Yogesh Bhattarai

Using 32 immune cell surface markers, we identified 23 monocyte clusters in murine blood. Diabetic gastroparesis was associated with a significant decrease in two circulating classical monocyte-like clusters and an upregulation of the Ccr2-Ccl2 axis in the gastric muscularis propria, suggesting increased tissue monocyte migration. This study offers new targets by pointing to a possible role for two classical monocyte subsets connected to the Ccr2- Ccl2 axis.

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized primarily by motor and non-motor gastrointestinal (GI) deficits. GI symptoms’ including compromised intestinal barrier function often accompanies altered gut microbiota composition and motor deficits in PD. Therefore, in this study, we set to investigate the role of gut microbiota and epithelial barrier dysfunction on motor symptom generation using a rotenone-induced mouse model of PD. We found that while six weeks of 10 mg/kg of chronic rotenone administration by oral gavage resulted in loss of tyrosine hydroxylase (TH) neurons in both germ-free (GF) and conventionally raised (CR) mice, the decrease in motor strength and coordination was observed only in CR mice. Chronic rotenone treatment did not disrupt intestinal permeability in GF mice but resulted in a significant change in gut microbiota composition and an increase in intestinal permeability in CR mice. These results highlight the potential role of gut microbiota in regulating barrier dysfunction and motor deficits in PD.

Parkinson's diseases (PD) is a common neurodegenerative disorder characterized by motor and gastrointestinal (GI) deficits. Despite its prevalence, the pathophysiology of PD is not well understood. Recent studies highlight the role of gut microbiota in neurological disorders. In this review, we summarize the potential role of gut microbiota in the pathophysiology of PD. We first describe how gut microbiota can be influenced by factors predisposing individuals to PD such as environmental toxins, aging, and host genetics. We then highlight the effect of gut microbiota on mechanisms implicated in the pathophysiology of PD including disrupted microbiota gut brain axis (GBA), barrier dysfunction and immune dysfunction. It is too early to connect the dots between gut microbiota and PD to establish causation, and experiments focused on investigating inter-relationship between gut microbiota and associated metabolites on GBA, barrier dysfunction and immune activation will be crucial to fill in the gaps.

Background: High‐fat diet, microbial alterations and lipopolysaccharide (LPS) are thought to cause enteric diabetic neuropathy and intestinal dysmotility. However, the role of the gut microbiota, lipoteichoic acid (LTA) from Gram‐positive bacteria and short‐chain fatty acids (SCFAs) in the development of diabetic enteric neuropathy and intestinal dysmotility is not well understood. Our aim was to examine the role of the gut microbiota, LTA and SCFAs in the development of diabetic enteric neuropathy and intestinal dysmotility.Methods: We fed germ‐free (GF) and conventionally raised (CR) mice either a high‐fat (HFD) or standard chow diet (SCD) for 8 weeks. We analyzed the microbial community composition in CR mice using 16S rRNA sequencing and damage to myenteric neurons using immunohistochemistry. We also studied the effects of LPS, LTA, and SCFAs on duodenal muscularis externa contractions and myenteric neurons using cultured preparations.Key Results: High‐fat diet ingestion reduced the total number and the number of nitrergic myenteric neurons per ganglion in the duodenum of CR but not in GF‐HFD mice. GF mice had fewer neurons per ganglion compared with CR mice. CR mice fed a HFD had increased abundance of Gram‐positive bacteria. LTA and LPS did not affect the frequency of duodenal muscularis contractions after 24 hours of cultured but reduced the density of nitrergic myenteric neurons and increased oxidative stress and TNFα production in myenteric ganglia. SCFAs did not affect muscularis contractions or injure myenteric neurons.Conclusions & Inferences: Gut microbial alterations induced increase in Gram‐positive bacterial LTA may contribute to enteric neuropathy.

The gastrointestinal barrier and the blood brain barrier represent an important line of defense to protect the underlying structures against harmful external stimuli. These host barriers are composed of epithelial and endothelial cells interconnected by tight junction proteins along with several other supporting structures. Disruption in host barrier structures has therefore been implicated in various diseases of the gastrointestinal tract and the central nervous system. While there are several factors that influence host barrier, recently there is an increasing appreciation of the role of gut microbiota and their metabolites in regulating barrier integrity. In the current issue of Neurogastroenterology and Motility, Marungruang et al. describe the effect of gastrointestinal barrier maturation on gut microbiota and the blood brain barrier adding to the growing evidence of microbiota‐barrier interactions. In this mini‐review I will discuss the effect of gut microbiota on host epithelial barriers and its implications for diseases associated with disrupted gut‐brain axis.

Serotonin [5-hydroxytryptamine (5-HT)], an important neurotransmitter and a paracrine messenger in the gastrointestinal tract, regulates intestinal secretion by its action primarily on 5-HT₃and 5-HT₄receptors. Recent studies highlight the role of gut microbiota in 5-HT biosynthesis. In this study, we determine whether human-derived gut microbiota affects host secretory response to 5-HT and 5-HT receptor expression. We used proximal colonic mucosa-submucosa preparation from age-matched Swiss Webster germ-free (GF) and humanized (HM; ex-GF colonized with human gut microbiota) mice. 5-HT evoked a significantly greater increase in short-circuit current (Δ I_sc) in GF compared with HM mice. Additionally, 5-HT₃receptor mRNA and protein expression was significantly higher in GF compared with HM mice. Ondansetron, a 5-HT₃receptor antagonist, inhibited 5-HT-evoked Δ I_scin GF mice but not in HM mice. Furthermore, a 5-HT₃receptor-selective agonist, 2-methyl-5-hydroxytryptamine hydrochloride, evoked a significantly higher Δ I_scin GF compared with HM mice. Immunohistochemistry in 5-HT_3A-green fluorescent protein mice localized 5-HT₃receptor expression to enterochromaffin cells in addition to nerve fibers. The significant difference in 5-HT-evoked Δ I_scbetween GF and HM mice persisted in the presence of tetrodotoxin (TTX) but was lost after ondansetron application in the presence of TTX. Application of acetate (10 mM) significantly lowered 5-HT₃receptor mRNA in GF mouse colonoids. We conclude that host secretory response to 5-HT may be modulated by gut microbiota regulation of 5-HT₃receptor expression via acetate production. Epithelial 5-HT₃receptor may function as a mediator of gut microbiota-driven change in intestinal secretion.NEW & NOTEWORTHY We found that gut microbiota alters serotonin (5-HT)-evoked intestinal secretion in a 5-HT₃receptor-dependent mechanism and gut microbiota metabolite acetate alters 5-HT₃receptor expression in colonoids.View this article's corresponding video summary at https://www.youtube.com/watch?v=aOMYJMuLTcw&feature=youtu.be .