Microbiota imprint gut–intrinsic neuronal programming and sympathetic activity

Abstract

P.A.M.), mucida@rockefeller.edu (D.M.) 15 16 Gut-brain connections monitor the intestinal tissue and its microbial and dietary content 1 , 17 regulating both intestinal physiological functions such as nutrient absorption and motility 2-4 , and 18 brain-wired feeding behaviour 3 . It is therefore plausible that circuits exist to detect gut microbes 19 and relay this information to central nervous system (CNS) areas that, in turn, regulate gut 20 physiology 5 . We characterized the influence of the microbiota on enteric-associated neurons (EAN) 21 by combining gnotobiotic mouse models with transcriptomics, circuit-tracing methods, and 22 functional manipulation. We found that the gut microbiome modulates gut-extrinsic sympathetic 23 neurons; while microbiota depletion led to increased cFos expression, colonization of germ-free 24 mice with short-chain fatty acid-producing bacteria suppressed cFos expression in the gut 25 sympathetic ganglia. Chemogenetic manipulations, translational profiling, and anterograde tracing 26 identified a subset of distal intestine-projecting vagal neurons positioned to play an afferent role in 27 microbiota-mediated modulation of gut sympathetic neurons. Retrograde polysynaptic neuronal 28 tracing from the intestinal wall identified brainstem sensory nuclei activated during microbial 29 depletion, as well as efferent sympathetic premotor glutamatergic neurons that regulate 30 gastrointestinal transit. These results reveal microbiota-dependent control of gut extrinsic 31 sympathetic activation through a gut-brain circuit. 33Extrinsic enteric-associated neurons (eEAN), comprised of sensory afferents, parasympathetic and

Adrenergic signaling in muscularis macrophages limits neuronal death following enteric infection

“…To address this question interbred a pan-neuronal Cre reporter mouse, Snap25 Cre , with Rpl22 lsl-HA (RiboTag) mice (Sanz et al, 2009), which express a hemagglutinin (HA)-tagged ribosomal subunit 22. Immunofluorescence (IF) analysis of HA+ cells in the myenteric plexus confirmed the significant loss of iEANs as initially determined by ANNA-1 staining (Figure 2A, Figure S2A) (Muller et al, 2019). It has been reported that in cases of overt intestinal inflammation, such as colitis, there is indiscriminate loss of iEANs (Mawe, 2015).…”

“…To gain insights into a possible mechanism involved in infection-induced iEAN cell death, we used neuronal-specific cell-sorting independent translating ribosomal affinity purification (TRAP) (Heiman et al, 2014;Muller et al, 2019). We compared iEANs with extrinsic neurons in the nodose ganglia using Snap25 RiboTag mice, which allow neuronal-specific immunoprecipitation of actively translated mRNA.…”

“…The source of catecholamines may be context dependent: enteric infections, including Salmonella, may result in the activation of extrinsic sympathetic neurons located in the celiac-superior mesenteric ganglion (Gabanyi et al, 2016); under conditions of systemic stress these signals could originate from the adrenal glands, a possibility also supported by our findings. Both of these pathways nevertheless require neural input, although the circuitry connecting luminal sensing to eEAN activation (and a possible involvement of the CNS), and how luminal stimulations can regulate it, remain to be determined (Muller et al, 2019;Pruss et al, 2017). Current literature suggests that the epithelium layer works as a primary site of sensory integration.…”

Neuro-Immune Circuits Regulate Immune Responses in Tissues and Organ Homeostasis

“…This interaction builds the basis of a neuro-epithelial circuit to the CNS that senses gut stimuli via glutamate as the main neurotransmitter (45). However, this finding is controversial because another study did not observe direct neuronal contact with epithelial cells (46). Thus, further experiments need to clarify the exact interaction between sensory neurons and epithelial cells.…”

“…The microbiota inhabit all mammalian body surfaces and play a pivotal role in the education of the host immune system (68). Recent evidence now suggests that the presence of commensal microbiota also shape the neuronal gene programs and eventually the extrinsic sympathetic activity (46,69). Muller and colleagues proposed that the commensal microbiota shape intrinsic enteric-associated neuronal programs (EAN) region-dependent along the intestine, whereas intrinsic EAN are functionally adapted to the specific intestinal region and its associated microbial challenge.…”