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A well-functioning immune system is key to providing good defence against pathogenic organisms and to providing tolerance to non-threatening organisms, to food components and to self. The immune system works by providing an exclusion barrier, by identifying and eliminating pathogens and by identifying and tolerating non-threatening sources of antigens, and by maintaining a memory of immunological encounters. The immune system is complex involving many different cell types distributed throughout the body and many different chemical mediators some of which are involved directly in defence while others have a regulatory role. Babies are born with an immature immune system that fully develops in the first few years of life. Immune competence can decline with ageing. The sub-optimal immune competence that occurs early and late in life increases susceptibility to infection. Undernutrition decreases immune defences, making an individual more susceptible to infection. However, the immune response to an infection can itself impair nutritional status and alter body composition. Practically all forms of immunity are affected by protein–energy malnutrition, but non-specific defences and cell-mediated immunity are most severely affected. Micronutrient deficiencies impair immune function. Here, vitamins A, D and E, and Zn, Fe and Se are discussed. The gut-associated lymphoid tissue is especially important in health and well-being because of its close proximity to a large and diverse population of organisms in the gastrointestinal tract and its exposure to food constituents. Certain probiotic bacteria which modify the gut microbiota enhance immune function in laboratory animals and may do so in human subjects.

The picture of chronic liver diseases (CLDs) has changed considerably in recent years. One of them is the increase of non-alcoholic fatty liver disease. More and more CLD patients, even those with liver cirrhosis (LC), tend to be presenting with obesity these days. The annual rate of muscle loss increases with worsening liver reserve, and thus LC patients are more likely to complicate with sarcopenia. LC is also characterized by protein-energy malnutrition (PEM). Since the PEM in LC can be invariable, the patients probably present with sarcopenic obesity (Sa-O), which involves both sarcopenia and obesity. Currently, there is no mention of Sa-O in the guidelines; however, the rapidly increasing prevalence and poorer clinical consequences of Sa-O are recognized as an important public health problem, and the diagnostic value of Sa-O is expected to increase in the future. Sa-O involves a complex interplay of physiological mechanisms, including increased inflammatory cytokines, oxidative stress, insulin resistance, hormonal disorders, and decline of physical activity. The pathogenesis of Sa-O in LC is diverse, with a lot of perturbations in the muscle–liver–adipose tissue axis. Here, we overview the current knowledge of Sa-O, especially focusing on LC.

Malnutrition refers to inadequate energy and/or nutrient intake. Malnutrition exhibits a bidirectional relationship with infections whereby malnutrition increases risk of infections that further aggravates malnutrition. Severe malnutrition (SM) is the main cause of secondary immune deficiency and mortality among children in developing countries. SM can manifest as marasmus (non-edematous), observed most often (68.6% of all malnutrition cases), kwashiorkor (edematous), detected in 23.8% of cases, and marasmic kwashiorkor, identified in ~7.6% of SM cases. Marasmus and kwashiorkor occur due to calorie-energy and protein-calorie deficiency (PCD), respectively. Kwashiorkor and marasmic kwashiorkor present with reduced protein levels, protein catabolism rates, and altered levels of micronutrients leading to uncontrolled oxidative stress, exhaustion of anaerobic commensals, and proliferation of pathobionts. Due to these alterations, kwashiorkor children present with profoundly impaired immune function, compromised intestinal barrier, and secondary micronutrient deficiencies. Kwashiorkor-induced alterations contribute to growth stunting and reduced efficacy of oral vaccines. SM is treated with antibiotics and ready-to-use therapeutic foods with variable efficacy. Kwashiorkor has been extensively investigated in gnotobiotic (Gn) mice and piglet models to understand its multiple immediate and long-term effects on children health. Due to numerous physiological and immunological similarities between pigs and humans, pig represents a highly relevant model to study kwashiorkor pathophysiology and immunology. Here we summarize the impact of kwashiorkor on children’s health, immunity, and gut functions and review the relevant findings from human and animal studies. We also discuss the reciprocal interactions between PCD and rotavirus—a highly prevalent enteric childhood pathogen due to which pathogenesis and immunity are affected by childhood SM.

Protein malnutrition promotes hepatic steatosis, decreases insulin-like growth factor (IGF)-I production and retards growth. To identify new molecules involved in such changes, we conducted DNA microarray analysis on liver samples from rats fed an isoenergetic low-protein diet for 8 h. We identified the fibroblast growth factor 21 gene (Fgf21) as one of the most strongly up-regulated genes under conditions of acute protein malnutrition (P<0·05, false-discovery rate<0·001). In addition, amino acid deprivation increased Fgf21 mRNA levels in rat liver-derived RL-34 cells (P<0·01). These results suggested that amino acid limitation directly increases Fgf21 expression. FGF21 is a polypeptide hormone that regulates glucose and lipid metabolism. FGF21 also promotes a growth hormone-resistance state and suppresses IGF-I in transgenic mice. Therefore, to determine further whether Fgf21 up-regulation causes hepatic steatosis and growth retardation after IGF-I decrease in protein malnutrition, we fed an isoenergetic low-protein diet to Fgf21-knockout (KO) mice. Fgf21-KO did not rescue growth retardation and reduced plasma IGF-I concentration in these mice. Fgf21-KO mice showed greater epididymal white adipose tissue weight and increased hepatic TAG and cholesterol levels under protein malnutrition conditions (P<0·05). Overall, the results showed that protein deprivation directly increased Fgf21 expression. However, growth retardation and decreased IGF-I were not mediated by increased FGF21 expression in protein malnutrition. Furthermore, FGF21 up-regulation rather appears to have a protective effect against obesity and hepatic steatosis in protein-malnourished animals.

Protein malnutrition (PM) results in pathological changes that are associated with peripheral leukopenia, bone marrow (BM) hypoplasia and alterations in the BM microenvironment leading to hematopoietic failure; however, the mechanisms involved are poorly understood. In this context, the BM mesenchymal stem cells (MSCs) are cells intimately related to the formation of the BM microenvironment, and their differentiation into adipocytes is important because adipocytes are cells that have the capability to negatively modulate hematopoiesis. Two-month-old male Balb/c mice were subjected to protein-energy malnutrition with a low-protein diet containing 2% protein, whereas control animals were fed a diet containing 12% protein. The hematopoietic parameters and the expression of CD45 and CD117 positive cells in the BM were evaluated. MSCs were isolated from BM, and their capability to produce SCF, IL-3, G-CSF and GM-CSF were analyzed. The expression of PPAR-γ and C/EBP-α as well as the expression of PPAR-γ and SREBP mRNAs were evaluated in MSCs together with their capability to differentiate into adipocytes in vitro. The malnourished animals had anemia and leukopenia as well as spleen and bone marrow hypoplasia and a reduction in the expression of CD45 and CD117 positive cells from BM. The MSCs of the malnourished mice presented an increased capability to produce SCF and reduced production of G-CSF and GM-CSF. The MSCs from the malnourished animals showed increased expression of PPAR-γ protein and PPAR-γ mRNA associated with an increased capability to differentiate into adipocytes. The alterations found in the malnourished animals allowed us to conclude that malnutrition committed MSC differentiation leading to adipocyte decision and compromised their capacity for cytokine production, contributing to an impaired hematopoietic microenvironment and inducing the bone marrow failure commonly observed in protein malnutrition states.

While protein-energy malnutrition in the adult has been reported to induce motor abnormalities and exaggerate motor deficits caused by stroke, it is not known if alterations in mature cortical neurons contribute to the functional deficits. Therefore, we explored if PEM in adult rats provoked changes in the biochemical profile of neurons in the forelimb and hindlimb regions of the motor cortex. Fourier transform infrared spectroscopic imaging using a synchrotron generated light source revealed for the first time altered lipid composition in neurons and subcellular domains (cytosol and nuclei) in a cortical layer and region-specific manner. This change measured by the area under the curve of the δ(CH2) band may indicate modifications in membrane fluidity. These PEM-induced biochemical changes were associated with the development of abnormalities in forelimb use and posture. The findings of this study provide a mechanism by which PEM, if not treated, could exacerbate the course of various neurological disorders and diminish treatment efficacy.

Pancreatic beta cell (β) dysfunction is an outcome of malnutrition. We assessed the role of the amplifying pathway (AMP PATH) in β cells in malnourished obese mice. C57Bl-6 mice were fed a control (C) or a low-protein diet (R). The groups were then fed a high-fat diet (CH and RH). AMP PATH contribution to insulin secretion was assessed upon incubating islets with diazoxide and KCl. CH and RH displayed increased glucose intolerance, insulin resistance and glucose-stimulated insulin secretion. Only RH showed a higher contribution of the AMP PATH. The mitochondrial membrane potential of RH was decreased, and ATP flux was unaltered. In RH islets, glutamate dehydrogenase (GDH) protein content and activity increased, and the AMP PATH contribution was reestablished when GDH was blunted. Thus, protein malnutrition induces mitochondrial dysfunction in β cells, leading to an increased contribution of the AMP PATH to insulin secretion through the enhancement of GDH content and activity.

Protein–energy malnutrition (PEM) causes a significant impairment of the immune system, the thymus being one of the most affected organs. It has been demonstrated that the administration of probiotic fermented milk (PFM) recovered the intestinal barrier, histological alterations and mucosal and systemic immune functions in a non-severe malnutrition model using BALB/c mice. The aim of the present study was to evaluate, in the same model of malnutrition, the effect of a PFM added to a re-nutrition diet on the recovery of the thymus, analysing histological and functional alterations caused by malnutrition. Mice were undernourished and divided into three groups according to the dietary supplement received during re-nutrition: milk, PFM or its bacterial-free supernatant (BFS). They were compared with well-nourished and malnourished mice. PFM was the most effective re-nutrition supplement to improve the histology of the thymus, decreasing cellular apoptosis in this organ and recovering the percentage of CD4 + /CD8 − single-positive thymocytes. Immature double-positive thymocytes were increased in the malnourished control (MC). The production of different cytokines in the thymus was increased in mice given PFM, compared with the mice that received other dietary supplements and MC. Mice given the BFS presented an improvement in the thymus similar to those that received milk. We demonstrated the importance of the whole PFM supplementation on the histological and functional recovery of the thymus in a non-severe PEM model.

Hypercaloric low-protein diet may lead to a state of malnutrition found in the low-income population of Northeastern Brazil. Although malnutrition during critical periods in the early life is associated with cardiovascular diseases in adulthood, the mechanisms of cardiac dysfunction are still unclear. Here we studied the effects of post-weaning malnutrition due to low protein intake induced by a regional basic diet on the cardiac contractility of young adult rats. In vivo arterial hemodynamic and in vitro myocardial contractility were evaluated in 3-month-old rats. Additionally, protein content of the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA), total phospholamban (PLB) and phosphorylated at serine 16 (p-Ser(16)-PLB), α2-subunit of the Na(+)/K(+)-ATPase (α2-NKA), and Na(+)/Ca(2+) exchanger (NXC) and in situ production of superoxide anion (O2(-)) were measured in the heart. Blood pressure and heart rate increased in the post-weaning malnourished (PWM) rats. Moreover, malnutrition decreased twitch force and inotropic responses of the isolated cardiac muscle. Protein expression of SERCA, PLB/SERCA, and p-Ser(16)-PLB/PLB ratios and α2-NKA were decreased without changing NCX. The contraction dependent on transsarcolemmal calcium influx was unchanged but responsiveness to Ca(2+) and tetanic peak contractions were impaired in the PWM group. Myocardial O2(-) production was significantly increased by PWM. Our data demonstrated that this hypercaloric low-protein diet in rats is associated with myocardial dysfunction, altered expression of major calcium handling proteins, and increased local oxidative stress. These findings reinforce the attention needed for pediatric care, since chronic malnutrition in early life is related to increased cardiovascular risk in adulthood. Graphical Abstract

Protein-energy malnutrition (PEM) can lead to growth hormone (GH) resistance. Leucine supplementation diets have been shown to increase protein synthesis in muscles. Our study aimed at investigating if long-term leucine supplementation could modulate GH-insulin-like growth factor (IGF)-1 system function and mammalian target of rapamycin (mTOR)-related signal transduction in skeletal muscles in a rat model of severe malnutrition. Male Sprague-Dawley rats (n = 50; weight, 302 ± 5 g) were divided into 5 treatment groups, including 2 control groups (a normal control group that was fed chow and ad libitum water [CON, n = 10] and a malnourished control group [MC, n = 10] that was fed a 50% chow diet). After undergoing a weight loss stage for 4 weeks, rats received either the chow diet (MC-CON, n = 10), the chow diet supplemented with low-dose leucine (MC-L, n = 10), or the chow diet supplemented with high-dose leucine (MC-H, n = 10) for 2 weeks. The muscle masses of the gastrocnemius, soleus, and extensor digitorum longus were significantly reduced in the MC group. Re-feeding increased muscle mass, especially in the MC-L and MC-H groups. In the MC group, serum IGF-1, IGF-binding protein (IGFBP)-3, and hepatic growth hormone receptor (GHR) levels were significantly decreased and phosphorylation of the downstream anabolic signaling effectors protein kinase B (Akt), mTOR, and ribosomal protein S6 kinase 1 (S6K1) were significantly lower than in other groups. However, serum IGF-1 and IGF binding protein (IGFBP)-3 concentrations and hepatic growth hormone receptor (GHR) levels were significantly higher in the MC-L and MC-H groups than in the MC-CON group, and serum IGFBP-1 levels was significantly reduced in the MC-L and MC-H groups. These changes were consistent with those observed for hepatic mRNA expression levels. Phosphorylation of the downstream anabolic signaling effectors Akt, mTOR, and S6K1 were also significantly higher in the MC-L and MC-H groups than in the MC-CON group. Our data are the first to demonstrate that long-term supplementation with leucine improved acquired growth hormone resistance in rats with protein-energy malnutrition. Leucine might promote skeletal muscle protein synthesis by regulating downstream anabolic signaling transduction.