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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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(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]

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]

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]

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]

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]

Metabolic alterations in the critically ill have been studied for more than a century, but the heterogeneity of the critically ill patient population, the varying duration and severity of the acute phase of illness, and the many confounding factors have hindered progress in the field. These factors may explain why management of metabolic alterations and related conditions in critically ill patients has for many years been guided by recommendations based essentially on expert opinion. Over the last decade, a number of randomized controlled trials have been conducted, providing us with important population-level evidence that refutes several longstanding paradigms. However, between-patient variation means there is still substantial uncertainty when translating population-level evidence to individuals. A cornerstone of metabolic care is nutrition, for which there is a multifold of published guidelines that agree on many issues but disagree on others. Using a series of nine questions, we provide a review of the latest data in this field and a background to promote efforts to address the need for international consistency in recommendations related to the metabolic care of the critically ill patient. Our purpose is not to replace existing guidelines, but to comment on differences and add perspective. [ABSTRACT FROM AUTHOR]