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Increased kynurenine-to-tryptophan ratio in the serum of patients infected with SARS-CoV2: An observational cohort study.
Lionetto, L, Ulivieri, M, Capi, M, De Bernardini, D, Fazio, F, Petrucca, A, Pomes, LM, De Luca, O, Gentile, G, Casolla, B, et al
Biochimica et biophysica acta. Molecular basis of disease. 2021;1867(3):166042
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Covid-19 infection may alter the immune system, but exactly how is still unclear. A key pathway in the regulation of the immune system is the kynurenine pathway of tryptopham. This observational cohort study aimed to determine how this pathway was affected following infection with Covid-19. The results showed that compared to healthy patients, individuals who tested positive to Covid-19 had an increased ratio of kynurenine:tryptopham and the increase was more pronounced in those who had severe infection and if they were male. It was concluded that the kynurenin:tryptopham ratio could be used as a marker for disease severity and useful for treatments. This study could be used by healthcare professionals to use the kynurenine:tryptopham ratio as a marker for disease severity and stratify patients accordingly for treatments.
Abstract
Immune dysregulation is a hallmark of patients infected by SARS-CoV2 and the balance between immune reactivity and tolerance is a key determinant of all stages of infection, including the excessive inflammatory state causing the acute respiratory distress syndrome. The kynurenine pathway (KP) of tryptophan (Trp) metabolism is activated by pro-inflammatory cytokines and drives mechanisms of immune tolerance. We examined the state of activation of the KP by measuring the Kyn:Trp ratio in the serum of healthy subjects (n = 239), and SARS-CoV2-negative (n = 305) and -positive patients (n = 89). Patients were recruited at the Emergency Room of St. Andrea Hospital (Rome, Italy). Kyn and Trp serum levels were assessed by HPLC/MS-MS. Compared to healthy controls, both SARS-CoV2-negative and -positive patients showed an increase in the Kyn:Trp ratio. The increase was larger in SARS-CoV2-positive patients, with a significant difference between SARS-CoV2-positive and -negative patients. In addition, the increase was more prominent in males, and positively correlated with age and severity of SARS-CoV2 infection, categorized as follows: 1 = no need for intensive care unit (ICU); 2 ≤ 3 weeks spent in ICU; 3 ≥ 3 weeks spent in ICU; and 4 = death. The highest Kyn:Trp values were found in SARS-CoV2-positive patients with severe lymphopenia. These findings suggest that the Kyn:Trp ratio reflects the level of inflammation associated with SARS-CoV2 infection, and, therefore, might represent a valuable biomarker for therapeutic intervention.
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COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status.
Thomas, T, Stefanoni, D, Reisz, JA, Nemkov, T, Bertolone, L, Francis, RO, Hudson, KE, Zimring, JC, Hansen, KC, Hod, EA, et al
JCI insight. 2020;5(14)
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There is increasing urgency for the development of Covid-19 therapies. Treatments preventing infection and decreasing the amount of virus in the body have largely been unsuccessful and so the focus has turned to host biological pathways, which may be altered by Covid-19 infection. This observational study of forty-nine Covid-19 positive and negative individuals aimed to determine alterations in the hosts metabolism. The results showed that Covid-19 infection was associated with disrupted host inflammatory and immune pathways. Markers for kidney dysfunction were also increased alongside raised blood sugar levels and fatty acids in the blood. It was concluded that inflammatory markers may be an indicator for disease severity and a target for Covid-19 therapy. Dietary therapy could be used to target blood fatty acid changes brought about by Covid-19 infection. This study could be used by healthcare professionals to understand that inflammation is increased in Covid-19 patients and in lieu of approved therapies, dietary intervention may be of benefit.
Abstract
BACKGROUNDReprogramming of host metabolism supports viral pathogenesis by fueling viral proliferation, by providing, for example, free amino acids and fatty acids as building blocks.METHODSTo investigate metabolic effects of SARS-CoV-2 infection, we evaluated serum metabolites of patients with COVID-19 (n = 33; diagnosed by nucleic acid testing), as compared with COVID-19-negative controls (n = 16).RESULTSTargeted and untargeted metabolomics analyses identified altered tryptophan metabolism into the kynurenine pathway, which regulates inflammation and immunity. Indeed, these changes in tryptophan metabolism correlated with interleukin-6 (IL-6) levels. Widespread dysregulation of nitrogen metabolism was also seen in infected patients, with altered levels of most amino acids, along with increased markers of oxidant stress (e.g., methionine sulfoxide, cystine), proteolysis, and renal dysfunction (e.g., creatine, creatinine, polyamines). Increased circulating levels of glucose and free fatty acids were also observed, consistent with altered carbon homeostasis. Interestingly, metabolite levels in these pathways correlated with clinical laboratory markers of inflammation (i.e., IL-6 and C-reactive protein) and renal function (i.e., blood urea nitrogen).CONCLUSIONIn conclusion, this initial observational study identified amino acid and fatty acid metabolism as correlates of COVID-19, providing mechanistic insights, potential markers of clinical severity, and potential therapeutic targets.FUNDINGBoettcher Foundation Webb-Waring Biomedical Research Award; National Institute of General and Medical Sciences, NIH; and National Heart, Lung, and Blood Institute, NIH.
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Effects of Periodic Fasting on Fatty Liver Index-A Prospective Observational Study.
Drinda, S, Grundler, F, Neumann, T, Lehmann, T, Steckhan, N, Michalsen, A, Wilhelmi de Toledo, F
Nutrients. 2019;11(11)
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Non-alcoholic fatty liver disease (NAFLD) comprises a number of liver disorders and is thought to have a prevalence of 20% in industrialised countries. NAFLD has been associated with dietary excess of saturated fatty acids, refined carbohydrates, and fructose. This prospective observational study evaluated the effects of periodic fasting on the fatty liver index (FLI), a combination of waist circumference, body mass index (BMI) and biochemical characteristics, which has been shown to closely correlate to magnetic resonance imaging (MRI) results, the gold standard for NAFLD diagnosis. 697 subjects fasted for 6-38 days (mean 8.5 days) in a clinical setting, whilst also engaging in an exercise programme, mindfulness and relaxation. Study subjects included both non-diabetics and type 2 diabetics. There were significant decreases in FLI, weight, BMI and waist circumference, as well as improvements in a number of metabolic blood parameters, in both diabetics and non-diabetics. There were no serious side effects and the intervention was well tolerated. The authors conclude that periodic fasting is an easily realisable, well-tolerated, non-pharmaceutical intervention, which effectively reduces the FLI.
Abstract
This prospective observational trial investigated effects and safety of periodic fasting in subjects with and without type 2 diabetes mellitus (T2DM). The primary end point was set as the change of fatty liver index (FLI) as a surrogate parameter of non-alcoholic fatty liver disease (NAFLD). Six-hundred and ninety-seven subjects (38 with T2DM) were enrolled. A baseline FLI ≥ 60 (the threshold for fatty liver) was found in 264 subjects (37.9%). The mean duration of fasting was 8.5 ± 4.0 days (range 6-38). FLI decreased significantly (-14.02 ± 11.67; p < 0.0001), with a larger effect in individuals with T2DM (-19.15 ± 11.0; p < 0.0001; p = 0.002 compared to non-diabetic subjects). Body mass index (BMI) decreased by -1.51 ± 0.82 kg/m2, and 49.9% of the subjects lost ≥5% body weight. After fasting, nearly half of the 264 subjects with FLI ≥ 60 (highest risk category) shifted to a lower category. The improvement of FLI correlated with the number of fasting days (r = -0.20, p < 0.0001) and with the magnitude of BMI reduction (r = 0.14, p = 0.0001). Periodic fasting with concomitant weight reduction leads to significant rapid improvement of FLI in subjects with and without T2DM.
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Effect of Weight Loss after Bariatric Surgery on Thyroid-Stimulating Hormone Levels in Euthyroid Patients with Morbid Obesity.
Juiz-Valiña, P, Outeiriño-Blanco, E, Pértega, S, Varela-Rodriguez, BM, García-Brao, MJ, Mena, E, Pena-Bello, L, Cordido, M, Sangiao-Alvarellos, S, Cordido, F
Nutrients. 2019;11(5)
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Obesity is associated with many health issues, including thyroid problems. The aim of this observational study was to investigate the effect of weight loss surgery on thyroid hormones. 129 morbidly obese people with normal thyroid function were included in the study. 12 months after weight loss surgery, the levels of thyroid stimulating hormone (TSH) had significantly decreased from 3.3 to 2.1 µU/mL. Levels of the thyroid hormone free thyroxine (T4) also significantly decreased from 1.47 to 1.12 ng/dL. Those that lost more weight following surgery tended to have a greater reduction in TSH. Fasting blood glucose also significantly improved after surgery. The authors concluded that obesity is associated with raised TSH levels, and this makes diagnosing thyroid problems in people with morbid obesity more complicated.
Abstract
Obesity is associated with several endocrine abnormalities, including thyroid dysfunction. The objective of this study was to investigate the effect of weight loss after bariatric surgery on thyroid-stimulating hormone (TSH) levels in euthyroid patients with morbid obesity. We performed an observational study, evaluating patients with morbid obesity submitted to bariatric surgery. We included 129 patients (92 women) and 31 controls (21 women). Clinical, anthropometric, biochemical, and hormonal parameters were evaluated. The primary endpoint was circulating TSH (µU/mL). Fasting TSH levels were higher in the obese group (3.3 ± 0.2) than in the control group (2.1 ± 0.2). The mean excessive body mass index (BMI) loss (EBMIL) 12 months after bariatric surgery was 72.7 ± 2.1%. TSH levels significantly decreased in the obese patients after surgery; 3.3 ± 0.2 vs. 2.1 ± 0.2 before and 12 months after surgery, respectively. Free thyroxine (T4) (ng/dL) levels significantly decreased in the obese patients after surgery; 1.47 ± 0.02 vs. 1.12 ± 0.02 before and 12 months after surgery, respectively. TSH decreased significantly over time, and the decrement was associated with the EBMIL. In euthyroid patients with morbid obesity, weight loss induced by bariatric surgery promotes a significant decline of the increased TSH levels. This decrement of TSH is progressive over time after surgery and significantly associated with excess BMI loss.
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Is waist-to-height ratio the best predictive indicator of hypertension incidence? A cohort study.
Rezende, AC, Souza, LG, Jardim, TV, Perillo, NB, Araújo, YCL, de Souza, SG, Sousa, ALL, Moreira, HG, de Souza, WKSB, do Rosário Gondim Peixoto, M, et al
BMC public health. 2018;18(1):281
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A variety of methods of measuring body fat are used as tools to predict the risk of developing certain lifestyle-related diseases such as high blood pressure. It is not yet clear which of these methods is the most accurate. The aim of this study was to evaluate and compare the effectiveness of using different measures of body fat to predict high blood pressure. The study was performed in Brazil. Adult volunteers with normal blood pressure were assessed for body fat using waist-to-height ratio (WHtR), body mass index (BMI) and waist circumference (WC), and then followed-up 13 years later to find out whether they had developed high blood pressure. 44% of the participants developed high blood pressure during the study period. BMI, WC and WHtR were all associated with the risk of high blood pressure and had similar accuracy in predicting the disease. However, the associations were only significant for women. The cut-off points for predicting high blood pressure agreed with current recommendations, except for the WC in men. The results suggest that both overall obesity (BMI) and central obesity (WC and WHtR) indicators can be used in this population to evaluate the risk of developing high blood pressure.
Abstract
BACKGROUND The best anthropometric indicator to verify the association between obesity and hypertension (HTN) has not been established. We conducted this study to evaluate and compare the discriminatory power of waist-to-height ratio (WHtR) in relation to body mass index (BMI) and waist circumference (WC) in predicting HTN after 13 years of follow-up. METHODS This study was an observational prospective cohort study performed in the city of Firminópolis, in Brazilian's midwest. The cohort baseline (phase 1) was initiated in 2002 with the evaluation of a representative sample of the normotensive population (≥ 18 years of age). The incidence of HTN was evaluated as the outcome (phase 2). Sociodemographic, dietary and lifestyle variables were used to adjust proportional hazards models and evaluate risk of HTN according to anthropometric indices. The areas under the receiver operating characteristic (ROC) curves were used to compare the predictive capacity of these indices. The best HTN predictor cut-offs were obtained based on sensitivity and specificity. RESULTS A total of 471 patients with a mean age of 38.9 ± 12.3 years were included in phase 1. The mean follow-up was 13.2 years, and 207 subjects developed HTN. BMI, WC and WHtR were associated with risk of HTN incidence and had similar power in predicting the disease. However, the associations were only significant for women. The cut-off points with a better HTN predictive capacity were in agreement with current recommendations, except for the WC in men. CONCLUSIONS The results suggest that both overall obesity (BMI) and central obesity (WC and WHtR) anthropometric indicators can be used in this population to evaluate the risk of developing hypertension.
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Brain fogginess, gas and bloating: a link between SIBO, probiotics and metabolic acidosis.
Rao, SSC, Rehman, A, Yu, S, Andino, NM
Clinical and translational gastroenterology. 2018;9(6):162
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D-lactic acid is produced by intestinal bacteria and a rise in levels can lead to D-lactic acidosis, causing neurological changes such as slurred speech and gait disturbances. This is frequently observed in short bowel syndrome. This small, observational study aimed to determine if brain fogginess (mental confusion, impaired judgement, poor short-term memory and difficulty concentrating) and intestinal gas and bloating is associated with D-lactic acidosis and small intestinal bacterial overgrowth (SIBO). 38 patients presenting with gas and bloating in the absence of short bowel syndrome, and with or without brain fog were assessed. All patients with brain fog were consuming probiotics, with a higher proportion of them diagnosed with SIBO and D-lactic acidosis, when compared to the non-brain fog group. The researchers stopped probiotics in all patients and administered antibiotics, observing a significant reduction in brain fog and gastrointestinal symptoms. Whilst this is a small, observational study, nutrition practitioners may wish to assess the likelihood of SIBO and D-lactic acidosis before recommending probiotics, especially in the presence of brain fog.
Abstract
BACKGROUND D-lactic acidosis is characterized by brain fogginess (BF) and elevated D-lactate and occurs in short bowel syndrome. Whether it occurs in patients with an intact gut and unexplained gas and bloating is unknown. We aimed to determine if BF, gas and bloating is associated with D-lactic acidosis and small intestinal bacterial overgrowth (SIBO). METHODS Patients with gas, bloating, BF, intact gut, and negative endoscopic and radiological tests, and those without BF were evaluated. SIBO was assessed with glucose breath test (GBT) and duodenal aspiration/culture. Metabolic assessments included urinary D-lactic acid and blood L-lactic acid, and ammonia levels. Bowel symptoms, and gastrointestinal transit were assessed. RESULTS Thirty patients with BF and 8 without BF were evaluated. Abdominal bloating, pain, distension and gas were the most severe symptoms and their prevalence was similar between groups. In BF group, all consumed probiotics. SIBO was more prevalent in BF than non-BF group (68 vs. 28%, p = 0.05). D-lactic acidosis was more prevalent in BF compared to non-BF group (77 vs. 25%, p = 0.006). BF was reproduced in 20/30 (66%) patients. Gastrointestinal transit was slow in 10/30 (33%) patients with BF and 2/8 (25%) without. Other metabolic tests were unremarkable. After discontinuation of probiotics and a course of antibiotics, BF resolved and gastrointestinal symptoms improved significantly (p = 0.005) in 23/30 (77%). CONCLUSIONS We describe a syndrome of BF, gas and bloating, possibly related to probiotic use, SIBO, and D-lactic acidosis in a cohort without short bowel. Patients with BF exhibited higher prevalence of SIBO and D-lactic acidosis. Symptoms improved with antibiotics and stopping probiotics. Clinicians should recognize and treat this condition.
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Profiling of lung microbiota in the patients with obstructive sleep apnea.
Lu, D, Yao, X, Abulimiti, A, Cai, L, Zhou, L, Hong, J, Li, N
Medicine. 2018;97(26):e11175
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Obstructive sleep apnoea is a disease of lower airways of the lungs. Numerous studies have reported that various commensal bacteria such as Streptococcus, Veillonella, Prevotella, and Actinomyces are predominant in healthy human lungs. Therefore the current study was designed to analyse and assess the lower airway microbiota in patients with Obstructive sleep apnoea (OSA) and compared it to that of control group (who did not have OSA but had other lung disease). Sleep apnoea was examined with a sleep diagnostic device and data were analysed with Profusion PSG software. The study was conducted in China and total number of subjects who took part in the study was 19. On comparison between the two groups revealed that, Fusobacteria species of bacteria was higher in OSA patients whilst firmicutes species was significantly less. The result from the study indicated that lung microbiota in OSA patients were different from those of control group(non OSA )patients and maybe manipulation of the microbiota could be considered as an intervention to increase airway immunity and decrease susceptibility to airway infections. Though the authors concluded that more studies are needed before these findings and interventions can be confirmed.
Abstract
Lung microbiota may affect innate immunity and treatment consequence in the obstructive sleep apnea (OSA) patients. Bronchoalveolar lavage fluid (BALF) was obtained from 11 OSA patients and 8 patients with other lung diseases as control, and used for lung microbiota profiling by PCR amplification and sequencing of the microbial samples. It was demonstrated that phyla of Firmicutes, Fusobacteria, and Bacteriodetes were relatively abundant in the lung microbiota. Alpha-diversity comparison between OSA and control group revealed that Proteobacteria and Fusobacteria were significantly higher in OSA patients (0.3863 ± 0.0631 and 0.0682 ± 0.0159, respectively) than that in control group (0.119 ± 0.074 and 0.0006 ± 0.0187, respectively, P < .05 for both phyla). In contrast, Firmicutes was significantly less in OSA patients (0.1371 ± 0.0394) compared with that in the control group (0.384 ± 0.046, P < .05). Comparison within a group (ß-diversity) indicated that the top 5 phyla in the OSA lung were Proteobacteria, Bacteroidetes, Firmicutes, Fusobacteria, and Acidobacteria, while the top 5 phyla in the control group were Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, and Acidobacteria. These findings indicated that lung microbiota in OSA is distinct from that of non-OSA patients. Manipulation of the microbiota may be an alternative strategy to augment airway immunity and to reduce susceptibility to airway infection.
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Elevated methane levels in small intestinal bacterial overgrowth suggests delayed small bowel and colonic transit.
Suri, J, Kataria, R, Malik, Z, Parkman, HP, Schey, R
Medicine. 2018;97(21):e10554
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Whilst the most conclusive way to diagnose SIBO is to use an invasive procedure (endoscopy) to take samples from the middle section of the small intestine (jejunum), lactulose breath testing of methane and hydrogen gasses has become the most commonly used test to rule SIBO in or out. This cohort study used historic data (retrospective) of 78 individuals to compare intestinal transit time in patients with a positive lactulose breath test to those with a negative result, as well as compare patients with hydrogen-positive results with those with methane-positive results. All patients experienced gastrointestinal (GI) symptoms of nausea, bloating, constipation, diarrhea and gas to varying degrees. No significant difference in GI symptom severity was found between those with a positive lactulose breath test and those with a negative result. However, those with a hydrogen-gas positive result had a significantly higher level of reported nausea compared to the methane-gas positive patients. A positive SIBO result on the breath test also did not affect GI transit time in comparison to a negative result. However, those with a methane-gas peak on their positive lactulose breath test had a statistically significant slower GI transit time when compared to those with a hydrogen-positive result.
Abstract
Limited research exists regarding the relationship between small intestinal bacterial overgrowth (SIBO), small bowel transit (SBT), and colonic transit (CT). Furthermore, symptom analysis is limited between the subtypes of SIBO hydrogen producing (H-SIBO) and methane producing (M-SIBO). The primary aims of this study are to: compare the SBT and CT in patients with a positive lactulose breath test (LBT) to those with a normal study; compare the SBT and CT among patients with H-SIBO or M-SIBO; compare the severity of symptoms in patients with a positive LBT to those with a normal study; compare the severity of symptoms among patients with H-SIBO or M-SIBO.A retrospective review was performed for 89 patients who underwent a LBT and whole gut transit scintigraphy (WGTS) between 2014 and 2016. Seventy-eight patients were included. WGTS evaluated gastric emptying, SBT (normal ≥40% radiotracer bolus accumulated at the ileocecal valve at 6 hours), and CT (normal geometric center of colonic activity = 1.6-7.0 at 24 hours, 4.0-7.0 at 48 hours, 6.2-7.0 at 72 hours; elevated geometric center indicates increased transit). We also had patients complete a pretest symptom survey to evaluate nausea, bloating, constipation, diarrhea, belching, and flatulence.A total of 78 patients (69 females, 9 males, mean age of 48 years, mean BMI of 25.9) were evaluated. Forty-seven patients had a positive LBT (H-SIBO 66%, M-SIBO 34%). Comparison of SBT among patients with a positive LBT to normal LBT revealed no significant difference (62.1% vs 58.6%, P = .63). The mean accumulated radiotracer was higher for H-SIBO compared to M-SIBO (71.5% vs 44.1%; P < .05). For CT, all SIBO patients had no significant difference in geometric centers of colonic activity at 24, 48, and 72 hours when compared to the normal group. When subtyping, H-SIBO had significantly higher geometric centers compared to the M-SIBO group at 24 hours (4.4 vs 3.1, P < .001), 48 hours (5.2 vs 3.8, P = .002), and at 72 hours (5.6 vs 4.3, P = .006). The symptom severity scores did not differ between the positive and normal LBT groups. A higher level of nausea was present in the H-SIBO group when compared to the M-SIBO group.Overall, the presence of SIBO does not affect SBT or CT at 24, 48, and 72 hours. However, when analyzing the subtypes, M-SIBO has significantly more delayed SBT and CT when compared to H-SIBO. These results suggest the presence of delayed motility in patients with high methane levels on LBT.
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Association between duration of intravenous antibiotic administration and early-life microbiota development in late-preterm infants.
Zwittink, RD, Renes, IB, van Lingen, RA, van Zoeren-Grobben, D, Konstanti, P, Norbruis, OF, Martin, R, Groot Jebbink, LJM, Knol, J, Belzer, C
European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. 2018;37(3):475-483
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Premature newborn babies are commonly given antibiotics in hospital to prevent or treat infections such as sepsis. This study, carried out in the Netherlands, looked at the effect of intravenous antibiotics on the development of the gut bacteria in premature babies. Stool samples were taken from 15 premature babies who had been exposed to either no antibiotic treatment, or short (less than 3 days) or long (at least 5 days) treatment with the commonly prescribed antibiotics amoxicillin or ceftazidime. At 3 weeks old, babies who had been treated with both short and long courses of antibiotics had significantly lower abundance of the beneficial bacteria Bifidobacterium than those who had received no antibiotics. In babies who received antibiotic treatment lasting 5 days or more, Bifidobacterium levels didn’t recover until they were 6 weeks old. Antibiotics were effective against Enterobacteriaceae, but allowed Enterococcus to thrive and remain dominant for up to two weeks after antibiotic treatment was stopped. The authors concluded that intravenous antibiotics during the first week of a baby’s life greatly affects the gut bacteria. However, short courses of antibiotics allow for a quicker recovery compared to longer courses. Disturbances in the development of gut bacteria caused by antibiotic treatment could influence the development of infants' immune and digestive systems.
Abstract
Antibiotic treatment is common practice in the neonatal ward for the prevention and treatment of sepsis, which is one of the leading causes of mortality and morbidity in preterm infants. Although the effect of antibiotic treatment on microbiota development is well recognised, little attention has been paid to treatment duration. We studied the effect of short and long intravenous antibiotic administration on intestinal microbiota development in preterm infants. Faecal samples from 15 preterm infants (35 ± 1 weeks gestation and 2871 ± 260 g birth weight) exposed to no, short (≤ 3 days) or long (≥ 5 days) treatment with amoxicillin/ceftazidime were collected during the first six postnatal weeks. Microbiota composition was determined through 16S rRNA gene sequencing and by quantitative polymerase chain reaction (qPCR). Short and long antibiotic treat ment significantly lowered the abundance of Bifidobacterium right after treatment (p = 0.027) till postnatal week three (p = 0.028). Long treatment caused Bifidobacterium abundance to remain decreased till postnatal week six (p = 0.009). Antibiotic treatment was effective against members of the Enterobacteriaceae family, but allowed Enterococcus to thrive and remain dominant for up to two weeks after antibiotic treatment discontinuation. Community richness and diversity were not affected by antibiotic treatment, but were positively associated with postnatal age (p < 0.023) and with abundance of Bifidobacterium (p = 0.003). Intravenous antibiotic administration during the first postnatal week greatly affects the infant's gastrointestinal microbiota. However, quick antibiotic treatment cessation allows for its recovery. Disturbances in microbiota development caused by short and, more extensively, by long antibiotic treatment could affect healthy development of the infant via interference with maturation of the immune system and gastrointestinal tract.