Protein Energy Malnutrition Is Associated with Worse Outcomes in Sepsis-A Nationwide Analysis.

BACKGROUND: Protein-energy malnutrition (PEM), resulting from depleted energy and nutrient stores, compromises the body's defense systems and may exacerbate sepsis and its impact. However, population-based studies examining the association of PEM on the prevalence and health-care burden of sepsis are lacking. OBJECTIVE: To investigate the relationship between PEM and sepsis, influence of PEM on clinical outcomes of sepsis, and impact of PEM on trends in sepsis mortality. DESIGN: The primary study is a retrospective cohort analysis of the 2012-2014 National Inpatient Sample (NIS) patient discharge records. Secondary analyses are cross-sectional study on the 2014 NIS and trend analysis on 2007-2014 NIS. PARTICIPANTS/SETTING: The primary study included adult inpatient hospitalizations for sepsis in the United States. MAIN OUTCOME MEASURES: Mortality, complicated sepsis, and 10 other metrics of clinical outcomes and health care utilization. STATISTICAL ANALYSIS: First, patients with sepsis (2014 NIS) were stratified into two groups: uncomplicated (without shock) and complicated (with shock). The adjusted odds ratio of having sepsis (total, uncomplicated, and complicated) was estimated with PEM as predictor using logistic regressions (binomial and multinomial). Second, among patients with sepsis (2012-2014 NIS), PEM cases were matched to cases without PEM (no-PEM) using a greedy-algorithm based propensity-matching methodology (1:1), and the outcomes were measured with conditional regression models. Finally, the trend in mortality from sepsis was calculated, stratified by PEM status, as an effect modifier, using Poisson models (2007-2014 NIS). All models accounted for the complex sampling methodology (SAS 9.4). RESULTS: In 2014, PEM was associated with higher odds for sepsis (3.97 [3.89 to 4.05], P<0.0001) and complicated vs uncomplicated sepsis (1.74 [1.67 to 1.81], P<0.0001). From 2012-2014, about 18% (167,133 of 908,552) of hospitalizations for sepsis had coexisting PEM. After propensity matching, PEM was associated with higher mortality (adjusted odds ratio: 1.35 [1.32 to 1.37], P<0.0001), cost ($160,724 [159,517 to 161,940] vs $86,650 [85,931 to 87,375], P<0.0001), length of stay (14.8 [14.9 to 14.8] vs 8.5 [8.5 to 8.6] days, P<0.0001), adverse events, and resource utilization. Although mortality in sepsis has been trending down from 2007-2014 (-1.19% per year, P trend<0.0001), the decrease was less pronounced among those with PEM vs no-PEM (-0.86% per year vs -1.29% per year, P<0.0001). CONCLUSIONS: PEM is a risk factor for sepsis and associated with poorer outcomes among patients with sepsis. A concerted effort involving all health care workers in the prevention, identification, and treatment of PEM in community-dwelling people before hospitalization might mitigate against these devastating outcomes.

Gut Microbiota Alteration is Characterized by a Proteobacteria and Fusobacteria Bloom in Kwashiorkor and a Bacteroidetes Paucity in Marasmus.

Kwashiorkor and marasmus are considered to be two different clinical diseases resulting from severe malnutrition, but this distinction has been questioned. In a previous study comparing children with kwashiorkor and healthy children from Niger and Senegal, we found a dramatic gut microbiota alteration with a predominant depletion of anaerobes and enrichment in Proteobacteria and Fusobacteria in kwashiorkor. However, it remained unknown whether this association was related to malnutrition or was a specific feature of kwashiorkor. In this continuation study, we added 7 new marasmus subjects and 71,162 new colonies from the same countries. Our results showed that, compared to marasmus, the kwashiorkor gut microbiota was characterized by an increased proportion of Proteobacteria (culturomics, Marasmus 5.0%, Kwashiorkor 16.7%, p < 0.0001; metagenomics, Marasmus 14.7%, Kwashiorkor 22.0%, p = 0.001), but there was a decreased proportion of Bacteroidetes in marasmus (culturomics, Marasmus 0.8%, Kwashiorkor 6.5%, p = 0.001; metagenomics, Marasmus 5.4%, Kwashiorkor 7.0%, p = 0.03). Fusobacterium was more frequently cultured from kwashiorkor. All detected potential pathogenic species were enriched in the kwashiorkor gut microbiota. These results provide a biological basis to support the usage of an antibiotic therapy more effective in suppressing the overgrowth of bacterial communities resistant to penicillin, combined with antioxidants and probiotics for nutritional recovery therapies, particularly for kwashiorkor.

Increased Urinary Trimethylamine N-Oxide Following Cryptosporidium Infection and Protein Malnutrition Independent of Microbiome Effects.

Cryptosporidium infections have been associated with growth stunting, even in the absence of diarrhea. Having previously detailed the effects of protein deficiency on both microbiome and metabolome in this model, we now describe the specific gut microbial and biochemical effects of Cryptosporidium infection. Protein-deficient mice were infected with Cryptosporidium parvum oocysts for 6-13 days and compared with uninfected controls. Following infection, there was an increase in the urinary excretion of choline- and amino-acid-derived metabolites. Conversely, infection reduced the excretion of the microbial-host cometabolite (3-hydroxyphenyl)propionate-sulfate and disrupted metabolites involved in the tricarboxylic acid (TCA) cycle. Correlation analysis of microbial and biochemical profiles resulted in associations between various microbiota members and TCA cycle metabolites, as well as some microbial-specific degradation products. However, no correlation was observed between the majority of the infection-associated metabolites and the fecal bacteria, suggesting that these biochemical perturbations are independent of concurrent changes in the relative abundance of members of the microbiota. We conclude that cryptosporidial infection in protein-deficient mice can mimic some metabolic changes seen in malnourished children and may help elucidate our understanding of long-term metabolic consequences of early childhood enteric infections.

Glycans affect DNA extraction and induce substantial differences in gut metagenomic studies.

Exopolysaccharides produced by bacterial species and present in feces are extremely inhibitory to DNA restriction and can cause discrepancies in metagenomic studies. We determined the effects of different DNA extraction methods on the apparent composition of the gut microbiota using Illumina MiSeq deep sequencing technology. DNA was extracted from the stool from an obese female using 10 different methods and the choice of DNA extraction method affected the proportional abundance at the phylum level, species richness (Chao index, 227 to 2,714) and diversity (non parametric Shannon, 1.37 to 4.4). Moreover DNA was extracted from stools obtained from 83 different individuals by the fastest extraction assay and by an extraction assay that degradated exopolysaccharides. The fastest extraction method was able to detect 68% to 100% genera and 42% to 95% species whereas the glycan degradation extraction method was able to detect 56% to 93% genera and 25% to 87% species. To allow a good liberation of DNA from exopolysaccharides commonly presented in stools, we recommend the mechanical lysis of stools plus glycan degradation, used here for the first time. Caution must be taken in the interpretation of current metagenomic studies, as the efficiency of DNA extraction varies widely among stool samples.

Microbial-Derived Metabolites Reflect an Altered Intestinal Microbiota during Catch-Up Growth in Undernourished Neonatal Mice.

BACKGROUND: Protein-energy undernutrition during early development confers a lifelong increased risk of obesity-related metabolic disease. Mechanisms by which metabolic abnormalities persist despite catch-up growth are poorly understood. OBJECTIVE: We sought to determine whether abnormal metabolomic and intestinal microbiota profiles from undernourished neonatal mice remain altered during catch-up growth. METHODS: Male and female CD1 mouse pups were undernourished by timed separation from lactating dams for 4 h at 5 d of age, 8 h at 6 d of age, and 12 h/d from 7 to 15 d of age, then resumed ad libitum nursing, whereas controls fed uninterrupted. Both groups were weaned simultaneously to a standard unpurified diet. At 3 time points (0, 1, and 3 wk after ending feed deprivation), metabolites in urine, plasma, and stool were identified with the use of mass spectrometry, and fecal microbes were identified with the use of 16S metagenomic sequencing. RESULTS: Undernourished mice completely recovered deficits of 36% weight and 9% length by 3 wk of refeeding, at which time they had 1.4-fold higher plasma phenyllactate and 2.0-fold higher urinary p-cresol sulfate concentrations than did controls. Plasma serotonin concentrations in undernourished mice were 25% lower at 0 wk but 1.5-fold higher than in controls at 3 wk. Whereas most urine and plasma metabolites normalized with refeeding, 117 fecal metabolites remained altered at 3 wk, including multiple N-linked glycans. Microbiota profiles from undernourished mice also remained distinct, with lower mean proportions of Bacteroidetes (67% compared with 83%) and higher proportions of Firmicutes (26% compared with 16%). Abundances of the mucolytic organisms Akkermansia muciniphila and Mucispirillum schaedleri were altered at 0 and 1 wk. Whereas microbiota from undernourished mice at 0 wk contained 11% less community diversity (P = 0.015), refed mice at 3 wk harbored 1.2-fold greater diversity (P = 0.0006) than did controls. CONCLUSION: Microbial-derived metabolites and intestinal microbiota remain altered during catch-up growth in undernourished neonatal mice.

THE RELEVANCE OF NUTRITIONAL STATUS AND HISTOPATHOLOGICAL FINDINGS ON THE INFECTIOUS PROCESS OF BALB/C MICE INOCULATED WITH Lacazia loboi.

The aim of this study was to evaluate the effects of the protein-calorie malnutrition in BALB/c isogenic mice infected with Lacazia loboi, employing nutritional and histopathological parameters. Four groups were composed: G1: inoculated with restricted diet, G2: not inoculated with restricted diet, G3: inoculated with regular diet, G4: not inoculated with regular diet. Once malnutrition had been imposed, the animals were inoculated intradermally in the footpad and after four months, were sacrificed for the excision of the footpad, liver and spleen. The infection did not exert great influence on the body weight of the mice. The weight of the liver and spleen showed reduction in the undernourished groups when compared to the nourished groups. The macroscopic lesions, viability index and total number of fungi found in the footpads of the infected mice were increased in G3 when compared to G1. Regarding the histopathological analysis of the footpad, a global cellularity increase in the composition of the granuloma was observed in G3 when compared to G1, with large numbers of macrophages and multinucleated giant cells, discrete numbers of lymphocytes were present in G3 and an increase was observed in G1. The results suggest that there is considerable interaction between Jorge Lobo's disease and nutrition.

THE RELEVANCE OF NUTRITIONAL STATUS AND HISTOPATHOLOGICAL FINDINGS ON THE INFECTIOUS PROCESS OF BALB/C MICE INOCULATED WITH Lacazia loboi / A relevância do estado nutricional e alterações histopatológicas no processo infeccioso de camundongos BALB/c inoculados com Lacazia loboi

SUMMARY The aim of this study was to evaluate the effects of the protein-calorie malnutrition in BALB/c isogenic mice infected with Lacazia loboi, employing nutritional and histopathological parameters. Four groups were composed: G1: inoculated with restricted diet, G2: not inoculated with restricted diet, G3: inoculated with regular diet, G4: not inoculated with regular diet. Once malnutrition had been imposed, the animals were inoculated intradermally in the footpad and after four months, were sacrificed for the excision of the footpad, liver and spleen. The infection did not exert great influence on the body weight of the mice. The weight of the liver and spleen showed reduction in the undernourished groups when compared to the nourished groups. The macroscopic lesions, viability index and total number of fungi found in the footpads of the infected mice were increased in G3 when compared to G1. Regarding the histopathological analysis of the footpad, a global cellularity increase in the composition of the granuloma was observed in G3 when compared to G1, with large numbers of macrophages and multinucleated giant cells, discrete numbers of lymphocytes were present in G3 and an increase was observed in G1. The results suggest that there is considerable interaction between Jorge Lobo's disease and nutrition.

RESUMO O objetivo do estudo foi avaliar os efeitos da desnutrição protéico-calórica em camundongos isogênicos da linhagem BALB/c inoculados com Lacazia loboi, empregando parâmetros nutricionais e histopatológicos. Foram constituídos quatro grupos: G1- inoculados com restrição dietética; G2- não inoculados com restrição dietética; G3- inoculados sem restrição dietética; G4- não inoculados sem restrição dietética. Após instalada a desnutrição, os animais foram inoculados via intradérmica no coxim plantar e após quatro meses foram sacrificados para remoção do coxim plantar, fígado e baço. A infecção não exerceu grande influência no peso corporal dos camundongos. O peso do fígado e baço apresentou redução nos grupos desnutridos em comparação aos grupos nutridos. A lesão macroscópica, a viabilidade e o número total de fungos dos coxins plantares dos camundongos inoculados revelaram aumento no G3 quando comparado com o G1. Em relação à análise histopatológica dos coxins plantares observou-se aumento da celularidade global na composição do granuloma no G3 em relação ao G1, com grande número de macrófagos e células gigantes multinucleadas, discretos números de linfócitos estavam presentes em G3 e aumentados no G1. Os resultados sugerem que existe grande interação entre nutrição e doença de Jorge Lobo.

The pleiotropic role of vitamin A in regulating mucosal immunity.

The effect of vitamin A on mucosal immunity has never been subjected to extensive studies until recently. We started to work in this area in the early 1970s when we observed that children with protein-calorie malnutrition (PCM) often had defective mucosal immunity, judging from the incidence of respiratory tract infections and diarrhea. We reported that these children had depressed secretory IgA (sIgA) levels in their nasal wash fluids. The IgA level in specimens collected from those superimposed with some degrees of vitamin A deficiency state appeared to be more severely affected. In order to better understand the underlying mechanism associated with this condition, we started to study more detail the deficiency state using experimental vitamin A-deficient rats. From a series of experiments using this animal model, we proposed that vitamin A was needed for transport and/or secretion of sIgA across the mucosa. This conclusion was based on the observation that the secretory component of sIgA synthesized by the epithelial cells of these vitamin A deficient animals was adversely affected as compared to the control animals. From that time onward, much progress has been made by several other groups showing that other mechanisms could also influence the integrity and immune function of the mucosa. For instance, recent studies demonstrated that retinoic acid which is a biologically active form of vitamin A has an essential role in mucosal homeostasis, controlling tolerance and immunity in these non-lymphoid tissues. Such a conclusion was made possible by the availability of sophisticated new molecular biology and genetic engineering techniques together with advances in the field of immunoregulation, e.g., the discovery of dendritic cells (DCs) and T helper cell subsets in 1980s, and the role of Toll-like receptors (TLRs) together with other innate immune regulators in controlling adaptive immune response in the early 1990s. These advances provided considerable new insights into the pleiotropic roles of vitamin A including educating mucosal DCs, differentiation of lymphocyte lineages and imprinting them with mucosal-homing properties as well as in regulating tolerance and immunity. The identification of a novel lymphocyte subpopulation, innate lymphoid cells (ILCs), at the beginning of this century has provided us with an additional insight into a new role of vitamin A in regulating homeostasis at the mucosal surface through influencing ILCs. Another new player that regulates intestinal homeostasis and mucosal immune response is microbiota whose composition is known to vary with vitamin A status. So it appears now that the role of vitamin A on mucosal immunity is far beyond regulating the adaptive Th1-Th2 cell response, but is highly pleiotropic and more complicating, e.g., polarizing the phenotype of mucosal DCs and macrophages, directing gut-homing migration of T and B cells, inducing differentiation of effector T cells and Treg subpopulation, balancing mucosal ILCs subpopulation and influencing the composition of microbiota. In this review, I will attempt to bring together these important advances to provide a comprehensive and contemporary perspective on the role of vitamin A in regulating mucosal immunity.

Composition and function of the undernourished neonatal mouse intestinal microbiome.

Undernutrition remains one of the key global health challenges facing children today. Distinct microbial profiles have been associated with obesity and undernutrition, although mechanisms behind these associations are unknown. We sought to understand how protein-energy undernutrition alters the microbiome and to propose mechanisms by which these alterations influence the malnourished phenotype. Outbred CD1 neonatal mice were undernourished by timed separation from lactating dams, while control animals nursed ad libitum. 16S rRNA gene sequencing and compositional analysis identified microbes from luminal contents of ileum, cecum and colon, while whole metagenome shotgun sequencing identified microbial gene content. Our results suggest that the most important determinant of microbiome composition is body compartment; communities derived from ileum are distinct from those from cecum and colon as observed by phylogenetic clustering analysis. However, within each compartment, microbiota from undernourished and control mice cluster separately. At the phylum level, undernourished mice harbor more Verrucomicrobia and less Bacteroidetes in the distal intestine; these changes are driven by an increase in Akkermansia muciniphila and decreases in Bacteroides and Alistipes. Undernourished mice have an overall loss of microbial community richness and diversity and are deficient in multiple microbial genetic pathways including N-glycan, inositol phosphate and one-carbon metabolism. Losses in these microbial genes may confer less efficient extraction of energy from nondigestible dietary components including glycans and phytates, whereas epigenetic alterations provide a means of persistently altering metabolism even after adequate nutrition is restored. Thus, the microbiome of an undernourished host may perpetuate states of poor nutrition via multiple mechanisms.

Alterations of gut barrier and gut microbiota in food restriction, food deprivation and protein-energy wasting.

Increasing evidence shows that gut microbiota composition is related to changes of gut barrier function including gut permeability and immune function. Gut microbiota is different in obese compared to lean subjects, suggesting that gut microbes are also involved in energy metabolism and subsequent nutritional state. While research on gut microbiota and gut barrier has presently mostly focused on intestinal inflammatory bowel diseases and more recently on obesity and type 2 diabetes, this review aims at summarizing the present knowledge regarding the impact, in vivo, of depleted nutritional states on structure and function of the gut epithelium, the gut-associated lymphoid tissue (GALT), the gut microbiota and the enteric nervous system. It highlights the complex interactions between the components of gut barrier in depleted states due to food deprivation, food restriction and protein energy wasting and shows that these interactions are multidirectional, implying the existence of feedbacks.

THE RELEVANCE OF NUTRITIONAL STATUS AND HISTOPATHOLOGICAL FINDINGS ON THE INFECTIOUS PROCESS OF BALB/C MICE INOCULATED WITH Lacazia loboi / A relevância do estado nutricional e alterações histopatológicas no processo infeccioso de camundongos BALB/c inoculados com Lacazia loboi

The aim of this study was to evaluate the effects of the protein-calorie malnutrition in BALB/c isogenic mice infected with Lacazia loboi, employing nutritional and histopathological parameters. Four groups were composed: G1: inoculated with restricted diet, G2: not inoculated with restricted diet, G3: inoculated with regular diet, G4: not inoculated with regular diet. Once malnutrition had been imposed, the animals were inoculated intradermally in the footpad and after four months, were sacrificed for the excision of the footpad, liver and spleen. The infection did not exert great influence on the body weight of the mice. The weight of the liver and spleen showed reduction in the undernourished groups when compared to the nourished groups. The macroscopic lesions, viability index and total number of fungi found in the footpads of the infected mice were increased in G3 when compared to G1. Regarding the histopathological analysis of the footpad, a global cellularity increase in the composition of the granuloma was observed in G3 when compared to G1, with large numbers of macrophages and multinucleated giant cells, discrete numbers of lymphocytes were present in G3 and an increase was observed in G1. The results suggest that there is considerable interaction between Jorge Lobo's disease and nutrition

O objetivo do estudo foi avaliar os efeitos da desnutrição protéico-calórica em camundongos isogênicos da linhagem BALB/c inoculados com Lacazia loboi, empregando parâmetros nutricionais e histopatológicos. Foram constituídos quatro grupos: G1- inoculados com restrição dietética; G2- não inoculados com restrição dietética; G3- inoculados sem restrição dietética; G4- não inoculados sem restrição dietética. Após instalada a desnutrição, os animais foram inoculados via intradérmica no coxim plantar e após quatro meses foram sacrificados para remoção do coxim plantar, fígado e baço. A infecção não exerceu grande influência no peso corporal dos camundongos. O peso do fígado e baço apresentou redução nos grupos desnutridos em comparação aos grupos nutridos. A lesão macroscópica, a viabilidade e o número total de fungos dos coxins plantares dos camundongos inoculados revelaram aumento no G3 quando comparado com o G1. Em relação à análise histopatológica dos coxins plantares observou-se aumento da celularidade global na composição do granuloma no G3 em relação ao G1, com grande número de macrófagos e células gigantes multinucleadas, discretos números de linfócitos estavam presentes em G3 e aumentados no G1. Os resultados sugerem que existe grande interação entre nutrição e doença de Jorge Lobo

Dietary supplementation with Lactobacilli improves emergency granulopoiesis in protein-malnourished mice and enhances respiratory innate immune response.

This work studied the effect of protein malnutrition on the hemato-immune response to the respiratory challenge with Streptococcus pneumoniae and evaluated whether the dietary recovery with a probiotic strain has a beneficial effect in that response. Three important conclusions can be inferred from the results presented in this work: a) protein-malnutrition significantly impairs the emergency myelopoiesis induced by the generation of the innate immune response against pneumococcal infection; b) repletion of malnourished mice with treatments including nasally or orally administered Lactobacillus rhamnosus CRL1505 are able to significantly accelerate the recovery of granulopoiesis and improve innate immunity and; c) the immunological mechanisms involved in the protective effect of immunobiotics vary according to the route of administration. The study demonstrated that dietary recovery of malnourished mice with oral or nasal administration of L. rhamnosus CRL1505 improves emergency granulopoiesis and that CXCR4/CXCR12 signaling would be involved in this effect. Then, the results summarized here are a starting point for future research and open up broad prospects for future applications of probiotics in the recovery of immunocompromised malnourished hosts.

Malnutrition and microbiota--a new relationship?

Severe acute malnutrition is a life-threatening disease affecting millions of children. A recent study has now identified an immature gut microbiome as an important contributing factor in children with kwashiorkor. The condition was transmissible into gnotobiotic mice by combining stool transplantation and region-specific diet. In addition, antibiotics reduce mortality in children with kwashiorkor.

Effect of Lactobacillus pentosus ONRIC b0240 on intestinal IgA production in mice fed differing levels of protein.

Protein-energy malnutrition (PEM) is frequently associated with the occurrence of infection due to a decline in immune function. Here, an experiment was conducted with the objective of enhancing mucosal immunity by administration of Lactobacillus pentosus ONRIC b0240 (b240) in PEM model mice. Three groups of male C3H/HeN mice aged approximately 12 weeks were caged in groups of five or six and received various treatments. The mice were fed 4 (low-protein diet; PEM model), 20 (standard-protein diet), or 40% (high-protein diet) ovalbumin (OVA) with or without 0.05% b240. Five weeks later, all mice were sacrificed, and the organs were extracted for analysis of the immune response. Acute toxicity was not observed in this study. The addition of b240 showed no influence on body weight; however, body weight decreased with increasing protein level. Interestingly, intestinal total IgA was significantly increased (p<0.05) in all test diets with b240. The in vitro study showed that the number of B cells and type 2 helper T (Th2) cells were significantly increased in mouse spleen cells with b240 treatment, whereas no differences were found in the number of Th1 cells. b240 also has the ability to augment IgA and IgG production in mouse Peyer's patch cells. These results suggest that b240 enhances IgA production and helps recover the intestinal immune system in PEM model mice via augmentation of humoral immunity.

Time course of bacterial diversity in stool samples of malnourished children with cholera receiving treatment.

BACKGROUND: Recent nutritional interventions have targeted colonic functions in patients with infectious diarrhea during rehydration and during recovery from malnutrition, with the assumption that the effects will be influenced by metabolism of complex carbohydrates by colonic bacteria. However, the diversity of colonic bacteria in patients with cholera is not known. AIM: To study the diversity of colonic bacteria in malnourished children with cholera before and during treatment with oral rehydration salt solutions containing 1 of these 3 substrates: glucose, rice, or amylase-resistant starch. PATIENTS AND METHODS: Serial fecal samples were collected from 30 malnourished children with cholera until completion of rehydration and partial nutritional recovery; 11 malnourished children without diarrhea; and 6 better nourished children. Polymerase chain reaction, using universal primers for 16S rDNA, was performed on chromosomal DNA extracted from the stool samples, and the products were separated by temporal temperature gradient gel electrophoresis. RESULTS: The Vibrio cholerae band was detected in all children at enrollment and disappeared within 2 days. On day 2, a rapid and significant increase in the band numbers was observed, which was followed by a steady increase until day 28. After full recovery from cholera and partial recovery from malnutrition, the number of bands (11.5+/-2.8) was lower than in healthy children (22.2+/-1.3). On day 3, the number of bands was greater with rice or amylase-resistant starch than with glucose (P<.05). CONCLUSIONS: Bacterial diversity was markedly but transiently altered in severely malnourished children with cholera receiving therapy.

Yoghurt accelerates the recovery of defence mechanisms against Streptococcus pneumoniae in protein-malnourished mice.

Experiments studied the effect of yoghurt on the recovery of defence mechanisms against Streptococcus pneumoniae respiratory infection in malnourished mice. Weaned mice were malnourished with a protein-free diet (PFD) for 21 d. Malnourished mice were made replete with a balanced diet (BD), yoghurt, or the BD with supplemental yoghurt (BD + Y) for 7, 14 or 21 d. The normal control (NC) group was fed the BD whereas malnourished control (MC) mice consumed only the PFD. Mice were challenged with pneumococci at the end of each dietary treatment. MC mice showed increased susceptibility to pneumococcal infection. Blood leucocytes, phagocyte activity and serum and bronco-alveolar anti-pneumococcal IgG and IgA were significantly lower in the MC than in the NC group. Repletion of malnourished mice with the BD for 21 d was necessary to obtain a response to infection similar to that of NC mice; however, administration of the BD + Y for 14 d was enough to normalise the immune defence mechanisms. Histological examination of MC lungs showed progressive loss of alveolar architecture. Lung injuries were significantly less pronounced in NC mice. Mice treated with the BD + Y for 14 d showed histological signs similar to the NC group. The present study showed that administration of yoghurt to malnourished mice induced an early recovery of the immunological parameters studied. Despite the uncertainties about the mechanisms involved and about the human relevance of the effects observed in animal models, the present study provides a strong rationale for the hypothesis that yoghurt consumption by malnourished hosts will accelerate the recovery of the immune mechanisms involved in the protection against respiratory infections.

Translocation model of Candida albicans in DBA-2/J mice with protein calorie malnutrition mimics hematogenous candidiasis in humans.

To elucidate the mechanism of translocation of Candida albicans from the intestine to the bloodstream, we attempted to establish a murine model for hematogenous translocation of C. albicans using DBA-2/J mice with protein calorie malnutrition (PCM). PCM severely affected the development of the intestinal epithelia; thereby, the keratin and mucinous layers became very thin. Oral inoculation with C. albicans resulted in long-term colonization in the intestine of the PCM mice but not the well-nourished animals. Chemotherapy with a combination of cyclophosphamide and methotrexate, which started four days after oral inoculation of C. albicans, resulted in the systemic dissemination of C. albicans from the intestine in the PCM mice. Among systemic organs, C. albicans was first isolated from the liver, in which focal necrosis, containing fungal balls of yeast-like forms and/or hyphae, was formed. Subsequently, C. albicans was first recovered from the blood of the infected PCM mice at one day after the isolation from the liver, and thereafter, candidemia continued to increase its intensity until death. Histological study indicated that C. albicans gained entry into the systemic organs from the epithelia of the esophago-cardiac junction as well as the Ileo-cecal portions of the infected mice. The results of our present study therefore suggest that this PCM mouse model may be useful for better understanding of the chemotherapy-induced translocation by C. albicans from the gut to the systemic organs in compromised humans.

[Caseous pneumonia in a 14-month-old infant]. / Pneumonie caséeuse chez un nourrisson de 14 mois.

We report a case of caseous pneumonia in a 14-month-old HIV-negative infant. This clinical picture is usually observed in healthy young adults, rarely in infants. The clinical and radiological signs of caseous pneumonia often simulate acute non-tuberculous respiratory disease. Bacteriological confirmation is required, but the diagnosis can be suggested in case of a pulmonary syndrome with no bacterial isolate and unresponsive to well-conducted antibiotic therapy. The clinical course is rapid with caseous involution of the lung. Early diagnosis is required for specific curative treatment and to limit sequelae.

Innate lung defenses and compromised Pseudomonas aeruginosa clearance in the malnourished mouse model of respiratory infections in cystic fibrosis.

Cystic fibrosis (CF) is characterized by dysfunction of the digestive and respiratory tracts resulting in generalized malnutrition and chronic respiratory infections. Chronic lung infections with Pseudomonas aeruginosa, intense neutrophil-dominated airway inflammation, and progressive lung disease are the major cause of high morbidity and mortality in CF. Here we investigated the effects of malnutrition in CF on innate lung defenses, susceptibility to P. aeruginosa colonization, and associated inflammation, using aerosol models of acute and chronic infections in normal, malnourished, and transgenic mice. CFTR(m1Unc-/-) knockout mice displayed body weight variations and showed variable pulmonary clearance of P. aeruginosa. This variability was not detected in bitransgenic CFTR(m1Unc-/-)(FABP-hCFTR) mice in which the intestinal defect had been corrected. Diet-induced protein calorie malnutrition in C57BL/6J mice resulted in impaired pulmonary clearance of P. aeruginosa. Tumor necrosis factor alpha (TNF-alpha) and nitrite levels detected upon exposure to P. aeruginosa aerosols were lower in the lungs of the malnourished C57BL/6J mice relative than in lungs of mice fed a normal diet. The role of TNF-alpha and reactive nitrogen intermediates in P. aeruginosa clearance was tested in TNF-alpha and inducible nitric oxide synthase (iNOS) knockout mice. P. aeruginosa clearance was diminished in transgenic TNF-alpha- and iNOS-deficient mice. In contrast to the effects of TNF-alpha and iNOS, gamma interferon knockout mice retained a full capacity to eliminate P. aeruginosa from the lung. Malnutrition also contributed to excessive inflammation in C57BL/6J mice upon chronic challenge with P. aeruginosa. The repeatedly infected malnourished host did not produce interleukin-10, a major anti-inflammatory cytokine absent or diminished in the bronchoalveolar fluids of CF patients. These results are consistent with a model in which defective CFTR in the intestinal tract leads to nutritional deficiency which in turn contributes to compromised innate lung defenses, bacterial colonization, and excessive inflammation in the CF respiratory tract.

Respiratory syncytial virus infections in malnourished children.

The prevalence of respiratory syncytial virus (RSV) infection among severely malnourished children was studied at the University of Benin Teaching Hospital, Benin City, Nigeria at a time when the infection was known to be prevalent in the community. Nasopharyngeal washings were obtained from subjects on admission and thereafter every 4 days until discharge. RSV was detected by ELISA technique. Of 20 well nourished children who served as controls, 11 were ELISA-positive for RSV (55%). Eight (16%) of the 51 patients who were malnourished were ELISA-positive, four of whom (8%) had nosocomial infection. Fever and rhinitis were the most common presenting features in the RSV-infected malnourished children. None of the children showed any clinical or radiological signs of lower respiratory tract infection. Malnourished children appear not to be at increased risk of RSV infection, and those who contract the infection usually do not manifest severe disease.