016). The role of gut microbiota in the development of obesity and diabetes. Lipids in Health and Disease, 15, 108.Find this resource:

Bauer, M. E., & Teixeira, A. L. (2019). Inflammation in psychiatric disorders: what comes first? Annals of the New York Academy of Sciences, 1437(1), 57–67.Find this resource:

Belkaid, Y., & Hand, T. W. (2014). Role of the microbiota in immunity and inflammation. Cell, 157, 121–141.Find this resource:

Bellinger, D. L., & Lorton, D. (2014). Autonomic regulation of cellular immune function. Autonomic Neuroscience, 182, 15–41.Find this resource:

Bercik, P., Verdu, E. F., Foster, J. A., Macri, J., Potter, M., Huang, X., . . . Collins, S. M. (2010). Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice. Gastroenterology, 139, 2102–2112.e2101.Find this resource:

Bilate, A. M., & Lafaille, J. J. (2012). Induced CD4+Foxp3+ regulatory T cells in immune tolerance. Annual Review of Immunology, 30, 733–758.Find this resource:

Bonaz, B. L., & Bernstein, C. N. (2013). Brain-gut interactions in inflammatory bowel disease. Gastroenterology, 144, 36–49.Find this resource:

Breit, S., Kupferberg, A., Rogler, G., & Hasler, G. (2018). Vagus nerve as modulator of the brain-gut axis in psychiatric and inflammatory disorders. Frontiers in Psychiatry, 9, 44.Find this resource:

Brommer, B., Engel, O., Kopp, M. A., Watzlawick, R., Müller, S., Prüss, H., . . . Schwab, J. M. (2016). Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level. Brain, 139, 692–707.Find this resource:

Browning, K. N., & Travagli, R. A. (2014). Central nervous system control of gastrointestinal motility and secretion and modulation of gastrointestinal functions. Comprehensive Physiology, 4, 1339–1368.Find this resource:

Cervi, A. L., Lukewich, M. K., & Lomax, A. E. (2014). Neural regulation of gastrointestinal inflammation: Role of the sympathetic nervous system. Autonomic Neuroscience, 182, 83–88.Find this resource:

Clarke, G., Stilling, R. M., Kennedy, P. J., Stanton, C., Cryan, J. F., & Dinan, T. G. (2014). Gut microbiota: The neglected endocrine organ. Molecular Endocrinology, 28(8), 1221–1238.Find this resource:

Collins, S. M., Surette, M., & Bercik, P. (2012). The interplay between the intestinal microbiota and the brain. Nature Reviews Microbiology, 10, 735–742.Find this resource:

Craig, A., Nicholson Perry, K., Guest, R., Tran, Y., Dezarnaulds, A., Hales, A., . . . Middleton, J. (2015). Prospective study of the occurrence of psychological disorders and comorbidities after spinal cord injury. Archives of Physical Medicine and Rehabilitation, 96, 1426–1434.Find this resource:

Craig, A., Tran, Y., & Middleton, J. (2009). Psychological morbidity and spinal cord injury: A systematic review. Spinal Cord, 47, 108–114.Find this resource:

Crumeyrolle-Arias, M., Jaglin, M., Bruneau, A., Vancassel, S., Cardona, A., Daugé, V., Naudon, L., & Rabot, S. (2014). Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats. Psychoneuroendocrinology, 42, 207–217.Find this resource:

Cryan, J. F., & Dinan, T. G. (2012). Mind-altering microorganisms: The impact of the gut microbiota on brain and behaviour. Nature Reviews Neuroscience, 13, 701–712.Find this resource:

Donaldson, G. P., Lee, S. M., & Mazmanian, S. K. (2016). Gut biogeography of the bacterial microbiota. Nature Reviews Microbiology, 14, 20–32.Find this resource:

Dwivedi, M., Kumar, P., Laddha, N.C., & Kemp, E. H. (2016). Induction of regulatory T cells: A role for probiotics and prebiotics to suppress autoimmunity. Autoimmune Reviews, 15, 379–392.Find this resource:

Eckburg, P. B., Bik, E. M., Bernstein, C. N., Purdom, E., Dethlefsen, L., Sargent, M., . . . Relman, D. A. (2005). Diversity of the human intestinal microbial flora. Science, 308, 1635–1638.Find this resource:

El Aidy, S., Dinan, T. G., & Cryan, J. F. (2015). Gut microbiota: The conductor in the orchestra of immune-neuroendocrine communication. Clinical Therapeutics, 37, 954–967.Find this resource:

Elenkov, I. J., Wilder, R. L., Chrousos, G. P., & Vizi, E. S. (2000). The sympathetic nerve—An integrative interface between two supersystems: the brain and the immune system. Pharmacology Reviews, 52, 595–638.Find this resource:

Erny, D., Hrabě de Angelis, A. L., Jaitin, D., Wieghofer, P., Staszewski, O., David, E., . . . Prinz, M. (2015). Host microbiota constantly control maturation and function of microglia in the CNS. Nature Neuroscience, 18, 965–977.Find this resource:

Failli, V., Kopp, M. A., Gericke, C., Martus, P., Klingbeil, S., Brommer, B., . . . Schwab, J. M. (2012). Functional neurological recovery after spinal cord injury is impaired in patients with infections. Brain, 135, 3238–3250.Find this resource:

Famouri, F., Shariat, Z., Hashemipour, M., Keikha, M., & Kelishadi, R. (2017). Effects of probiotics on nonalcoholic fatty liver disease in obese children and adolescents. Journal of Pediatric Gastroenterology and Nutrition, 64, 413–417.Find this resource:

Fann, J. R., Bombardier, C. H., Richards, J. S., Tate, D. G., Wilson, C. S., Temkin, N., & Investigators, P. (2011). Depression after spinal cord injury: Comorbidities, mental health service use, and adequacy of treatment. Archives of Physical Medicine and Rehabilitation, 92, 352–360.Find this resource:

Felten, D. L., Ackerman, K. D., Wiegand, S. J., & Felten, S. Y. (1987). Noradrenergic sympathetic innervation of the spleen: I. Nerve fibers associate with lymphocytes and macrophages in specific compartments of the splenic white pulp. Journal of Neuroscience Research, 18, 28–36, 118–121.Find this resource:

Felten, S. Y., & Olschowka, J. (1987). Noradrenergic sympathetic innervation of the spleen: II. Tyrosine hydroxylase (TH)-positive nerve terminals form synapticlike contacts on lymphocytes in the splenic white pulp. Journal of Neuroscience Research, 18, 37–48.Find this resource:

Fleshner, M., Frank, M., & Maier, S. F. (2017). Danger signals and inflammasomes: Stress-evoked sterile inflammation in mood disorders. Neuropsychopharmacology, 42, 36–45.Find this resource:

Forsythe, P., Bienenstock, J., & Kunze, W. A. (2014). Vagal pathways for microbiome-brain-gut axis communication. Advances in Experimental Medicine and Biology, 817, 115–133.Find this resource:

Foster, J. A., & McVey Neufeld, K. A. (2013). Gut-brain axis: How the microbiome influences anxiety and depression. Trends in Neuroscience, 36, 305–312.Find this resource:

Gater, D. R. (2007). Obesity after spinal cord injury. Physical Medicine and Rehabilitation Clinics of North America, 18, 333–351, vii.Find this resource:

Gatt, M., Reddy, B. S., & MacFie, J. (2007). Review article: Bacterial translocation in the critically ill—evidence and methods of prevention. Alimentary Pharmacology & Therapeutics, 25, 741–757.Find this resource:

Gershon, M. D., & Tack, J. (2007). The serotonin signaling system: From basic understanding to drug development for functional GI disorders. Gastroenterology, 132, 397–414.Find this resource:

Gill, S. R., Pop, M., Deboy, R. T., Eckburg, P. B., Turnbaugh, P. J., Samuel, B. S., . . . Nelson, K. E. (2006). Metagenomic analysis of the human distal gut microbiome. Science, 312, 1355–1359.Find this resource:

Gorgey, A. S., Dolbow, D. R., Dolbow, J. D., Khalil, R. K., Castillo, C., & Gater, D. R. (2014). Effects of spinal cord injury on body composition and metabolic profile—Part I. Journal of Spinal Cord Medicine, 37, 693–702.Find this resource:

Gorgey, A. S., Mather, K. J., & Gater, D. R. (2011). Central adiposity associations to carbohydrate and lipid metabolism in individuals with complete motor spinal cord injury. Metabolism, 60, 843–851.Find this resource:

Gris, D., Hamilton, E. F., & Weaver, L. C. (2008). The systemic inflammatory response after spinal cord injury damages lungs and kidneys. Experimental Neurology, 211, 259–270.Find this resource:

Gu, S., Chen, D., Zhang, J. N., Lv, X., Wang, K., Duan, L. P., . . . Wu, X. L. (2013). Bacterial community mapping of the mouse gastrointestinal tract. PLoS One, 8, e74957.Find this resource:

Gungor, B., Adiguzel, E., Gursel, I., Yilmaz, B., & Gursel, M. (2016). Intestinal microbiota in patients with spinal cord injury. PLoS One, 11, e0145878.Find this resource:

Hawrelak, J. A., & Myers, S. P. (2004). The causes of intestinal dysbiosis: A review. Alternative Medicine Review, 9, 180–197.Find this resource:

Hill, D. A., & Artis, D. (2010). Intestinal bacteria and the regulation of immune cell homeostasis. Annual Review of Immunology, 28, 623–667.Find this resource:

Hollister, E. B., Gao, C., & Versalovic, J. (2014). Compositional and functional features of the gastrointestinal microbiome and their effects on human health. Gastroenterology, 146, 1449–1458.Find this resource:

Hooper, L. V., Littman, D. R., & Macpherson, A. J. (2012). Interactions between the microbiota and the immune system. Science, 336, 1268–1273.Find this resource:

Hou, S., & Rabchevsky, A. G. (2014). Autonomic consequences of spinal cord injury. Comprehensive Physiology, 4, 1419–1453.Find this resource:

Ichinohe, T., Pang, I. K., Kumamoto, Y., Peaper, D. R., Ho, J. H., Murray, T. S., & Iwasaki, A. (2011). Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proceedings of the National Academy of Sciences of the United States of America, 108, 5354–5359.Find this resource:

Inskip, J. A., Ramer, L. M., Ramer, M. S., & Krassioukov, A. V. (2009). Autonomic assessment of animals with spinal cord injury: tools, techniques and translation. Spinal Cord, 47, 2–35.Find this resource:

Kabatas, S., Yu, D., He, X. D., Thatte, H. S., Benedict, D., Hepgul, K. T., . . . Teng, Y. D. (2008). Neural and anatomical abnormalities of the gastrointestinal system resulting from contusion spinal cord injury. Neuroscience, 154, 1627–1638.Find this resource:

Kasatpibal, N., Whitney, J. D., Saokaew, S., Kengkla, K., Heitkemper, M. M., & Apisarnthanarak, A. (2017). Effectiveness of probiotic, prebiotic, and synbiotic therapies in reducing postoperative complications: A systematic review and network meta-analysis. Clinical Infectious Diseases, 64, S153–S160.Find this resource:

Kazemi, A., Noorbala, A. A., Azam, K., Eskandari, M. H., & Djafarian, K. (2019). Effect of probiotic and prebiotic vs placebo on psychological outcomes in patients with major depressive disorder: A randomized clinical trial. Clinical Nutrition, 38(2), 522–528.Find this resource:

Kigerl, K. A., Hall, J. C., Wang, L., Mo, X., Yu, Z., & Popovich, P. G. (2016). Gut dysbiosis impairs recovery after spinal cord injury. Journal of Experimental Medicine, 213, 2603–2620.Find this resource:

Kim, M. S., Park, E. J., Roh, S. W., & Bae, J. W. (2011). Diversity and abundance of single-stranded DNA viruses in human feces. Applied and Environmental Microbiology, 77, 8062–8070.Find this resource:

Kobyliak, N., Abenavoli, L., Mykhalchyshyn, G., Kononenko, L., Boccuto, L., Kyriienko, D., & Dynnyk, O. (2018). A multi-strain probiotic reduces the fatty liver index, cytokines and aminotransferase levels in NAFLD patients: Evidence from a randomized clinical trial. Journal of Gastrointestinal and Liver Diseases, 27, 41–49.Find this resource:

Kopp, M. A., Watzlawick, R., Martus, P., Failli, V., Finkenstaedt, F. W., Chen, Y., . . . Schwab, J. M. (2017). Long-term functional outcome in patients with acquired infections after acute spinal cord injury. Neurology, 88, 892–900.Find this resource:

Kornblith, L. Z., Kutcher, M. E., Callcut, R. A., Redick, B. J., Hu, C. K., Cogbill, T. H., . . . Group, W. T. A. S. (2013). Mechanical ventilation weaning and extubation after spinal cord injury: A Western Trauma Association multicenter study. Journal of Acute Trauma and Acute Care Surgery, 75, 1060–1069; discussion 1069–1070.Find this resource:

Krych, L., Hansen, C. H., Hansen, A. K., van den Berg, F. W., & Nielsen, D. S. (2013). Quantitatively different, yet qualitatively alike: A meta-analysis of the mouse core gut microbiome with a view towards the human gut microbiome. PLoS One, 8, e62578.Find this resource:

Kwon, H. K., Kim, G. C., Kim, Y., Hwang, W., Jash, A., Sahoo, A., . . . Im, S. H. (2013). Amelioration of experimental autoimmune encephalomyelitis by probiotic mixture is mediated by a shift in T helper cell immune response. Clinical Immunology, 146, 217–227.Find this resource:

Lach, G., Schellekens, H., Dinan, T. G., & Cryan, J. F. (2018). Anxiety, depression, and the microbiome: A role for gut peptides. Neurotherapeutics, 15, 36–59.Find this resource:

Lavasani, S., Dzhambazov, B., Nouri, M., Fåk, F., Buske, S., Molin, G., . . .Weström, B. (2010). A novel probiotic mixture exerts a therapeutic effect on experimental autoimmune encephalomyelitis mediated by IL-10 producing regulatory T cells. PLoS One, 5, e9009.Find this resource:

Lavekar, A. S., Raje, D. V., Manohar, T., & Lavekar, A. A. (2017). Role of probiotics in the treatment of nonalcoholic fatty liver disease: A meta-analysis. Euroasian Journal of Hepatogastroenterology, 7, 130–137.Find this resource:

Lee, B. B., Toh, S. L., Ryan, S., Simpson, J. M., Clezy, K., Bossa, L., . . . Kotsiou, G. (2016). Probiotics [LGG-BB12 or RC14-GR1] versus placebo as prophylaxis for urinary tract infection in persons with spinal cord injury [ProSCIUTTU]: A study protocol for a randomised controlled trial. BMC Urology, 16, 18.Find this resource:

Levatte, M. A., Mabon, P. J., Weaver, L. C., & Dekaban, G. A. (1998). Simultaneous identification of two populations of sympathetic preganglionic neurons using recombinant herpes simplex virus type 1 expressing different reporter genes. Neuroscience, 82, 1253–1267.Find this resource:

Ley, R. E., Turnbaugh, P. J., Klein, S., & Gordon, J. I. (2006). Microbial ecology: Human gut microbes associated with obesity. Nature, 444, 1022–1023.Find this resource:

Liu, J., An, H., Jiang, D., Huang, W., Zou, H., Meng, C., & Li, H. (2004). Study of bacterial translocation from gut after paraplegia caused by spinal cord injury in rats. Spine, 29, 164–169.Find this resource:

Lucin, K. M., Sanders, V. M., Jones, T. B., Malarkey, W. B., & Popovich, P. G. (2007). Impaired antibody synthesis after spinal cord injury is level dependent and is due to sympathetic nervous system dysregulation. Experimental Neurology, 207, 75–84.Find this resource:

Lucin, K. M., Sanders, V. M., & Popovich, P. G. (2009). Stress hormones collaborate to induce lymphocyte apoptosis after high level spinal cord injury. Journal of Neurochemistry, 110, 1409–1421.Find this resource:

Mabon, P. J., LeVatte, M. A., Dekaban, G. A., & Weaver, L. C. (1997). Identification of sympathetic preganglionic neurons controlling the small intestine in hamsters using a recombinant herpes simplex virus type-1. Brain Research, 753, 245–250.Find this resource:

MacFie, J. (2004). Current status of bacterial translocation as a cause of surgical sepsis. British Medical Bulletin, 71, 1–11.Find this resource:

Macpherson, A. J., & Smith, K. (2006). Mesenteric lymph nodes at the center of immune anatomy. Journal of Experimental Medicine, 203, 497–500.Find this resource:

Magnotti, L. J., & Deitch, E. A. (2005). Burns, bacterial translocation, gut barrier function, and failure. Journal of Burn Care & Rehabilitation, 26, 383–391.Find this resource:

Manns, P. J., McCubbin, J. A., & Williams, D. P. (2005). Fitness, inflammation, and the metabolic syndrome in men with paraplegia. Archives of Physical Medicine and Rehabilitation, 86, 1176–1181.Find this resource:

Manzanares, W., Lemieux, M., Langlois, P. L., & Wischmeyer, P. E. (2016). Probiotic and synbiotic therapy in critical illness: A systematic review and meta-analysis. Critical Care, 19, 262.Find this resource:

Maruyama, Y., Mizuguchi, M., Yaginuma, T., Kusaka, M., Yoshida, H., Yokoyama, K., . . . Hosoya, T. (2008). Serum leptin, abdominal obesity and the metabolic syndrome in individuals with chronic spinal cord injury. Spinal Cord, 46, 494–499.Find this resource:

Mignini, F., Streccioni, V., & Amenta, F. (2003). Autonomic innervation of immune organs and neuroimmune modulation. Autonomic and Autacoid Pharmacology, 23, 1–25.Find this resource:

Molloy, M. J., Bouladoux, N., & Belkaid, Y. (2012). Intestinal microbiota: Shaping local and systemic immune responses. Seminars in Immunology, 24, 58–66.Find this resource:

Morrow, L. E., Gogineni, V., & Malesker, M. A. (2012). Probiotic, prebiotic, and synbiotic use in critically ill patients. Current Opinion in Critical Care, 18, 186–191.Find this resource:

Morrow, L. E., Kollef, M. H., & Casale, T. B. (2010). Probiotic prophylaxis of ventilator-associated pneumonia: A blinded, randomized, controlled trial. American Journal of Respiratory and Critical Care Medicine, 182, 1058–1064.Find this resource:

Nelson, M. D., Widman, L. M., Abresch, R. T., Stanhope, K., Havel, P. J., Styne, D. M., & McDonald, C. M. (2007). Metabolic syndrome in adolescents with spinal cord dysfunction. Journal of Spinal Cord Medicine, 30(Suppl. 1), S127–139.Find this resource:

Nicholson, J. K., Holmes, E., Kinross, J., Burcelin, R., Gibson, G., Jia, W., & Pettersson, S. (2012). Host-gut microbiota metabolic interactions. Science, 336, 1262–1267.Find this resource:

O’Connor, G., Jeffrey, E., Madorma, D., Marcillo, A., Abreu, M. T., Deo, S. K., . . . Daunert, S. (2018). Investigation of microbiota alterations and intestinal inflammation post-spinal cord injury in rat model. Journal of Neurotrauma.Find this resource:

Ochoa-Repáraz, J., Mielcarz, D. W., Begum-Haque, S., & Kasper, L. H. (2011). Gut, bugs, and brain: Role of commensal bacteria in the control of central nervous system disease. Annals of Neurology, 69, 240–247.Find this resource:

Perry, R. J., Samuel, V. T., Petersen, K. F., & Shulman, G. I. (2014). The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature, 510, 84–91.Find this resource:

Pinto-Sanchez, M. I., Hall, G. B., Ghajar, K., Nardelli, A., Bolino, C., Lau, J. T., . . . Bercik, P. (2017). Probiotic Bifidobacterium longum NCC3001 reduces depression scores and alters brain activity: A pilot study in patients with irritable bowel syndrome. Gastroenterology, 153, 448–459.e448.Find this resource:

Prüss, H., Tedeschi, A., Thiriot, A., Lynch, L., Loughhead, S. M., Stutte, S., . . . Schwab, J. M. (2017). Spinal cord injury-induced immunodeficiency is mediated by a sympathetic-neuroendocrine adrenal reflex. Nature Neuroscience, 20, 1549–1559.Find this resource:

Qualls-Creekmore, E., Tong, M., & Holmes, G. M. (2010). Time-course of recovery of gastric emptying and motility in rats with experimental spinal cord injury. Neurogastroenterology & Motility, 22, 62–69, e27–68.Find this resource:

Reyes, A., Haynes, M., Hanson, N., Angly, F. E., Heath, A. C., Rohwer, F., & Gordon, J. I. (2010). Viruses in the faecal microbiota of monozygotic twins and their mothers. Nature, 466, 334–338.Find this resource:

Reyes, A., Semenkovich, N. P., Whiteson, K., Rohwer, F., & Gordon, J. I. (2012). Going viral: Next-generation sequencing applied to phage populations in the human gut. Nature Reviews Microbiology, 10, 607–617.Find this resource:

Riegger, T., Conrad, S., Liu, K., Schluesener, H. J., Adibzahdeh, M., & Schwab, J. M. (2007). Spinal cord injury-induced immune depression syndrome (SCI-IDS). European Journal of Neuroscience, 25, 1743–1747.Find this resource:

Riegger, T., Conrad, S., Schluesener, H. J., Kaps, H. P., Badke, A., Baron, C., . . . Schwab, J. M. (2009). Immune depression syndrome following human spinal cord injury (SCI): A pilot study. Neuroscience, 158, 1194–1199.Find this resource:

Rothhammer, V., Mascanfroni, I. D., Bunse, L., Takenaka, M. C., Kenison, J. E., Mayo, L., . . . Quintana, F. J. (2016). Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nature Medicine, 22, 586–597.Find this resource:

Round, J. L., & Mazmanian, S. K. (2009). The gut microbiota shapes intestinal immune responses during health and disease. Nature Reviews Immunology, 9, 313–323.Find this resource:

Saltzman, E. T., Palacios, T., Thomsen, M., & Vitetta, L. (2018). Intestinal microbiome shifts, dysbiosis, inflammation, and non-alcoholic fatty liver disease. Frontiers in Microbiology, 9, 61.Find this resource:

Sauerbeck, A. D., Laws, J. L., Bandaru, V. V., Popovich, P. G., Haughey, N. J., & McTigue, D. M. (2015). Spinal cord injury causes chronic liver pathology in rats. Journal of Neurotrauma, 32, 159–169.Find this resource:

Sawas, T., Al Halabi, S., Hernaez, R., Carey, W. D., & Cho, W. K. (2015). Patients receiving prebiotics and probiotics before liver transplantation develop fewer infections than controls: A systematic review and meta-analysis. Clinical Gastroenterology and Hepatology, 13, 1567–1574.e1563; quiz e1143–1564.Find this resource:

Sender, R., Fuchs, S., & Milo, R. (2016). Revised estimates for the number of human and bacteria cells in the body. PLoS Biology,14, e1002533.Find this resource:

Shi, C., Jia, T., Mendez-Ferrer, S., Hohl, T. M., Serbina, N. V., Lipuma, L., Leiner, I., Li, . . . Pamer, E. G. (2011). Bone marrow mesenchymal stem and progenitor cells induce monocyte emigration in response to circulating toll-like receptor ligands. Immunity, 34, 590–601.Find this resource:

Slykerman, R. F., Hood, F., Wickens, K., Thompson, J. M. D., Barthow, C., Murphy, R., . . . Group, P.i . P. S. (2017). Effect of Lactobacillus rhamnosus HN001 in pregnancy on postpartum symptoms of depression and anxiety: A randomised double-blind placebo-controlled trial. EBioMedicine, 24, 159–165.Find this resource:

Sudo, N., Chida, Y., Aiba, Y., Sonoda, J., Oyama, N., Yu, X. N., . . . Koga, Y. (2004). Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. Journal of Physiology, 558, 263–275.Find this resource:

Tate, D. G., Forchheimer, M., Rodriguez, G., Chiodo, A., Cameron, A. P., Meade, M., & Krassioukov, A. (2016). Risk factors associated with neurogenic bowel complications and dysfunction in spinal cord injury. Archives of Physical Medicine and Rehabilitation, 97, 1679–1686.Find this resource:

Thion, M. S., Low, D., Silvin, A., Chen, J., Grisel, P., Schulte-Schrepping, J., . . . Garel, S. (2018). Microbiome influences prenatal and adult microglia in a sex-specific manner. Cell, 172, 500–516.e516.Find this resource:

Tilg, H., & Kaser, A. (2011). Gut microbiome, obesity, and metabolic dysfunction. Journal of Clinical Investigation, 121, 2126–2132.Find this resource:

Tilg, H., & Moschen, A. R. (2010). Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis. Hepatology, 52, 1836–1846.Find this resource:

Tillisch, K. (2014). The effects of gut microbiota on CNS function in humans. Gut Microbes, 5.Find this resource:

Toh, S. L., Boswell-Ruys, C. L., Lee, B. S. B., Simpson, J. M., & Clezy, K. R. (2017). Probiotics for preventing urinary tract infection in people with neuropathic bladder. Cochrane Database of Systematic Reviews, 9, CD010723.Find this resource:

Turnbaugh, P. J., Bäckhed, F., Fulton, L., & Gordon, J. I. (2008). Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host & Microbe, 3, 213–223.Find this resource:

Turnbaugh, P. J., & Gordon, J. I. (2009). The core gut microbiome, energy balance and obesity. Journal of Physiology, 587, 4153–4158.Find this resource:

Turnbaugh, P. J., Ley, R. E., Mahowald, M. A., Magrini, V., Mardis, E. R., & Gordon, J. I. (2006). An obesity-associated gut microbiome with increased capacity for energy harvest. Nature, 444, 1027–1031.Find this resource:

Ueno, M., Ueno-Nakamura, Y., Niehaus, J., Popovich, P. G., & Yoshida, Y. (2016). Silencing spinal interneurons inhibits immune suppressive autonomic reflexes caused by spinal cord injury. Nature Neuroscience, 19, 784–787.Find this resource:

Wallace, C. J. K., & Milev, R. (2017). The effects of probiotics on depressive symptoms in humans: A systematic review. Annals of General Psychiatry, 16, 14.Find this resource:

Wang, Y., & Kasper, L. H. (2014). The role of microbiome in central nervous system disorders. Brain, Behavior, and Immunity, 38, 1–12.Find this resource:

Wikoff, W. R., Anfora, A. T., Liu, J., Schultz, P. G., Lesley, S. A., Peters, E. C., Siuzdak, G. (2009). Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proceedings of the National Academy of Sciences of the United States of America, 106, 3698–3703.Find this resource:

Wu, H. J., Ivanov, I. I., Darce, J., Hattori, K., Shima, T., Umesaki, Y., . . . Mathis, D. (2010). Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity, 32, 815–827.Find this resource:

Yano, J. M., Yu, K., Donaldson, G. P., Shastri, G. G., Ann, P., Ma, L., . . . Hsiao, E. Y. (2015). Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell, 161, 264–276.Find this resource:

Zhang, Y., Guan, Z., Reader, B., Shawler, T., Mandrekar-Colucci, S., Huang, K., . . . Popovich, P. G. (2013). Autonomic dysreflexia causes chronic immune suppression after spinal cord injury. Journal of Neuroscience, 33, 12970–12981.Find this resource: