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ABSTRACTThe role of gut microbiome in health, a century-old concept, has been on the center stage of medical research recently. While different body sites, disease conditions, and populations have been targeted, neonatal and early infancy appear to be the most suitable period for such interventions. It is intriguing to note that, unlike traditional use in diarrhea and maintenance of gastrointestinal health, microbiome-mediating therapies have now addressed the most serious medical conditions in young infants such as necrotizing enterocolitis and neonatal sepsis. Unfortunately, almost all new endeavors in this space have been carried out in the Western world leaving behind millions of neonates that can benefit from such manipulations while serving as a large resource for further learning. In this review, an attempt has been made to quantify the global burden of neonatal morbidity and mortality, examples presented on interventions that have failed as a result of drawing from studies conducted in the West, and a case made for manipulating the neonatal gut microbiome to address the biggest killers in early life. A brief comparative analysis has been made to demonstrate the differences in the gut microbiota of North and South and a large clinical trial of synbiotics conducted by our group in a South Asian setting has been presented. Although challenging, the value of conducting such global health research is introduced with an intent to invite medical scientists to engage in well-planned, scientifically robust research endeavors. This can bring about innovation while saving and serving the most vulnerable citizens now and protecting them from the negative health consequences in the later part of their lives, ultimately shaping a resilient and equitable world as pledged by 193 United Nations member countries in 2015.

ABSTRACT: Aging is associated with alterations in gut function, including intestinal inflammation, leaky gut, and impaired epithelial regeneration. Rejuvenating the aged gut is imperative to extend the laying cycle of aged laying hens. Genistein is known to have beneficial effects on age-related diseases, but its precise role in homeostasis of the aged gut of laying hens remains to be elucidated. In this study, 160 45-wk-old Hyline Brown laying hens were continuously fed a basal diet or a diet supplemented with 40 mg/kg genistein until they reached 100 wk of age. The results revealed that long-term genistein supplementation led to an improvement in the egg production rate and feed conversion ratio, as well as an increase in egg quality. Moreover, the expression levels of senescence markers, such as β-galactosidase, P16, and P21, were decreased in the gut of genistein-treated aged laying hens. Furthermore, genistein ameliorated gut dysfunctions, such as intestinal inflammation, leaky gut, and impaired epithelial regeneration. Treg cell-derived IL-10 plays a crucial role in the genistein-induced regulation of age-related intestinal inflammation. This study demonstrates that long-term consumption of genistein improves homeostasis in the aged gut and extends the laying cycle of aged laying hens. Moreover, the link between genistein and Treg cells provides a rationale for dietary intervention against age-associated gut dysfunction.

近年来，肠道菌群被认为与卒中后肺炎有关，肠道菌群及其代谢产物通过神经-免疫影响卒中后肺炎，靶向调节肠道菌群如粪菌移植、补充益生菌/益生元有望成为控制卒中后肺炎的重要手段。本文从肠道菌群对卒中后肺炎的影响、可能作用机制及肠道菌群调节在卒中后肺炎治疗中的应用效果等方面进行综述，阐述了卒中后感染的一个易被忽视的重要传染源，以期促进卒中后肺炎靶向治疗策略的发展。 Abstract: In recent years, gut microbiota is considered to be related to post-stroke pneumonia. gut microbiota and its metabolites affect post-stroke pneumonia through neuroimmunity. Targeted regulation of gut microbiota, such as fecal bacteria transplantation, and supplementation of probiotics/prebiotics are expected to become important means to control post-stroke pneumonia. This paper reviewed the influence of gut microbiota on post-stroke pneumonia, and its possible mechanism, as well as the effect of gut microbiota regulation in the treatment of post-stroke pneumonia, described an important neglected infectious source of post-stroke infection, in order to promote the development of targeted therapy strategies for post-stroke pneumonia.

Individuals with autism often experience gastrointestinal issues but the cause is unknown. Many gene mutations that modify neuronal synapse function are associated with autism and therefore may impact the enteric nervous system that regulates gastrointestinal function. A missense mutation in the Nlgn3 gene encoding the cell adhesion protein Neuroligin-3 was identified in two brothers with autism who both experienced severe gastrointestinal dysfunction. Mice expressing this mutation (Nlgn3R451C mice) are a well-studied preclinical model of autism and show autism-relevant characteristics, including impaired social interaction and communication, as well as repetitive behaviour. We previously showed colonic dysmotility in response to GABAergic inhibition and increased myenteric neuronal numbers in the small intestine in Nlgn3R451C mice bred on a mixed genetic background. Here, we show that gut dysfunction is a persistent phenotype of the Nlgn3 R451C mutation in mice backcrossed onto a C57BL/6 background. We report that Nlgn3R451C mice show a 30.9% faster gastrointestinal transit (p = 0.0004) in vivo and have 6% longer small intestines (p = 0.04) compared to wild-types due to a reduction in smooth muscle tone. In Nlgn3R451C mice, we observed a decrease in resting jejunal diameter (proximal jejunum: 10.6% decrease, p = 0.02; mid: 9.8%, p = 0.04; distal: 11.5%, p = 0.009) and neurally regulated dysmotility as well as shorter durations of contractile complexes (mid: 25.6% reduction in duration, p = 0.009; distal: 30.5%, p = 0.004) in the ileum. In Nlgn3R451C mouse colons, short contractions were inhibited to a greater extent (57.2% by the GABAA antagonist, gabazine, compared to 40.6% in wild-type mice (p = 0.007). The inhibition of nitric oxide synthesis decreased the frequency of contractile complexes in the jejunum (WT p = 0.0006, Nlgn3R451C p = 0.002), but not the ileum, in both wild-type and Nlgn3R451C mice. These findings demonstrate that changes in enteric nervous system function contribute to gastrointestinal dysmotility in mice expressing the autism-associated R451C missense mutation in the Neuroligin-3 protein. [ABSTRACT FROM AUTHOR]

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• Shouchella clausii SF174 has a beneficial effect in the context of high fructose diet. • Shouchella clausii SF174 vegetative cells and spores are able to digest part of the fructose at the ileum level. • Both Shouchella clausii SF174 vegetative cells and spores are the major players of the observed probiotic beneficial effects. • Future possibilities to use Shouchella clausii SF174 in most commercial products. The oral administration of probiotics is nowadays recognized as a strategy to treat or prevent the consequences of unhealthy dietary habits. Here we analyze and compare the effects of the oral administration of vegetative cells or spores of Shouchella clausii SF174 in counteracting gut dysfunctions induced by 6 weeks of high fructose intake in a rat model. Gut microbiota composition, tight junction proteins, markers of inflammation and redox homeostasis were evaluated in ileum and colon in rats fed fructose rich diet and supplemented with cells or spores of Shouchella clausii SF174. Our results show that both spores and cells of SF174 were effective in preventing the fructose-induced metabolic damage to the gut, namely establishment of "leaky gut", inflammation and oxidative damage, thus preserving gut function. Our results also suggest that vegetative cells and germination-derived cells metabolize part of the ingested fructose at the ileum level. [Display omitted] [ABSTRACT FROM AUTHOR]

(1) Background: Heavy and chronic alcohol drinking leads to altered gut dysfunction, coupled with a pro-inflammatory state. Thyroid-associated hormones and proteins may be dysregulated by heavy and chronic alcohol intake; however, the mechanism for altered gut-derived changes in thyroid function has not been studied thus far. This study investigates the role of alcohol-induced gut dysfunction and pro-inflammatory cytokine profile in the thyroid function of patients with alcohol use disorder (AUD). (2) Methods: Male and female AUD patients (n = 44) were divided into Gr.1, patients with normal thyroid-stimulating hormone (TSH) levels (n = 28, 0.8 ≤ TSH ≤ 3 mIU/L); and Gr.2, patients with clinically elevated TSH levels (n = 16, TSH > 3 mIU/L). Demographics, drinking measures, comprehensive metabolic panels, and candidate thyroid markers (TSH, circulating triiodothyronine (T3), and free thyroxine (fT4)) were analyzed. Gut-dysfunction-associated markers (lipopolysaccharide (LPS), LPS-binding protein (LBP), and soluble LPS-induced pathogen-associated protein (sCD14)), and candidate pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, IL-8, MCP-1, PAI-1) were also evaluated. (3) Results: Patients in both groups presented with a borderline overweight BMI category. Gr.2 reported numerically higher indices of chronic and heavy drinking patterns than Gr.1. The fT4 levels were elevated, while T3 was within normal limits in both groups. The gut dysfunction markers LBP and sCD14 were numerically elevated in Gr.2 vs. Gr.1, suggesting subtle ongoing changes. Candidate pro-inflammatory cytokines were significantly elevated in Gr.2, including IL-1 β, MCP-1, and PAI-1. Gr.2 showed a strong and statistically significant effect on the gut–immune–thyroid response (r = 0.896, 36 p = 0.002) on TSH levels in a multivariate regression model with LBP, sCD14, and PAI-1 levels as upstream variables in the gut–thyroid pathway. In addition, AUROC analysis demonstrated that many of the cytokines strongly predicted TSH in Gr.2, including IL-6 (area = 0.774, 39 p < 0.001) and TNF-α (area = 0.708, p = 0.017), among others. This was not observed in Gr.1. Gr.2 demonstrated elevated fT4, as well as TSH, which suggests that there was subclinical thyroiditis with underlying CNS dysfunction and a lack of a negative feedback loop. (4) Conclusions: These findings reveal the toxic effects of heavy and chronic drinking that play a pathological role in thyroid gland dysregulation by employing the gut–brain axis. These results also emphasize potential directions to carefully evaluate thyroid dysregulation in the overall medical management of AUD. [ABSTRACT FROM AUTHOR]

Introduction: Bowel dysfunction (BD) is reported as a common and disabling symptom in multiple sclerosis (MS) patients. To date, no studies have explored the prevalence of these symptoms in a large multicenter outpatient setting. The aims of the present study are to assess: (i) the prevalence of BD in a large multicenter Italian MS population, and (ii) the correlation between clinico-demographic variables and the severity of BD. Methods: Each of the nine participating center screened MS patients prospectively: 1100 subjects were enrolled. All patients underwent the Expanded Disability Status Scale (EDSS) and completed the Neurogenic Bowel Dysfunction score (NBDs). Multivariable linear and logistic regression models were used to assess the association between NBDs and several clinico-demographic variables. Results: Fourteen percent of MS patients showed a moderate/severe BD (NBDs > 10); this percentage increased in patients with high disability, ranging from 26 to 32%. Moderate/severe BD was more frequent in MS patients with: progressive phenotypes, higher disability, older age, and longer disease duration. NBDs severity was predicted by female sex, ambulation impairment and bladder symptoms. Conclusion: This study confirms the relatively high prevalence of moderate/severe BD in a large, multicenter, unselected, outpatient MS population. BD appears to be mainly associated to female sex and MS-related disability. [ABSTRACT FROM AUTHOR]

Glyphosate, the most popular herbicide globally, has long been considered safe for mammals. However, whether glyphosate can disturb gut microbiota via inhibiting aromatic amino acid (AAA) synthesis has been under debate recently. Here, we evaluated the impacts of chronic exposure to Roundup on gut health with the addition of AAA and explored the mechanism behind Roundup-induced gut dysfunction by performing fecal microbiota transplantation. 500 mg/kg·bw of Roundup, independent of AAA deficiency, caused severe damage to gut function, as characterized by gut microbial dysbiosis, oxidative stress damage, intestinal inflammation, and histopathological injury, particularly in female rats. Notably, similar to Roundup, Roundup-shaped gut microbiome evidently damaged serum, cecum, and colon profiling of oxidative stress biomarkers (malonaldehyde (MDA), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), glutathione (GSH), and H 2 O 2 ). Moreover, it induced 0.65-, 3.29-, and 2.36-fold increases in colonic IL-1β, IL-6, and TNF-α levels, and 0.34-fold decreases in the IL-10 level. Upon transplanting healthy fecal microbiota to Roundup-treated rats, they exhibited a healthier gut microenvironment with mitigated inflammation, oxidative damage, and intestinal injury. Overall, our findings provide new insights into the safety of Roundup, highlight the crucial role of gut microbiota in Roundup-induced gut dysfunction, and pave the way for developing gut-microbiota-based strategies to address Roundup-related safety issues.

Septic shock is a public health burden and defined as a subset of sepsis whereby abnormalities in microcirculatory and cellular metabolism manifest as acute circulatory failure. At the level of the gut, septic shock impairs epithelial barrier function (EBF), and the gut initiates proinflammatory responses contributing to multiple organ dysfunction syndrome. The timing and dose of enteral nutrition (EN) in septic shock remains a conundrum. On the one hand, early EN preserves EBF. On the other hand, serious gastrointestinal complications such as bowel necrosis may limit EN initiation in septic shock. We (1) describe the pathophysiologic conundrum septic shock poses for EN initiation, (2) outline guideline‐based recommendations for EN in septic shock, (3) identify the role of parenteral nutrition in septic shock, and (4) identify and appraise postguideline literature on the timing, dose, and titration of EN in septic shock. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that antibiotic administration causes gut injury, negatively affecting nutrient digestion, immune regulation, and colonization resistance against pathogens due to the disruption of gut microbiota. However, the time-course effects of therapeutic antibiotics on alterations of gut microbes and short-chain fatty acids (SCFAs) in young swine are still unknown. In this study, twenty piglets were assigned into two groups and fed commercial diets with or without lincomycin in the first week for a 28-day trial period. Results showed that 1-week lincomycin exposure (LE) did reduce the body weight on day 14 (p = 0.0450) and 28 (p = 0.0362). The alpha-diversity notably reduced after 1-week LE, and then gradually raised and reached the control group level in the second week on cessation of LE, indicated by the variation of Sobs, Chao, Shannon, and ACE index (p < 0.05). Beta-diversity analysis revealed that the distinct microbial cluster existed persistently for the whole trial period between two groups (p < 0.001). The relative abundance of most microbes including fiber-degrading (e.g., Agathobacter and Coprococcus), beneficial (e.g., Lactobacillus and Mitsuokella), or pathogenic bacteria (e.g., Terrisporobacter and Lachnoclostridium) decreased (LDA score > 3), and the concentration of SCFAs also diminished in the feces of 1-week lincomycin-administrated young swine, indicating that therapeutic LE killed most bacteria and reduced SCFA production with gut dysbiosis occurring. After the LE stopped, the state of gut dysbiosis gradually attenuated and formed new gut-microbe homeostasis distinct from microbial homeostasis of young pigs unexposed to lincomycin. The increased presence of potential pathogens, such as Terrisporobacter, Negativibacillus, and Escherichia-Shigella, and decreased beneficial bacteria, such as Lactobacillus and Agathobacter, were observed in new homeostasis reshaped by short-lincomycin administration (LDA score > 3 or p < 0.05), adversely affecting gut development and health of young pigs. Collectively, these results suggested that severe disruption of the commensal microbiota occurred after short-term LE or termination of LE in young swine. Key points: • Therapeutic lincomycin exposure induced gut dysbiosis, killing most bacteria and reducing short-chain fatty acid production. • Gut dysbiosis gradually attenuated and formed new homeostasis after lincomycin exposure stopped. • The new homeostasis, increased Escherichia-Shigella etc. and decreased Lactobacillus etc., was potentially harmful to gut health. [ABSTRACT FROM AUTHOR]

Background: Gastrointestinal (GI) complications, that severely impact patient quality of life, are a common occurrence in patients with Parkinson's disease (PD). Damage to enteric neurons and the accumulation of alpha-synuclein in the enteric nervous system (ENS) are thought to contribute to this phenotype. Copper or iron chelators, that bind excess or labile metal ions, can prevent aggregation of alpha-synuclein in the brain and alleviate motor-symptoms in preclinical models of PD. Objective: We investigated the effect of ATH434 (formally PBT434), a small molecule, orally bioavailable, moderate-affinity iron chelator, on colonic propulsion and whole gut transit in A53T alpha-synuclein transgenic mice. Methods: Mice were fed ATH434 (30 mg/kg/day) for either 4 months (beginning at ∼15 months of age), after the onset of slowed propulsion ("treatment group"), or for 3 months (beginning at ∼12 months of age), prior to slowed propulsion ("prevention group"). Results: ATH434, given after dysfunction was established, resulted in a reversal of slowed colonic propulsion and gut transit deficits in A53T mice to WT levels. In addition, ATH434 administered from 12 months prevented the slowed bead expulsion at 15 months but did not alter deficits in gut transit time when compared to vehicle-treated A53T mice. The proportion of neurons with nuclear Hu+ translocation, an indicator of neuronal stress in the ENS, was significantly greater in A53T than WT mice, and was reduced in both groups when ATH434 was administered. Conclusion: ATH434 can reverse some of the GI deficits and enteric neuropathy that occur in a mouse model of PD, and thus may have potential clinical benefit in alleviating the GI dysfunctions associated with PD. [ABSTRACT FROM AUTHOR]

Aging is associated with alterations in gut function, including intestinal inflammation, leaky gut, and impaired epithelial regeneration. Rejuvenating the aged gut is imperative to extend the laying cycle of aged laying hens. Genistein is known to have beneficial effects on age-related diseases, but its precise role in homeostasis of the aged gut of laying hens remains to be elucidated. In this study, 160 45-wk-old Hyline Brown laying hens were continuously fed a basal diet or a diet supplemented with 40 mg/kg genistein until they reached 100 wk of age. The results revealed that long-term genistein supplementation led to an improvement in the egg production rate and feed conversion ratio, as well as an increase in egg quality. Moreover, the expression levels of senescence markers, such as β-galactosidase, P16 , and P21 , were decreased in the gut of genistein-treated aged laying hens. Furthermore, genistein ameliorated gut dysfunctions, such as intestinal inflammation, leaky gut, and impaired epithelial regeneration. T reg cell-derived IL-10 plays a crucial role in the genistein-induced regulation of age-related intestinal inflammation. This study demonstrates that long-term consumption of genistein improves homeostasis in the aged gut and extends the laying cycle of aged laying hens. Moreover, the link between genistein and T reg cells provides a rationale for dietary intervention against age-associated gut dysfunction. [ABSTRACT FROM AUTHOR]

(1) Background: Heavy and chronic alcohol drinking leads to altered gut dysfunction, coupled with a pro-inflammatory state. Thyroid-associated hormones and proteins may be dysregulated by heavy and chronic alcohol intake; however, the mechanism for altered gut-derived changes in thyroid function has not been studied thus far. This study investigates the role of alcohol-induced gut dysfunction and pro-inflammatory cytokine profile in the thyroid function of patients with alcohol use disorder (AUD). (2) Methods: Male and female AUD patients (n = 44) were divided into Gr.1, patients with normal thyroid-stimulating hormone (TSH) levels (n = 28, 0.8 ≤ TSH ≤ 3 mIU/L); and Gr.2, patients with clinically elevated TSH levels (n = 16, TSH > 3 mIU/L). Demographics, drinking measures, comprehensive metabolic panels, and candidate thyroid markers (TSH, circulating triiodothyronine (T3), and free thyroxine (fT4)) were analyzed. Gut-dysfunction-associated markers (lipopolysaccharide (LPS), LPS-binding protein (LBP), and soluble LPS-induced pathogen-associated protein (sCD14)), and candidate pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, IL-8, MCP-1, PAI-1) were also evaluated. (3) Results: Patients in both groups presented with a borderline overweight BMI category. Gr.2 reported numerically higher indices of chronic and heavy drinking patterns than Gr.1. The fT4 levels were elevated, while T3 was within normal limits in both groups. The gut dysfunction markers LBP and sCD14 were numerically elevated in Gr.2 vs. Gr.1, suggesting subtle ongoing changes. Candidate pro-inflammatory cytokines were significantly elevated in Gr.2, including IL-1 β, MCP-1, and PAI-1. Gr.2 showed a strong and statistically significant effect on the gut–immune–thyroid response (r = 0.896, 36 p = 0.002) on TSH levels in a multivariate regression model with LBP, sCD14, and PAI-1 levels as upstream variables in the gut–thyroid pathway. In addition, AUROC analysis demonstrated that many of the cytokines strongly predicted TSH in Gr.2, including IL-6 (area = 0.774, 39 p < 0.001) and TNF-α (area = 0.708, p = 0.017), among others. This was not observed in Gr.1. Gr.2 demonstrated elevated fT4, as well as TSH, which suggests that there was subclinical thyroiditis with underlying CNS dysfunction and a lack of a negative feedback loop. (4) Conclusions: These findings reveal the toxic effects of heavy and chronic drinking that play a pathological role in thyroid gland dysregulation by employing the gut–brain axis. These results also emphasize potential directions to carefully evaluate thyroid dysregulation in the overall medical management of AUD.

Subclinical doses of antimicrobials are commonly used in the swine industry to control infectious diseases and growth performance. Accumulating evidence suggests that swine administered with antibiotics are susceptible to disease development due to disruption of the beneficial gut microbial community, which is associated with host immune regulation, nutrient digestion, and colonization resistance against pathogens. In this study, we found that finishing swine administered with lincomycin showed gut dysbiosis and increased diarrhea incidence compared with control swine. 16S rRNA amplicon sequencing was used to analyze the gut microbiota in finishing swine administered with lincomycin. The relative abundance of detrimental microbes, such as species of Clostridium, Aerococcus, Escherichia-Shigella, and Corynebacterium was increased in the feces of lincomycin-administered finishing swine, but that of bacteria associated with fiber degradation, such as species of Treponema, Succinivibrio, Fibrobacter, and Cellulosilyticum was decreased. Moreover, administration of lincomycin significantly increased the enrichment of metabolic pathways related to pathogenicity and deficiency of polysaccharide degradation. These results suggest that lincomycin treatment could cause severe disruption of the commensal microbiota in finishing swine.

Gastrointestinal symptoms are prevalent extrapulmonary systemic manifestations of Chronic Obstructive Pulmonary Disease (COPD), but have been rarely studied. We dissected the perturbations in intestinal function in human patients with COPD using comprehensive metabolic and physiological approaches. In this observational study, small intestinal membrane integrity and active carrier-mediated glucose transport were quantified by sugar permeability test in 21 clinically stable patients with moderate to severe COPD (mean FEV 1 , 41.2 (3.2) % of predicted) and 16 healthy control subjects. Protein digestion and absorption was analyzed using stable tracer kinetic methods. Plasma acetate, propionate, and butyrate concentrations were measured as markers of intestinal microbial metabolism. Compared with healthy controls, non carrier-mediated permeability was higher (0.062 (95% CI [0.046, 0.078]) vs. 0.037 (95% CI [0.029, 0.045]), P = 0.009) and active glucose transport lower in COPD (31.4 (95% CI [23.4, 39.4])% vs. 48.0 (95% CI [37.8, 58.3])%, P = 0.010). Protein digestion and absorption was lower in COPD (0.647 (95% CI [0.588, 0.705]) vs. 0.823 (95% CI [0.737, 0.909]), P = 0007), and impairment greater in patients with dyspnea (P = 0.038), exacerbations in preceding year (P = 0.052), and reduced transcutaneous oxygen saturation (P = 0.051), and was associated with reduced physical activity score (P = 0.016) and lower quality of life (P = 0.0007). Plasma acetate concentration was reduced in COPD (41.54 (95% CI [35.17, 47.91]) vs. 80.44 (95% CI [54.59, 106.30]) μmol/L, P = 0.001) suggesting perturbed intestinal microbial metabolism. We conclude that intestinal dysfunction is present in COPD, worsens with increasing disease severity, and is associated with reduced quality of life. [ABSTRACT FROM AUTHOR]

Subclinical doses of antimicrobials are commonly used in the swine industry to control infectious diseases and growth performance. Accumulating evidence suggests that swine administered with antibiotics are susceptible to disease development due to disruption of the beneficial gut microbial community, which is associated with host immune regulation, nutrient digestion, and colonization resistance against pathogens. In this study, we found that finishing swine administered with lincomycin showed gut dysbiosis and increased diarrhea incidence compared with control swine. 16S rRNA amplicon sequencing was used to analyze the gut microbiota in finishing swine administered with lincomycin. The relative abundance of detrimental microbes, such as species of Clostridium , Aerococcus , Escherichia-Shigella , and Corynebacterium was increased in the feces of lincomycin-administered finishing swine, but that of bacteria associated with fiber degradation, such as species of Treponema , Succinivibrio, Fibrobacter , and Cellulosilyticum was decreased. Moreover, administration of lincomycin significantly increased the enrichment of metabolic pathways related to pathogenicity and deficiency of polysaccharide degradation. These results suggest that lincomycin treatment could cause severe disruption of the commensal microbiota in finishing swine. [ABSTRACT FROM AUTHOR]

Background: Gastrointestinal (GI) dysfunction, including constipation, is a common non‐motor symptom of Parkinson's disease (PD). The toxin 6‐hydroxydopamine (6OHDA) produces the symptoms of PD, surprisingly including constipation, after it is injected into the medial forebrain bundle (MFB). However, the mechanisms involved in PD‐associated constipation caused by central application of 6OHDA remain unknown. We investigated effects of 6OHDA lesioning of the MFB on motor performance and GI function. Methods: Male Sprague Dawley rats were unilaterally injected with 6OHDA in the MFB. Colorectal propulsion was assessed by bead expulsion after 4 weeks and by recording colorectal contractions and propulsion after 5 weeks. Enteric nervous system (ENS) neuropathy was examined by immunohistochemistry. Key Results: When compared to shams, 6OHDA‐lesioned rats had significantly increased times of bead expulsion from the colorectum, indicative of colon dysmotility. Administration of the colokinetic, capromorelin, that stimulates defecation centers in the spinal cord, increased the number of contractions and colorectal propulsion in both groups compared to baseline; however, the effectiveness of capromorelin in 6OHDA‐lesioned rats was significantly reduced in comparison with shams, indicating that 6OHDA animals have reduced responsiveness of the spinal defecation centers. Enteric neuropathy was observed in the distal colon, revealing that lesion of the MFB has downstream effects at the cellular level, remote from the site of 6OHDA administration. Conclusions & Inferences: We conclude that there are trans‐synaptic effects of the proximal, forebrain, lesion of pathways from the brain that send signals down the spinal cord, at the levels of the defecation centers and the ENS. [ABSTRACT FROM AUTHOR]

Background: Chronic stress exacerbates motor deficits and increases dopaminergic cell loss in several rodent models of Parkinson's disease (PD). However, little is known about effects of stress on gastrointestinal (GI) dysfunction, a common non‐motor symptom of PD. We aimed to determine whether chronic stress exacerbates GI dysfunction in the A53T mouse model of PD and whether this relates to changes in α‐synuclein distribution. Methods: Chronic isolation stress was induced by single‐housing WT and homozygote A53T mice between 5 and 15 months of age. GI and motor function were compared with mice that had been group‐housed. Key Results: Chronic isolation stress increased plasma corticosterone and exacerbated deficits in colonic propulsion and whole‐gut transit in A53T mice and also increased motor deficits. However, our results indicated that the novel environment‐induced defecation response, a common method used to evaluate colorectal function, was not a useful test to measure exacerbation of GI dysfunction, most likely because of the reported reduced level of anxiety in A53T mice. A53T mice had lower corticosterone levels than WT mice under both housing conditions, but single‐housing increased levels for both genotypes. Enteric neuropathy was observed in aging A53T mice and A53T mice had a greater accumulation of alpha‐synuclein (αsyn) in myenteric ganglia under both housing conditions. Conclusions & Inferences: Chronic isolation stress exacerbates PD‐associated GI dysfunction, in addition to increasing motor deficits. However, these changes in GI symptoms are not directly related to corticosterone levels, worsened enteric neuropathy, or enteric αsyn accumulation. [ABSTRACT FROM AUTHOR]

The role of gut microbiome in health, a century-old concept, has been on the center stage of medical research recently. While different body sites, disease conditions, and populations have been targeted, neonatal and early infancy appear to be the most suitable period for such interventions. It is intriguing to note that, unlike traditional use in diarrhea and maintenance of gastrointestinal health, microbiome-mediating therapies have now addressed the most serious medical conditions in young infants such as necrotizing enterocolitis and neonatal sepsis. Unfortunately, almost all new endeavors in this space have been carried out in the Western world leaving behind millions of neonates that can benefit from such manipulations while serving as a large resource for further learning. In this review, an attempt has been made to quantify the global burden of neonatal morbidity and mortality, examples presented on interventions that have failed as a result of drawing from studies conducted in the West, and a case made for manipulating the neonatal gut microbiome to address the biggest killers in early life. A brief comparative analysis has been made to demonstrate the differences in the gut microbiota of North and South and a large clinical trial of synbiotics conducted by our group in a South Asian setting has been presented. Although challenging, the value of conducting such global health research is introduced with an intent to invite medical scientists to engage in well-planned, scientifically robust research endeavors. This can bring about innovation while saving and serving the most vulnerable citizens now and protecting them from the negative health consequences in the later part of their lives, ultimately shaping a resilient and equitable world as pledged by 193 United Nations member countries in 2015.

The consumption of Westernized diets leads to hyperphagia and obesity, as well as intestinal alterations. In the present study, we evaluated the effect of the administration of a grape seed proanthocyanidin extract (GSPE) at different time points on the modulation of intestinal barrier function (intestinal permeability and metabolic endotoxemia), in rats with high-fat/high-carbohydrate diet-induced obesity. Animals were fed a cafeteria diet (CAF) supplemented with a preventive (PRE-CAF) or simultaneously intermittent (SIT-CAF) GSPE treatment (500 mg/kg bw). Changes in the plasma levels of an orally administered marker of intestinal permeability (ovalbumin, OVA), lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF-α) were analyzed after animals were fed the obesogenic diet for 8, 12 and 17 weeks. In addition, ex vivo variations in transepithelial electrical resistance (TEER), the expression of tight junction (TJ) genes and the activity of myeloperoxidase (MPO) in the small and large intestines were monitored at the end of the experiment. The CAF diet increased OVA, LPS, MPO and TNF-α levels, accompanied by decreased TEER values in the small and large intestines. Interestingly, both GSPE treatments prevented these detrimental effects of the CAF diet, being the SIT-CAF group the most effective after 17 weeks of diet intervention. For the first time, this study provides evidence of the ameliorative effect of a proanthocyanidin extract, administered before or together with an obesogenic diet, on barrier dysfunction, as measured by intestinal permeability and metabolic endotoxemia. [ABSTRACT FROM AUTHOR]

Objectives: Delayed gastric emptying occurs in critically ill patients and impairs the delivery, digestion, and absorption of enteral feeding. A pathophysiologic role of the enterohormones peptide YY and ghrelin is supported by preclinical data. To compare the circulating plasma levels of peptide YY and ghrelin in control subjects and in critically ill patients, during feeding and fasting, and to search for a correlation with gastric emptying.Design: A prospective observational trial.Settings: Mixed ICU of an academic hospital.Subjects: Healthy volunteers and patients expected to stay in ICU for at least 3 days in whom enteral nutrition was indicated.Interventions: None.Measurements and Main Results: Plasma peptide YY and ghrelin (enzyme-linked immunosorbent assay) were measured once in 10 fasting volunteers (controls) and daily from admission until day 5 of the ICU stay in 30 critically ill patients (median [interquartile range] age 63 [57-67] yr, median [interquartile range] Acute Physiology and Chronic Health Evaluation II score 21 [14-24]). Eight patients could not be fed (fasting group). In fed patients, 13 never had a gastric residual volume higher than 250 mL (low gastric residual volume group), in contrast to the high gastric residual volume group (n = 9). The plasma levels of peptide YY did not differ between patients (6.4 [0-18.1] pg/mL) and controls (4.8 [0.3-17.7] pg/mL). Ghrelin levels were lower in patients than in control (213 [54.4-522.7] vs 1,435 [1,321.9-1,869.3] pg/mL; p < 0.05). Plasma peptide YY or ghrelin did not differ between fasting and fed patients or between the high and low gastric residual volume groups.Conclusions: In critically ill patients, plasma concentration of ghrelin significantly differs from that of controls, irrespective of the feeding status. No correlation was found between the temporal profile of ghrelin or peptide YY plasma concentration with bedside functional assessment of gastric emptying. [ABSTRACT FROM AUTHOR]

• Emotional-Single Prolonged Stress-induced depressive/anxiety-like phenotype in mice. • Emotional-Single Prolonged Stress-induced predominant diarrhea in mice. • Emotional-Single Prolonged Stress modulated the gut microbiota profile in mice. • Emotional-Single Prolonged Stress is a model to elucidate the brain-gut axis. Excessive stress can precipitate depression and anxiety diseases, and damage gastrointestinal functionality and microbiota changes, favoring the development of functional gastrointestinal disorders (FGIDs) – defined by dysregulation in the brain-gut interaction. Therefore, the present study investigated if Emotional-Single Prolonged Stress (E-SPS) induces depressive/anxiety-like phenotype and gut dysfunction in adult Swiss male mice. For this, mice of the E-SPS group were subjected to three stressors sequential exposure: immobilization, swimming, and odor of the predator for 7 days (incubation period). Next, animals performed behavior tests and 24 h later, samples of feces, blood, and colon tissue were collected. E-SPS increased the plasma corticosterone levels, immobility time in the tail suspension and forced swim test, decreased the grooming time in the splash test, OAT%, and OAE% in the elevated plus-maze test, as well as increased anxiety index. Mice of E-SPS had increased % of intestinal transit rate, % of fecal moisture content, and fecal pellets number, and decreased Claudin1 content in the colon. E-SPS decreased the relative abundance of Bacteroidetes phylum, Bacteroidia class, Bacteroidales order, Muribaculaceae and Porphyromonadaceae family, Muribaculum , and Duncaniella genus. However, E-SPS increased Firmicutes and Actinobacteria phylum, Coriobacteriales order, and the ratio of Firmicutes/Bacteroidetes, and demonstrated Mucispirillum genus presence. The present study showed that E-SPS induced depressive/anxiety-like phenotype, predominant diarrhea gut dysfunction, and modulated the gut bacterial microbiota profile in male adult Swiss mice. E-SPS might be a promising model for future studies on the brain-gut interaction and the development of FGIDs with psychological comorbidities. [ABSTRACT FROM AUTHOR]

Abstract: Gastrointestinal disorders, constipation in particular, are the most common non-motor dysfunctions affecting Parkinson''s disease (PD) patients. We have previously reported that rats bearing unilateral nigrostriatal lesion caused by 6-hydroxydopamine (6-OHDA) stereotaxic injection develop severe constipation together with a region-specific decrease of neuronal nitric oxide synthase (nNOS) in enteric neurons of the lower intestinal tract. Here, we extend these observations on other enteric neuronal subpopulations, investigating also the propulsive activity of isolated colonic specimens. Four weeks post 6-OHDA injection, lesioned rats showed a significant increase of vasoactive intestinal polypeptide (VIP) concomitant with the reduced expression of nNOS in the myenteric plexus of distal ileum and proximal colon; in particular VIP increased in a subpopulation of neurons actively expressing nNOS. On the other hand, choline acetyltransferase (ChAT) was not modified in any of the intestinal segments analyzed. Interestingly, we found a reduced expression of dopamine receptor type 2 (D2R) in proximal (−66.8%) and distal (−54.5%) colon, together with reduced peristalsis efficiency (decrease in intraluminal pressure and frequency of peristaltic events) in the 6-OHDA-lesioned rats. The selective depletion of dopaminergic nigrostriatal neurons is associated with changes in the expression of enteric inhibitory neurotransmitters, as well as of the D2R in intestinal specific regions. Moreover, 6-OHDA-lesioned rats demonstrated altered colon propulsive activity referable to the D2R decrease. Our findings unveil subtle mechanisms underlying the enteric neurochemical plasticity events evoked by disruption of the normal brain-gut cross-talk, giving a peculiar point of view on the pathophysiology of the severe constipation that frequently affects PD patients. [Copyright &y& Elsevier]

Abstract: Patients with Parkinson''s disease develop motor disturbances often accompanied by peripheral autonomic dysfunctions, including gastrointestinal disorders, such as dysphagia, gastric stasis and constipation. While the mechanisms subserving enteric autonomic dysfunctions are not clearly understood, they may involve the enteric dopaminergic and/or nitrergic systems. In the present study, we demonstrate that rats with unilateral 6-hydroxydopamine lesion of nigrostriatal dopaminergic neurons develop a marked inhibition of propulsive activity compared to sham-operated controls, as indicated by a 60% reduction of daily fecal output at the 4th week of observation. Immunohistochemical data revealed that 6-hydroxydopamine treatment did not affect the total number of HuC/D-positive myenteric neurons in both the proximal and distal segments of ileum and colon. Conversely, in the distal ileum and proximal colon the number of nitrergic neurons was significantly reduced. These results suggest that a disturbed distal gut transit, reminiscent of constipation in the clinical setting, may occur as a consequence of a reduced propulsive motility, likely due to an impairment of a nitric oxide-mediated descending inhibition during peristalsis. [Copyright &y& Elsevier]

Owing to the development of intensive care units, many patients survive their initial insults but progress to chronic critical illness (CCI). Patients with CCI are characterized by prolonged hospitalization, poor outcomes, and significant long-term mortality. Some of these patients get into a state of persistent low-grade inflammation, suppressed immunity, and ongoing catabolism, which was defined as persistent inflammation, immunosuppression, and catabolism syndrome (PICS) in 2012. Over the past few years, some progress has been made in the treatment of PICS. However, most of the existing studies are about the role of persistent inflammation and suppressed immunity in PICS. As one of the hallmarks of PICS, hypercatabolism has received little research attention. In this review, we explore the potential pathophysiological changes and molecular mechanisms of hypercatabolism and its role in PICS. In addition, we summarize current therapies for improving the hypercatabolic status and recommendations for patients with PICS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Luo, Miao and Zhong.)

Objective: In order to prevent gastric microbial overgrowth, which may complicate nasogastric feeding, administration of nutrients more distally into the gut has been advocated in intensive care patients, as it offers the advantage of keeping the stomach empty and acid. In this study, we assessed the impact of jejunal feeding upon gastic pH in a group of mechanically ventilated, critically ill patients, with special focus on duodenogastric reflux as a possible cause of gastric alkalinization during jejunal nutrition. Design: Prospective experimental study. Setting: Multidisciplinary intensive care unit of a university hospital. Patients and methods: Gastric pH was recorded by continuous pHmetry over a 4-h period of fasting followed by a 4-h period of nasojejunal feeding at 100 kcal/h in 21 mechanically ventilated, critically ill patients. To determine the contribution of duodenogastric reflux to modifications of gastric acidity, the diet was traced with [111In] DTPA (pentetic acid) in 11 of these 21 patients; gastric contents were aspirated every 30 min, then analysed for measurement of radioactivity, glucose, and bile acid concentration. Measurements and results: Median intragastric pH increased slightly from 1.59 (1.20–2.73; interquartile range) (fasting) to 2.33 (1.65–4.64) (feeding) ( p = 0.013), and the length of time that the pH was 4 or above increased from 1 (0–24) to 9 (0–142) min ( p = 0.026). The variability of pH values and the number of acute alkalinization episodes did not change between the two phases. In 10 of 11 patients in which the diet was labeled with [111In] DTPA, reflux was documented at a given time of the feeding period. Bile acid concentrations in the stomach increased from 392 (61–1076) (fasting) to 1446 (320–2770) μmol/l (feeding) ( p = 0.010) and mean glucose concentration increased from 59 (28–95) to 164 (104–449) mg/dl ( p = 0.006). Conclusion: Duodenogastric reflux is common in mechanically ventilated critically ill patients with nasojejunal feeding tubes. It occurs both during fasting and during nasojejunal feeding. During nasojejunal feeding, moderate alkalinization of the gastric contents occurs as a result of bile and nutrient reflux. [ABSTRACT FROM AUTHOR]

Objectives: To describe the incidence of problems associated with enteral feeding in different patient groups and intensive care units (ICUs). To compare this incidence with specific feeding protocols and volumes of feed delivered. To identify for future study any interventions likely to improve delivery of enteral feed and to manage or eliminate problems.Design: A prospective, descriptive study of problems associated with enteral feeding in five ICUs over a period of 9 months.Setting: ICUs in two district general and three university hospitals.Patients: ICU patients (age > 18 years) who received enteral feeding for a period > 24 h.Measurements and Results: 193 patients were studied for a total of 1929 patient-days. On average, only 76% of the quantity of feed prescribed was delivered to the patient. The two main problems preventing delivery of feed were gut dysfunction and elective stoppage for procedures. ICUs with well-defined feeding protocols delivered significantly greater volumes of feed (p < 0.0001) than those without. Feeding was abandoned in 11% of patients, half of these due to gastric dysfunction. Only 2 of 193 patients were fed jejunally.Conclusions: The major factors associated with the interruption in delivery of feed are problems with gut function and stopping feed prior to a procedure. Use of specific feeding protocols is clearly associated with a greater volume of feed delivered and a greater percentage of the prescription delivered. These should be an integral part of all ICU protocols. [ABSTRACT FROM AUTHOR]

Host sensing in the gut microbiota has been crucial in the regulation of intestinal homeostasis. Although inflammatory bowel diseases (IBDs), multifactorial chronic inflammatory conditions of the gastrointestinal tract, have been associated with intestinal dysbiosis, the detailed interactions between host and gut microbiota are still not completely understood. Enteroendocrine cells (EECs) represent 1% of the intestinal epithelium. Accumulating evidence indicates that EECs are key sensors of gut microbiota and/or microbial metabolites. They can secrete cytokines and peptide hormones in response to microbiota, either in traditional endocrine regulation or by paracrine impact on proximal tissues and/or cells or via afferent nerve fibers. Enteroendocrine cells also play crucial roles in mucosal immunity, gut barrier function, visceral hyperalgesia, and gastrointestinal (GI) motility, thereby regulating several GI diseases, including IBD. In this review, we will focus on EECs in sensing microbiota, correlating enteroendocrine perturbations with IBD, and the underlying mechanisms., (© 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Early involvement of gut is observed in Parkinson's disease (PD) and symptoms such as constipation may precede motor symptoms. α-Synuclein pathology is extensively evident in the gut and appears to follow a rostrocaudal gradient. The gut may act as the starting point of PD pathology with spread toward the central nervous system. This spread of the synuclein pathology raises the possibility of prion-like propagation in PD pathogenesis. Recently, the role of gut microbiota in PD pathogenesis has received attention and some phenotypic correlation has also been shown. The extensive involvement of the gut in PD even in its early stages has led to the evaluation of enteric α-synuclein as a possible biomarker of early PD. The clinical manifestations of gastrointestinal dysfunction in PD include malnutrition, oral and dental disorders, sialorrhea, dysphagia, gastroparesis, constipation, and defecatory dysfunction. These conditions are quite distressing for the patients and require relevant investigations and adequate management. Treatment usually involves both pharmacological and non-pharmacological measures. One important aspect of gut dysfunction is its contribution to the clinical fluctuations in PD. Dysphagia and gastroparesis lead to inadequate absorption of oral anti-PD medications. These lead to response fluctuations, particularly delayed-on and no-on, and there is significant relationship between levodopa pharmacokinetics and gastric emptying in patients with PD. Therefore, in such cases, alternative routes of administration or drug delivery systems may be required.