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.
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).
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).
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).
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).
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).
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).
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.
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