But Are CNS Therapies Targeting the Microbiome Commercially Doomed from the Start?
Our previous blog outlined the influence of the gut microbiome on multiple sclerosis, an autoimmune disease of the central nervous system (CNS). While an effect of the gut bacterial composition on a CNS disease is counterintuitive, the microbiome has been implicated in multiple autoimmune disorders such as Crohn’s or Type 1 diabetes. Here we cover three disparate CNS disorders that are not autoimmune in nature, and yet the gut microbiome also appears to influence their pathophysiology: Parkinson’s Disease (PD), Alzheimer’s Disease (AD), and Autism Spectrum Disorders (ASD).
While no typical microbiome profile appears to be a marker of these disorders, patients’ microbiome compositions are altered (i.e., dysbiosis) compared with healthy individuals. The gut microbiome acts via the gut-brain axis, comprised of three “pathways”:
- Neuronal connection: The vagus nerve connects the lower brainstem with the enteric nervous system (ENS). The ENS controls gut motility and is the largest neuronal system in the peripheral nervous system, earning it the title of “Second Brain.”
- Immune connection: The microbiome influences lymphocytes circulating in and around the intestine and its lumen, which can then mediate pro- or anti-inflammatory signals across the body and across the blood-brain barrier (BBB) into the brain.
- Neuroendocrine connection: Hormones or neuropeptides acting via the hypothalamic-pituitary-adrenal (HPA) axis can affect the gut and, conversely, neuroendocrine signals produced by the gut can affect the CNS (for instance 95% of blood serotonin is produced by colonic enterochromaffin cells in the gut). Similarly, gut bacteria can secrete metabolites (e.g., tryptophan metabolites) that act as neuroendocrine signals to the ENS and CNS (i.e., tryptophan is a precursor to serotonin).
The microbiome also appears to play a role in neural development by affecting microglia, a cell type which supports patterning and wiring of the developing brain (Shigemoto-Mogani Y, 2014). Microglia are macrophage-like cells in the CNS, and much like the microbiome affects the peripheral immune system, evidence exists that the microbiome affects microglia. Indeed, microglia morphology, density, and maturity are altered in GF mice (Erny D, 2015). Changes in microglial activity due to dysbiosis could cause neurological and behavioral outcomes seen in disorders where neuronal development seems implicated, such as autism and schizophrenia. Epidemiological observations support these connections: the use of antibiotics in pregnancy or infection in the second or third trimesters of pregnancy are potential risks for ASD.
#1 Parkinson’s Disease
One of the earliest signs of PD is GI symptoms, particularly constipation but also inflammatory bowel-like symptoms; these symptoms appear over 15 years, on average, before the onset of motor symptoms (Fasano A., 2015; Mertsalmi T., 2017). Interestingly, the accumulation of α-synuclein into Lewy bodies, the hallmark of PD, begins in the ENS and the vagus nerve before progressing to the CNS (Shannon K, 2012; Holmqvist S, 2014). Multiple lines of evidence suggest that α-synuclein acts like a prion, able to transmit between different neurons, causing the characteristic patterns of Lewy body deposits in PD (Goedert M., 2017). Because Lewy bodies are also found early on in olfactory neurons, one theory holds that environmental factors such as pollutants precipitate the aggregation of α-synuclein in the gut and olfactory neurons, which are in most direct contact with the pollutant through ingestion and respiration.
The microbiome composition of PD patients is different from that of normal individuals. Levels of pro-inflammatory cytokines are increased in colon biopsies of PD patients and these levels increase with disease duration (Devos D., 2013). Similarly, the levels of some bacteria, such as Enterobacteriaceae, are positively correlated with disease severity of postural instability and gait symptoms (Scheperjans F., 2015), suggesting that metabolites from these bacteria influence the development of PD symptoms. In support of this theory, the systemic application of the bacterial toxin lipopolysaccharide (LPS) secreted by E. coli leads to the expression of α-synuclein in the large intestines of mice (Forsyth C., 2011).
In an elegant series of experiments, Sampson and colleagues demonstrated that the gut microbiome is necessary to induce α-synuclein aggregation, neural inflammation, and motor deficits in mice overexpressing α-synuclein (Sampson T., 2016). The group looked at α-synuclein pathology in mice raised under germ-free (GF) conditions and in specific pathogen free (SPF) mice (with a microbiome known to be free of specific pathogens). SPF mice displayed progressive motor decline much earlier, were more constipated, and had higher levels of pro-inflammatory cytokines (TNF-α and IL-6), increased microglial activation, and neuroinflammation compared with GF mice. SPF mouse brains also had greater levels of α-synuclein aggregates than GF mice. Remarkably, SPF mice treated with antibiotics displayed less α-synuclein pathology than untreated SPF mice. Finally, GF mice inoculated with the microbiomes of PD patients showed worse α-synuclein pathology, neuroinflammation, and motor decline than GF mice transplanted with the microbiomes of healthy individuals.
Seven clinical trials are recruiting or plan to recruit patients to assess the role of the microbiome in PD. One large-scale study (n=836 patients) will assess the microbiomes of patients with impaired REMS sleep behavioral disorder, a sleep disorder believed to be an early symptom of PD (NCT03645226). The study will also enroll patients’ first order relatives, in the event these individuals also progress to PD.
#2 Alzheimer’s Disease
Changes in microbiome composition toward a more pro-inflammatory profile are also seen in AD patients compared with healthy age-matched individuals and several observations implicate the microbiome in AD. Vogt and colleagues documented a positive correlation between increases in certain bacteria in AD patients’ microbiota and increased levels of AD biomarkers in their cerebrospinal fluid. (Vogt N., 2017). Moreover, upon treatment with antibiotics, a mouse model of AD showed less amyloid plaque deposition than untreated controls (Minter M., 2016). Finally, transgenic mouse models of AD raised under GF conditions have shown reduced levels of amyloid β in their brain and blood (Harach T., 2017).
Metabolites secreted by gut bacteria are also implicated in the pathology of AD, although direct causality is lacking. For instance, certain gut bacteria can generate amyloids and LPS can promote the formation of additional amyloid peptides in vitro (Astl A., 2017) and in mouse models of AD (Sheng J, 2003).
Changes in the microbiome of AD patients have also been associated with an increase in the permeability of the gut wall compared to age-matched individuals, similar to observations in multiple sclerosis. One theory on the cause of the disease suggests that the production of bacterial metabolites by a modified gut microbiome in AD patients leads to the generation of Aβ42 peptides, which enter the bloodstream and pass into the CNS. Once in the CNS, amyloids can promote microglial activation and prolonged neuroinflammation, a hallmark of AD.
Only three clinical trials are recruiting or about to recruit patients to evaluate the role of the microbiome in AD, one assessing microbiome composition in AD patients (NCT03487380) and two evaluating the effect of diet and exercise on AD patients (NCT03117829 and NCT03593941).
#3 Autism Spectrum Disorders
Changes in the microbiome composition of bacteria and yeast, as well as GI symptoms, are observed in ASD patients compared with healthy individuals. 23-70% of children with ASD suffer from GI symptoms, up to 85% have constipation and the severity of GI symptoms correlates with the severity of ASD (Gorrindo P., 2012). Moreover, treatment of ASD patients with antibiotics transiently improves not only GI symptoms but also cognitive and behavioral symptoms (e.g., repetitive behaviors).
Like other diseases in which the microbiome composition is shifted, ASD patients show evidence of increased intestinal permeability, suggesting that bacterial metabolites and toxins could leak into the bloodstream, leading to behavioral and cognitive symptoms. Indeed, levels of LPS are elevated in the bloodstream of ASD patients and their levels are correlated with more impaired social and behavioral symptoms (Emanuele E., 2010). Similarly, levels of propionic acid, a metabolite from intestinal bacteria, are elevated in autistic patients compared with healthy controls (Wang L., 2012), and propionic acid can induce autistic-like behaviors when injected into ventricles of rodents (MacFabe D., 2007). Moreover, in a mouse model of ASD, treating mice with probiotics known to improve gut barrier permeability alters their microbiota to one closer to that of normal mice. In addition, antibiotic treatment improved communication, motor, and anxiety symptoms, similar to the changes seen in ASD patients treated with antibiotics.
Seven clinical trials are listed as “ongoing”, “recruiting”, or “completed” on clinicaltrials.gov, more than in AD or PD. Small studies manipulating the microbiome in ASD patients using probiotics, prebiotic, fecal microbiota transplantation, and diet appear promising in that patients’ microbiota normalizes and behavioral symptoms improve in ASD patients and in mouse models, however, these preliminary results must be confirmed in larger studies. Nutraceutical products such as the short chain fatty acid butyric acid are marketed as nutritional supplements for ASD patients, but they are currently not approved for the treatment of ASD.
Prospects for Therapeutic Interventions
Studies evaluating the effect of the microbiome in CNS disorders are still small and observational, however many provide early evidence that altering the gut microbiome may have beneficial outcomes. The sudden broadening of focus in pathophysiological research in each of these indications to include the microbiome, the immune system, neuroinflammation, and gut communication via bacterial metabolites is exciting and intriguing. Much more work remains to better define the role of the microbiome in these CNS indications, and therapeutic trials remain several years away.
Altering the microbiome in neurodegenerative disorders such as PD and AD may be easier to address than disorders with a neural development component such as ASD because interventions can directly target the patient’s microbiome rather than maternal-fetal microbiomes. Nevertheless, the apparent safety of microbiome interventions bodes well for therapeutic applications in both neurodegenerative and neurodevelopmental disorders.
Unmet need in PD, AD, and ASD remains high since no therapies currently available address their underlying causes, but the likelihood that that microbiome-targeting therapies can make meaningful gains against this unmet need is equally unknown. What’s more, the framing of therapies targeting the microbiome as “nutritional supplements” carries the risk of undercutting progress in this promising avenue of research should developers— fearing narrow commercial and pricing prospects for novel microbiome-targeted drugs perceived as nutraceuticals by payer authorities—forgo investment in large-scale trials necessary for regulatory approval.
Our next blog will focus on the influence of the microbiome on a highly prevalent psychiatric disorder: depression.
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