Abstract The gut microbiota and immune system maintain intestinal homeostasis and regulate gut physiology in concert with the enteric nervous system (ENS). However, the underlying mechanisms remain incompletely understood. Using wildtype and T-cell deficient germ-free mice colonized with segmented filamentous bacteria (SFB) or specific pathogen-free (SPF) microbiota, we studied immune regulation of the ENS and intestinal motility. Colonization markedly increased Th17 cells and Treg expressing RORγ + T cells in both the ileum and colon of wildtype mice. T cells were necessary for the normalization of intestinal motility after colonization by SPF microbiota, and for SFB to restore neuronal density in the ENS of the ileum of germ-free mice. T cells were also required for neurogenic responses in myenteric neurons of the ileum, but not the colon, and for regulating the levels of nestin expression. The cytokines IL-1β and IL-17A mediate the enteric neurogenic response to an SPF microbiota but were not involved in the regulation of intestinal motility. Together, our findings provide new insights into the microbiota-neuroimmune dialogue that regulates intestinal physiology. 

pdf/t-cells-regulate-intestinal-motility-and-shape-enteric-y8brozv9jz.pdf

T cells regulate intestinal motility and shape enteric neuronal responses to intestinal microbiota.

ABSTRACT Stool consistency explains a large proportion of inter-individual variation in gut microbiota and represents a useful measure of gut transit time, which is pivotal for bacterial metabolism and vice versa . However, in infants and small children, a detailed understanding of how gut microbiota and the metabolome associate with stool consistency is lacking. We analyzed both stool microbiota and metabolome of 2.5 (n=360), 6 (n=229), 14 (n=274), and 30-month-old children (n=169) from the FinnBrain Birth Cohort Study using 16s rRNA sequencing and mass spectrometry-based targeted techniques. We used stool water content and parent-reported stool consistency as proxies for stool consistency. We found that microbiota community composition as well as the relative abundance of specific genera such as Clostridium , Hungatella , and Lactobacillus were associated with stool consistency. Of the metabolites, lower concentrations of conjugated bile acids and acetic acid were associated with having constipation and lower water content. Branched short-chain fatty acid concentrations were negatively associated with stool water content. The findings reflect a shift in bacterial saccharolytic to proteolytic metabolism in the gut. Parental crude reports agreed with the objective measure of child stool consistency, and associated with similar features in the stool metabolome. Overall, our findings support the concept that stool consistency and total water content associate with gut microbiota composition and metabolic activity in infants and young children. 

pdf/fecal-microbiota-and-metabolite-composition-associates-with-374pic02o2.pdf

Fecal microbiota and metabolite composition associates with stool consistency in young children

The therapeutic benefits of opioids are compromised by the development of analgesic tolerance, which necessitates higher dosing for pain management thereby increasing the liability for dependence and addiction. Rodent models indicate opposing roles of the gut microbiota in tolerance: morphine-induced gut dysbiosis exacerbates tolerance, whereas probiotics ameliorate tolerance. Not all individuals develop tolerance which could be influenced by differences in microbiota, and yet no study has capitalized upon this natural variation to identify specific features linked to tolerance. We leveraged this natural variation in a murine model of voluntary oral morphine self-administration to elucidate the mechanisms by which microbiota influences tolerance. Although all mice shared similar and predictive morphine-driven microbiota changes that largely masked informative associations with variability in tolerance, our high-resolution temporal analyses revealed a divergence in the progression of dysbiosis that best explained differences in the development in tolerance. Mice that did not develop tolerance also maintained a higher abundance of taxa capable of producing the short-chain fatty acid (SCFA) butyrate, known to bolster intestinal barriers, suppress inflammation, and promote neuronal homeostasis. Furthermore, dietary butyrate supplementation significantly reduced the development of tolerance. These findings could inform immediate therapies to extend the analgesic efficacy of opioids.

Gut dysbiosis was inevitable, but tolerance was not: temporal responses of the murine microbiota that maintain its capacity for butyrate production correlate with sustained antinociception to chronic voluntary morphine

New insights in the gut–brain axis: the role of bioelectrical microbiome

Enteric neurons are essential regulators of intestinal physiology, yet their responses to varying microbial and immune environments along the intestinal tract and or during challenges remain poorly understood. In this study, we regionally profiled enteric neurons across gnotobiotic, allergic, and parasite-infected mice. Timing and complexity of microbial perturbations and type 2 inflammation result in motor neuron state shifts and alter multiple functionally distinct sensory neurons, including interleukin-13– and leukotriene-responsive Nmu -hi cells and Grp -hi neurons, which expand in germ-free colonic tissue and interact with Grpr + interstitial cells of Cajal. Leveraging adeno-associated virus–based Perturb-seq, we identified Edf1 and Mitf as controllers of motor neuron state transition and gastrointestinal transit time, directly linking enteric neuron states to physiology. 

Regional encoding of enteric nervous system responses to microbiota and type 2 inflammation

Peripheral Neuronal Activation Shapes the Microbiome and Alters Gut Physiology

The gastrointestinal (GI) tract is innervated by intrinsic neurons of the enteric nervous system (ENS) and extrinsic neurons of the central nervous system and peripheral ganglia. The GI tract also harbors a diverse microbiome, but interactions between the ENS and the microbiome remain poorly understood. Here, we activate choline acetyltransferase (ChAT)-expressing or tyrosine hydroxylase (TH)-expressing gut-associated neurons in mice to determine effects on intestinal microbial communities and their metabolites as well as on host physiology. The resulting multi-omics datasets support broad roles for discrete peripheral neuronal subtypes in shaping microbiome structure, including modulating bile acid profiles and fungal colonization. Physiologically, activation of either ChAT+ or TH+ neurons increases fecal output, while only ChAT+ activation results in increased colonic contractility and diarrhea-like fluid secretion. These findings suggest that specific subsets of peripherally activated neurons differentially regulate the gut microbiome and GI physiology in mice without involvement of signals from the brain. 

Peripheral neuronal activation shapes the microbiome and alters gut physiology.

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Peripheral Neuronal Activation Shapes the Microbiome and Alters Gut Physiology

Peripheral neuronal activation shapes the microbiome and alters gut physiology.