Bacterial Signaling to the Nervous System through Toxins and Metabolites

Abstract

Mammalian hosts interface intimately with commensal and pathogenic bacteria. It is increasingly clear that molecular interactions between the nervous system and microbes contribute to health and disease. Both commensal and pathogenic bacteria are capable of producing molecules that act on neurons and affect essential aspects of host physiology. Here we highlight several classes of physiologically important molecular interactions that occur between bacteria and the nervous system. First, clostridial neurotoxins block neurotransmission to or from neurons by targeting the SNARE complex, causing the characteristic paralyses of botulism and tetanus during bacterial infection. Second, peripheral sensory neurons-olfactory chemosensory neurons and nociceptor sensory neurons-detect bacterial toxins, formyl peptides, and lipopolysaccharides through distinct molecular mechanisms to elicit smell and pain. Bacteria also damage the central nervous system through toxins that target the brain during infection. Finally, the gut microbiota produces molecules that act on enteric neurons to influence gastrointestinal motility, and metabolites that stimulate the "gut-brain axis" to alter neural circuits, autonomic function, and higher-order brain function and behavior. Furthering the mechanistic and molecular understanding of how bacteria affect the nervous system may uncover potential strategies for modulating neural function and treating neurological diseases.

Keywords: bacteria; gut–brain axis; microbiota; neurons; toxins.

Figure 1. Bacterial blockade of neurotransmission by clostridial neurotoxins

Botulinum neurotoxins (BoNTs) from Clostridium botulinum enter synaptic vesicles by binding to membrane polysialogangliosides (PSGs) and to a proteinaceous receptor such as the synaptic vesicle protein SV2 or synaptotagmin. Acidification of the vesicles triggers a conformational change allowing the heavy chain of BoNT to translocate its light chain into the cytoplasm. The BoNT light chains are metalloproteases that cleave components of the SNARE complex. Tetanus neurotoxin (TeNT) from Clostridium tetani binds to PSGs and nidogens in peripheral nerve terminals to enter an endocytic vesicle, which subsequently undergoes axonal retrograde transport. TeNT is then transcytosed to inhibitory interneurons in the spinal cord, where the TeNT light chain enters the cytoplasm and cleaves VAMP to block neurotransmission.

Figure 2. Bacterial modulation of the sensory nervous system

(a) Caenorhabditis elegans olfactory neurons detect bacterial metabolites, autoinducers and surfactants through G-protein coupled receptors to mediate bacterial foraging behavior and avoid bacterial pathogens. Mammalian vomeronasal olfactory sensory neurons express formyl peptide receptors (Fpr-rs1, Fpr-rs3, Fpr-rs4, Fpr-rs6 and Fpr-rs7), which allow them to detect bacterial N-formyl peptides. (b) Mammalian nociceptor sensory neurons detect distinct bacterial ligands to elicit or silence pain. N-formyl peptides activate nociceptor-expressed FPR1 to produce pain. Staphylococcus aureus α-hemolysin perforates the neuronal cell membrane to cause ionic influx and pain. Mycobacterium ulcerans mycolactone activates the angiotensin II receptor (AT₂R) to silence pain through inducing hyperpolarization. Somatosensory neurons also detect LPS through TLR4 and TRPA1, bacterial flagellins through TLR5, and CpG motifs in bacterial DNA through TLR9.

Figure 3. Gut bacterial modulation of the nervous system

Bacterial metabolites and structural components produced in the gut lumen may act on neurons directly after crossing the epithelial barrier, or stimulate enterochromaffin cells (ECs) to secrete neuroactive compounds such as serotonin. Within the gut lumen, bacteria can signal to the enteric nervous system (ENS) to regulate gut motility. The ENS forms a complete sensori-motor reflex composed of intrinsic primary afferent neurons (IPANs), interneurons and motor neurons. Beyond the gut, bacteria also signal to the brain through extrinsic afferent nerve fibers, or through secreted molecules that enter the circulation and reach the CNS. This gut microbe-neuron signaling is part of the “gut-brain-axis”. Extrinsic sensory nerves include vagal afferents that project from the gut to the brainstem, and spinal afferents that project from the gut to the spinal cord. Bacterial inputs affect how the central nervous system (CNS) regulates homeostatic functions such as metabolism and appetite, or higher order brain functions such as anxiety and social behavior.