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Review paper

The role of nutrition and dietary supplements in the management of diarrhoea in HIV patients: a review of the literature

Ivan Armando Osuna-Padilla
1, 2
,
Claudia Patricia Maza-Moscoso
3
,
Isabel Martínez Del Río-Requejo
4

1.
Centro de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico
2.
Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico
3.
Department of Nutrition and Dietetic, Centro Médico Militar, Guatemala City, Guatemala
4.
Nutrition Division, Hospital 20 de Noviembre, ISSSTE, Mexico City, Mexico
HIV AIDS Rev 2019; 18, 3: 158-164
Online publish date: 2019/09/09
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Introduction

Although progress has been made in the global fight against human immunodeficiency virus (HIV), the prevalence continued to increase and diarrhoea is one of the main causes of morbidity and mortality, being present in 28-60% of people living with HIV (PLWHIV) [1, 2]. HIV infection per se leads to alterations in the intestinal barrier integrity with changes in the following: (a) the biological barrier, producing a variation in the composition of the intestinal microbiota, a reduction in Bifidobacterium and lactobacilli, and an increase in opportunistic pathogen families, such as Pseudomonas aeruginosa and Candida albicans; (b) the immunological barrier, with a massive depletion of CD4+ and Th17 cells in the intestine, altering the balance of immunological cells; and (c) the mechanical barrier, with atrophy in the intestinal villi and alterations in the expression of intestinal tight junctions [3].

Definition and classification of diarrhea

The World Health Organization define diarrhoea as “the passage of three or more loose or liquid stools per day, or more frequently than normal for the individual” [4]. The Bristol Stool Chart scale may be useful to evaluate the consistency of evacuations, where types 5, 6, and 7 tend toward diarrhoea [5].
Diarrhoea may be classified by duration and aetiology. Considering the duration, diarrhoea is classified as acute when the duration is from 0 to 13 days, persistent when existing from 14 to 29 days, and chronic when the duration is more than 30 days [6, 7].
Considering the aetiology, diarrhoea is classified as infectious or non-infectious. Infectious diarrhoea is common in HIV patients who are not receiving antiretroviral therapy (ART) because intestinal alterations lead to bacterial translocation, defined by Zevin et al. as the movement of microbial products from the gut mucosa into circulation [8], which are phagocytosed and contribute to the intestinal inflammatory response and predispose to developing diarrhoea by overgrowth of opportunistic bacterial, protozoal, viral, and fungal pathogens in the intestinal lumen [1]. On the other hand, some translocated bacteria and toxic compounds are drained by the mesenteric lymph system, which can induce the development of chronical local and systemic immune stimulation [8].
The most common microorganisms that cause diarrhoea in PLWHIV are: Escherichia coli, Cryptosporidium, Microsporidia, Cystoisospora belli, Cytomegalovirus, and Mycobacte¬rium avium complex [7].
Non-infectious diarrhoea in PLWHIV is caused by alterations in the mechanical barrier, also known as enteropathy associated with HIV or associated with ART [9], which is defined as an idiopathic form of diarrhoea where no pathogen agent is identified, and it is characterised by histological changes in the intestinal microarchitecture. Malabsorption is a consequence of this type of diarrhoea, which leads to weight loss and malnutrition [10]. Diarrhoea is also an adverse effect of ART, mainly in those treated with protease inhibitors drugs, which increase the water and electrolyte secretion to the intestinal lumen, although all medicines generally cause a higher incidence of diarrhoea [11].

Nutritional implications of diarrhoea in HIV

Acute and chronic diarrhoea have serious implications for the nutritional status of PLWHIV, reducing food intake and the ability to nutrient absorption, which leads to malnutrition. An observational study of faecal losses of energy (measured by bomb calorimetry) in critically ill patients with severe diarrhoea showed a low intestinal energy-absorption capacity in patients who evacuated more than 350 g/day, and documented a faecal energy loss of 445.5 ± 201.3 kcal/day [12].
Chronic diarrhoea has other nutritional implications including fat and muscle wasting and higher prevalence of nutritional deficiencies, mainly vitamin B12. However, no prevalence data are available [13]. Additionally, infectious diarrhoea is associated with increased catabolism, higher use of nutrients, reduction in quality of life [14], and increased risk of infection due to the reduction of immune response and damage to the intestinal mucosa [15].

Nutritional management

In infectious diarrhoea, the medical treatment is the eradi¬cation of identified pathogens; however, there is no specific treatment for non-infectious diarrhoea. The use of antisec¬retory medications, antimotility agents, adsorbent agents, and others is suggested [16].
The use of non-pharmacological strategies, including dietary modifications and supplementation of some nutrients, could have an impact on the number and consistency of stool depositions; however, there are a lack of clinical trials evaluating the effectiveness of nutrition therapy [17]. Recommendations from guidelines and literature reviews remark the importance to obtain a food intake history from each patient with the aim of quantifying food and nutrient consumption, in order to establish the association of food intake and symptoms and assess the adequacy of intake. Capili et al. analysed nutrient intake (seven-day food diary) in a sample of 75 PLWHIV on ART with non-pathogen diarrhoea, and reports suboptimal intake of fibre due to the low consumption of fruit and vegetables [18, 19].

Dietary modifications

The aim of nutritional intervention is to promote the intake of optimal amounts of energy and protein in order to maintain or improve the patient’s nutritional status and quality of life. Resting energy expenditure should be measured by indirect calorimetry or estimated using Mifflin St. Jeor equations in patients with normal weight and Harris-Benedict in obese patients [20]. It is important to take into account the aetiology of diarrhoea to design the best nutritional strategy, and to consider the provision of a higher energy supply (50-100% extra) in cases of malabsorption. The Academy of Nutrition and Dietetics recommends 1.0-1.4 g/kg of protein for maintenance of the body mass or 1.5-2.0 g/kg in malnutrition status [21]. Other international societies suggest an energy prescription considering the HIV classification proposed by the Centres for Disease Control and Prevention, providing 30-35 kcal/kg in patients in phase A, 35-40 kcal/kg in phase B, and 40-50 kcal/kg in phase C; however, there are no clinical data about the accuracy of this method [22].
Clinical guidelines state that certain foods may aggravate or reduce chronic diarrhoea [17] because the damage to the intestinal mucosa reduces the absorption of carbohydrates which increases in the intestinal lumen, causing liquid retention due to osmolality and fermentation by gut microbiota, increasing gastrointestinal symptoms. Taking this into consideration, restriction of refined sugars and lactose is recommended, attention has been focused on reducing the supply of foods rich in fructose (e.g. fruit juices and other sweet beverages). On the other hand, high-fat diets are associated with a loss of liquids, electrolytes, bile acids, and divalent cations to the intestinal lumen; therefore it is recommended that the amount of fat in the diet is reduced; caffeine restriction is also recommended due to the stimulation peristaltic movement. Lack of clinical trials evaluating the impact of food restriction in HIV-positive patients are available. Anastasi et al. evaluated in 65 patients with PLWHIV the impact of dietary modifications (diet low in fat, lactose, and insoluble fibre) and reported a reduction of 28% in the frequency of stool depositions and improvement in faecal consistency after six months of intervention [23].
Eat small meals recommendation (more than three meals per day) may be useful to increase the consumption of nutrients and promote longer use of the absorption surface area in the intestine for more time during the day [18]. There is a lack of evidence to support this recommendation alone, but these interventions may be useful as part of a comprehensive intervention plan.
FODMAP is an acronym that stands for Fermentable-Oligo-Di-Monosaccharides and Polyols. These are carbohydrates that are present naturally in many foods and play an important role in inducing diarrhoea and other symptoms in irritable bowel syndrome (IBS) patients; fructose and polyols are absorbed slowly in the small intestine; lactose cannot be digested by many patients; and oligosaccharides also cannot be digested. After intake of a meal high in FODMAP or gluten, these carbohydrates pass undigested into the large intestine and are fermented, producing gas, diarrhoea, bloating and distention in the IBS population [24]. Mechanisms of diarrhoea in IBS patients are different from those of HIV+ patients; however, bacterial translocations are present in both conditions (intestinal permeability correlates with stool frequency in IBS conditions [25]), and one cross-sectional study reports a greater prevalence of IBS in HIV-positive compared with HIV-negative subjects (10.2% vs. 2.2%, p ≤ 0.002) [26], which might be explained by the possible role of some pathogenic infections in the development and exacerbation of this condition [27]. Some studies suggest that a low-FODMAP or gluten-free diet might improve stool consistency and frequency in IBS [24, 28, 29] by improving intestinal permeability, but no evidence from observational or clinical trial data in HIV patients are available.
In patients with suboptimal energy and protein intake, prescription of elemental nutrition formulations (containing hydrolyzed whey protein and medium-chain triglycerides) may be considered, in order to increase the intake of nutrients and improve their absorption [30]. Salomon et al. reported a decrease in the number of stools and improvement in faecal fat excretion after nine days of enteral feeding with an elemental diet in 11 PLWHIV and diarrhoea [31]. In a randomised trial comparing elemental formula (85% of medium-chain triglycerides, n = 13) and control formula (100% long-chain triglycerides, n = 10) in patients with malabsorption and HIV, Craig et al. reported a decreased in stool fat and stool nitrogen, an increase in fat absorption, and a trend toward as decreased number of bowel movements after 12 days of elemental formula [32]. Limitations of both studies were the number of individuals included in the analysis and the limited data about the randomisation process.
Vitamin and mineral supplementation must be considered in patients with suboptimal intake, mainly in cases of malabsorption. Total parenteral nutrition (TPN) prescription does not provide greater benefit than enteral nutrition or oral nutritional supplements and is more expensive [33, 34]; however, it may be considered in patients who are nutritionally at-risk or malnourished, and who unlikely to achieve energy and protein goals in the first three to five days, according the American Society for Parenteral and Enteral Nutrition (ASPEN) [35].
It is important to consider that once the pharmacological therapy is initiated in patients with infectious diarrhoea, improvement is expected in the short-term. In these cases, the purpose of the nutritional management is to maintain adequate hydration and optimal intake of nutrients and electrolytes [36]. Some dietetic recommendations are mentioned in Table 1.

Nutritional supplementation strategies

Zinc

Zinc deficiency has negative effects on the immune system and exacerbates diarrhoea by diverse mechanisms: a) on innate response, deficiency reduces the phagocytic capacity of macrophages and neutrophils as well as NK activity, increasing the vulnerability to infections, b) on adaptive response, it reduces lymphocytes count and proliferation mediated by thymus apoptosis and atrophy. In the gut bar¬rier, zinc deficiency alters liquid secretion [37].
For diarrhoea treatment, World Health Organization sug¬gests the supplementation of 10 mg/day in children < 6 months old for 10-14 days, and 20 mg/day in those > 6 months old [38]. A systematic review of 33 randomised clinical trials in children > 6 months old showed that zinc supplementation can reduce the duration of diarrhoea (MD = –11.46 hours, 95% CI: –19.72 to –3.19 hours). In children with malnutrition, the reduction of diarrhoea seems to be more significant (MD = –26.39 hours, 95% CI: –36.54 to –16.23 hours) [39].
There is no established dose for supplementation in HIV adult patients. Cárcamo et al. supplemented 100 mg/day of elemental zinc in patients with persistent diarrhoea and did not observe any improvement in diarrhoea after 14 days of supplementation [40]. Baum et al. observed an improvement in the incidence of diarrhoea (OR = 0.40, 95% CI: 0.183 to 0.981, p = 0.019) after supplementation of 12 mg in women and 15 mg in men for 18 months in a sample of 231 PLWHIV with low plasma zinc levels [41]. Among other benefits in PLWHIV, zinc supplementation has shown an increased CD4+ count, improved serum concentration of zinc, and prevention of opportunistic infections [42].

Glutamine

Glutamine represents the most abundant amino acid present in plasma, which plays an important role in various metabolic and biochemical processes. One of them is the regulation of the integrity in the intestinal surface by increasing protein synthesis in the epithelial intestinal cells [43].
Different authors have evaluated the safety and efficacy of glutamine supplementation in PLWHIV. Noyer et al. documented improvements in the intestinal permeability after glutamine supplementation for 28 days in patients with intestinal permeability diagnosed by alterations in the mannitol and lactulose test, using an oral dose of glutamine of 4-8 g/day, suggesting doses of at least 20 g/day [44]. Similar results were reported by Bushen et al. after supplementing oral doses of 30 g/day of glutamine or 44 g/day of alanine glutamine dipeptide for seven days in PLWHIV [45]. Subsequently, Huffman et al. documented a reduction in the severity of diarrhoea associated with ART (nelfinavir), as well as an improvement in the quality of life, using an oral dose of 30 g/day L-glutamine for 10 days in 25 PLWHIV [46]. Recently, Leite et al. evaluated the effect of glutamine in the intestinal permeability in 46 PLWHIV, and reported an increase in the excreted urinary mannitol, after 10 days of an oral solution that contain 24 g of alanine glutamine dipeptide [47]. More recently, an in vitro study in colon biopsies of IBS patients reported an increase in the expression of tight junctions, specifically in Claudin-1, after exposure to different glutamine concentrations, which could explain such benefits in the intestinal permeability improvement and the diarrhoea episodes [48]. Currently there is no consensus about the dose to be used in PLWHIV. Therefore, the recommendations of ASPEN could be followed, suggesting a dose of 0.2-0.5 g/kg/day [49].

Fibre and prebiotics

Fibre is defined as polymers of carbohydrates, which are not hydrolysed by enzymes in the gut, while prebiotics are non-digestible compounds that, after being metabolised by the microorganisms in the intestine, have modulatory functions in the composition and activity of the gut microbiota, producing benefits to the host. Both components have been studied due to their possible benefit in PLWHIV with diarrhoea, specifically in diarrhoea mediated by microbial toxins that alter fluid balance and electrolytes in the intestinal lumen. The use of prebiotics (fructooligosaccharides, oligosaccharides, and inulin) has been suggested as a strategy to prevent diarrhoea and gel forming fibres (Plantago psyllium and guar gum) [50]. ASPEN suggests the use of fermentable soluble fibres (fructooligosaccharides and inulin); specifically, 10-20 g divided into several doses during a period of 24 hours in patients with severe diarrhoea [51], although there is a lack of evidence to support this recommendation. Recently, a meta-analysis that included three randomised clinical trials of two prebiotics and one product of prebiotic fermentation (fructooligosaccharides, galactooligosaccharide, and sodium butyrate) did not show and effect on diarrhoea prevention (RR = 0.83, 95 CI%: 0.58-1.18) [52].
There are no guidelines about the dosage and type of fibres to be used in HIV patients; however, some cross-sectional studies have shown that patients who take Plantago psyllium have reduced incidence of diarrhoea and better consistency in their faeces; therefore, it should be considered as a low-cost strategy [53]. The action mechanism of P. psyllium is its capacity to form gels, contributing to the retention of liquids present in the intestinal lumen, thus improving the stool consistency and frequency of evacuations [54]. Some authors suggest a dose of 18-30 g/day of P. psyllium to normalise the stools in patients with chronic diarrhoea, suggesting a gradually increasing dose to improve tolerance [55]. More recently, Lertpipopmetha et al. reported no beneficial effect on reducing incidence of diarrhoea in general medical patients (43% with infectious diseases) receiving enteral nutrition enriched with 15.2 g/l of psyllium fibre [56].

Probiotics

Probiotics are “live microorganisms which when administered in adequate amounts confer a health benefit on the host” [57]. Several meta-analyses have shown a possible benefit after their use in severe infectious diarrhea and in persistent diarrhea in children and adult patients [58, 59].
Probiotics can reduce infectious diarrhoea in PLWHIV through several mechanisms: (a) they can compete for nutrients and adhere to the epithelium and intestinal mucosa, inhibiting the epithelial invasion by pathogens and preventing the bacterial translocation; and (b) they stimulate the production of antimicrobial substances and IgA [60]. However, their effectiveness is not clear because a meta-analysis published by Carter et al., which included nine clinical trials, did not find benefits in the management of diarrhoea associated with HIV, documenting a possible benefit when products with Saccharomyces boulardii were used [61].
A randomised clinical trial conducted by Santos et al. evaluated the effectiveness of two treatments for reduction of gastrointestinal symptoms in adult patients with ART: group 1 (n = 25) received nutritional treatment + maltodextrin and group 2 (n = 23) received nutritional treatment + symbiotic (6 g fructooligosaccharides and Lactobacillus rhamnosus, L. paracasei, L. acidophilus and Bifidobacterium lactis) for six months. Significant reduction in diarrhoea incidence in both groups was reported, but no difference between the groups was observed [62].
Bacteraemia caused by the use of probiotics is reported in the literature; therefore, their use should not be widespread [63, 64]. The Academy of Nutrition and Dietetics (AND) suggests monitoring the consumption of probiotics in patients with counts of CD4+ < 200 cells/mm3 and in those with CD4+ < 15% [21].
The use of probiotics for the treatment of non-infectious diarrhoea in PLWHIV, especially those receiving ART, is not supported by literature. There is some controversy about probiotics causing damage in patients receiving ART with immunological reconstitution [11].

Conclusions

HIV infection causes anatomic, structural, and biological alterations to the gut, resulting in a greater incidence of diarrhoea episodes. Infectious diarrhoea is common in HIV patients who are not receiving ART, due to intestinal alterations caused by bacterial translocation. Non-infectious diarrhoea is usually present due to enteropathy associated with HIV and as a secondary effect of ART. Acute and chronic diarrhoea cause a reduction in dietary intake and also reduce the ability to absorb nutrients, leading to patient malnutrition and impacting the quality of life. The medical treatment for infectious diarrhoea is the eradication of pathogens; however, there is no specific treatment for non-infectious diarrhoea, which suggests the use of antisecretory medications, antimotility, and adsorbent agents, as well as the use of non-pharmacological strategies such as the dietary modifications and nutrition supplements like zinc, glutamine, fibre, and probiotics.

Acknowledgments

The authors would like to thank Mrs. Miriam Moscoso De Maza for her assistance in technical editorial and medical writing.

Conflict of interest

The authors declare no conflict of interest with respect to the research, authorship, and/or publication of this article.

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