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Suresh Gyan Vihar University International Journal of Environment, Science and Technology
Volume 4, Issue 2, August 2018, pp. 1-17
ISSN: 2394-9570
Changes in Nutritional Factors Affecting
Tuberculosis: A Systematic Review
Amarachi Ruth Anigbo1, Elizabeth Kanayo Ngwu2, Manjinder Kour3*
1Research Scholar, School of Applied Sciences , Suresh Gyan Vihar University, Jaipur, India
2Professor, Department of Nutrition and Dietetics, University of Nigeria, Nsukka, Nigeria
3Assistant Professor, School of Applied Sciences , Suresh Gyan Vihar University, Jaipur, India
*Corresponding author, email: manjinderkour1992@gmail.com
Abstract
Nutrition plays a major role in the management and prevention of tuberculosis(TB); this happens
in terms of the body immune response to the pathogenic organism. Nutrients like macro-nutrients
and micronutrients, vitamins, proteins, carbohydrates are associated with boosting immune
responses against pathogen mycobacterium tuberculosis causing tuberculosis. These nutrients
have an immunomodulatory effects in controlling exposure to infectious agents, the process of
inflammation and nutritional deficiency. When there is malnutrition, it increases the individual or
group of population’s susceptibility to progressive stages from infection to disease. This review
looks at various nutritional factors which includes the body mass index, weight, height, mid-arm
circumference which are nutritional indicators that show when an individual is healthy or
malnourished which leads to poor immune response that in turn affects an individual’s ability to
fight mycobacterium tuberculosis infection or disease. Some researches have been carried out to
show the relationship between nutritional factors and the roles they play in mycobacterium
tuberculosis infection and prevention. But, very few evidences in the literature has shown a
specific quantity of food that can alter the course of tuberculosis disease.
Keywords: Tuberculosis, Micronutrients, Macronutrients, Body mass Index, Mid Arm
Circumference.
2
1. INTRODUCTION
Tuberculosis is a bacterial disease caused by
Mycobacterium tuberculosis a condition in
which the body oxidizes an abnormally large
quantity of protein from foods rather than
using them for protein synthesis and leading
to a condition protein energy malnutrition
which is a high-risk factor that exposes an
individual or a group of persons to
tuberculosis [1]. According to the World
Health Organization (WHO), Tuberculosis
has been ranked number 9 among the world
leading cause of death [2], and these has been
attributed to so many factors, but specifically
to poor nutritional status especially among
the regions classified as high burdened
regions; of which India is ranked 5th among
the list of 30 countries.
Nutrition can be defined as the science of
eating food and the effects of food
components on the metabolism, health,
performance and disease resistance of human
and animals. Food is good, but an adequate
food is best for the immune system to
function properly so as to be able to defend
the entire body system when there are
exposures to infection. For an individual or
group of population to have adequate
nutritional intake, the six classes of food
which includes protein, carbohydrate, fats
and oil, vitamins and minerals have to be
taken in appropriate proportion. There is a
very close relationship between nutrition and
tuberculosis as deficiency of one or more
nutrients in the body for a long period of time
leads to the weakening of the immune system
which pre-disposes the individual or group of
population [3].
Nutritional indicators to show that a disease
condition like tuberculosis is present includes
body weight, height, body mass index, iron,
calcium, magnesium levels, vitamin D, K, C,
B12 levels. [4]. More so, when there is a pre-
existing condition like human
immunodeficiency virus (HIV), it plays a key
role in enhancing the rate of infection while
individual or group of population is exposed
to TB transmission; this could be termed as
exogenous factors. Certain factors like
socioeconomic, environmental and
behavioral are classified under exogenous
factors as they play a vital role in determining
the nutritional status of a population.
The objective of this study is to show
nutritional factors that positively or
negatively promote or prevent the occurrence
3
of tuberculosis infection individually or in a
group of population.
2. BODY MASS INDEX AND
TUBERCULOSIS
Body mass index (BMI) plays a very
important role in the well being of an
individual or a population [5]. Based on the
BMI an individual or group of individuals
can be classified as underweight, normal and
overweight Table1 [6]. A research conducted
in rural China with adults; showed that BMI
is associated with so many infections, and a
low BMI is associated with a susceptibility to
tuberculosis [7].
Classification BMI (kg/m2 )
Healthy Weight 18.5-24.9
Overweight 25-29.9
Obesity I 30-34.9
Obesity II 35-39.9
Obesity III 40 and above
Table 1: Source: Adapted from WHO 1995, WHO 2000 and WHO 2004. Accessed
22/12/2017
BMI has also been shown as a major tool in
determining the death rate among
tuberculosis patient’s in China, It was
observed that when there is malnutrition it
leads to underweight in an individual or a
group, that impairs or weakens the immune
system [9]. Further more a study conducted
in the United States showed that BMI, varied
amongst races and gender still using the
WHO BMI standards; Hispanic and men
from other races (which includes the
White/Caucasian, Black/African American,
Middle eastern, Indian, native American,
East-Asian, South-east Asian, pacific
islanders) had a high BMI of 26kg/m2 and
25kg/m2 respectively and the females had a
high body fat and a short height [10].
Undernutrition which results to a low BMI is
one of the major problem faced by TB
patients globally, especially in developing
countries and it is was discovered in the study
that one-third of the TB patients in Addis
Abba health Centre were undernourished,
and the prevalence of undernutrition among
the adults TB patients was high [11].
4
3. THE ROLE OF VITAMINS
IN TUBERCULOSIS
TB patients lack vital nutrients like vitamins,
causing them to get malnourished, and
placing them at a higher risk of getting
infection due to weakened immune response.
Vitamin as a dietary supplement has to be
taken exogenously because human beings
cannot synthesize vitamins or; if produced,
the concentration can’t be sufficient. Human
beings can synthesize Niacin (Vitamin B3)
and Vitamin D but lack the ability to
synthesize Thiamine (Vitamin B1),
Riboflavin (Vitamin B2), Pantothenic Acid
(Vitamin B5), Pyridoxine (Vitamin B6),
Biotin (Vitamin B7), Folate (Vitamin B9),
Cobalamin (Vitamin B12), Vitamin E,
Vitamin C, and Vitamin K [12]. Nutritional
supplements that has essential vitamins and
minerals could help patients to fight against
the disease by building up and strengthening
their immune response [13]. Vitamins always
have been considered an important
supplement that boosts immunity. Recent
studies have discovered the
antimycobacterial nature of vitamins[14]. In
one of the studies, it was discovered that
Vitamin D possesses antimycobacterial
properties which acts directly when added
into a growth medium [15]. The same was
also discovered for Vitamin A. Recently, a
study by Vilchèze et al. [16] Showed that
Vitamin C can inhibit M. tuberculosis
through hydroxyl radicals produced in
Fenton’s reaction. A common mechanism
used by bactericidal antibiotics to cause cell
death involves the generation of highly
reactive hydroxyl radicals through fenton’s
reaction. Hydroxyl radicals induce cell death
by damaging the DNA, which is in part due
to the oxidation of the guanine nucleotide
pool.
In the presence of reductants like vitamin C
in Fentons reaction, ferrous ions are produced
by reduction of ferric ions. Therefore vitamin
C has been discovered as a compound that
speeds up fentons reaction which makes
mycobacterium tuberculosis highly
susceptible to killing. In a cross-sectional
study carried out in Ethiopia, the
concentration of Vitamin C, Vitamin E, and
Vitamin A was found to be low in
Tuberculosis patients as compared to the
healthy controls [15]. Some reports states that
maintenance of an adequate level of Vitamin
D could be effective as a prophylactic method
against some respiratory tract infections [17].
In addition, a close relationship has been
found between Vitamin D levels and
Tuberculosis [13]. In fact, in the advent of
antibiotics, cod liver oil and exposure to
sunlight was used for Tuberculosis treatment.
5
Vitamin D activates production of
cathelicidin in white blood cells to kill TB
[18], Not only antimycobacterial properties
of vitamins but also essential biosynthetic
pathways operational in M. tuberculosis
involving vitamins are being studied from the
drug target perspective. Absence of
corresponding pathways in human beings
makes biotin and thiamin biosynthesis
pathways attractive drug targets [19].
Vitamins play diverse role in the infection
and pathogenicity of Tuberculosis. Studies
involving thiamin, biotin, Vitamin C, and
Vitamin D have gained significance
primarily due to their potency as drug targets
or because of their antimycobacterial
properties [20].
A. VITAMIN B1
Vitamin B1 also known as thiamine is an
essential micronutrient required for the
proper functioning of amino acid and
carbohydrate metabolic enzymes in its active
form, i.e., thiamin diphosphate [21-22]. It is
required for the biological activity of
pyruvate dehydrogenase, transketolase,
acetohydroxy acid synthase, and
2‑oxoglutarate dehydrogenase. M.
tuberculosis does not have thiamin
compensating mechanisms, making thiamin
biosynthetic mechanisms an attractive drug
target [23]. M. tuberculosis thiamin
phosphate synthase, a gene involved in the
synthesis of thiamin phosphate which is
further phosphorylated to the final product,
i.e., thiamin pyrophosphate in mycobacteria,
was screened bioinformatically for drug
targets by investigators. Results obtained
after virtual screening were tested in vitro and
one of the tested compounds showed potent
antimycobacterial activity having a low
inhibitory concentration (MIC) of 6 μg/ml
[24]. Further studies are required to validate
these findings and possibly reveal more
potential drug targets.
B. VITAMIN B7
Vitamin B7 also called biotin is essential for
growth and pathogenicity of M. tuberculosis.
It works as a cofactor in two key enzymes
required for fatty acid synthesis and
anaplerosis namely acyl CoA carboxylase
and pyruvate carboxylase [25]. These
enzymes are responsible for the metabolic
fixation of carbon dioxide. Biotin is an
indispensable vitamin for all living
organisms. However, its synthesis in plants,
and some fungi is limited. Like thiamin,
human beings are dependent on a dietary
supplement and gut microflora for their daily
uptake of biotin [26]. It has been suggested
that de novo biotin biosynthesis is necessary
6
for M. tuberculosis since it lacks biotin
transporters as discovered by genetic studies.
Moreover serum concentration of biotin is
very small in human beings to meet the
requirement needed [27]. Biotin is produced
with the help of enzymes BioF, BioA, BioD,
and BioB using pimeloyl‑CoA as a precursor
[28-30]. Synthesis of biotin from
pimeloyl‑CoA is well conserved in all the
biotin producing organisms.
C. VITAMIN C
Vitamin C also called ascorbic acid is an
essential micronutrient for human beings
which has to be taken as a dietary supplement
since humans cannot synthesize vitamin C
because of the mutation in the gene encoding
the enzyme gulonolactone oxidase
[31]. Vitamin C protects its host from
reactive oxygen and reactive nitrogen
intermediates generated during
mycobacterial infection [32]. For prevention
of common cold and influenza, Linus Pauling
in 1976 recommended 1–3 g/day of vitamin
C. Several studies have suggested the role of
vitamin C in the prevention and treatment of
TB by oral administration the vitamin.
Vitamin C deficiency has also been linked to
TB infection [33]. A study conducted on a
sample size of 1100 individuals diagnosed as
not having tuberculosis initially, correlated
their nutrition status with the susceptibility of
Tuberculosis development. Of all
individuals, 28 developed TB during the
course of the study and it was observed that
they had a less amount vitamin C
concentration [34]. It has also been shown
that Vitamin C acts as an activator for
inducing dormancy in M. tuberculosis.
Vitamin C induces DevR (DosR) regulation
which is responsible for the development of
dormancy in bacteria [35].
A study identifying antagonistic effects of
vitamin C when used with rifampicin and
isoniazid found some interesting results. It
was observed that there was reduction in the
colony forming units of wild type H37Rv
strain as well as drug-resistant strains, when
grown in the presence of vitamin C and
rifampicin at substantial Minimum Inhibitory
Concentration. Reduction in Colony Forming
Unit in wild type and drug-resistant strains
was also observed when vitamin C was tested
together with isoniazid. However, isoniazid-
vitamin C combination showed a weaker
effect against resistant strains as compared to
wild type H37Rv [36]. Narwadiya et al. have
shown an association between vitamin C
concentration and anti-TB properties of
medicinal plants [37]. Vitamin C reduces
ferric to ferrous ion which generates
superoxide, hydrogen peroxide, and hydroxyl
7
radicals in the presence of oxygen through
Fenton and Haber–Weiss reaction
[15]. These radicals damage the DNA and
lipids of M. tuberculosis leading to growth
impediment . Vitamin C is also believed to
reduce the level of guanosine 5'-diphosphate-
3'-diphosphate (ppGpp), a molecule thought
to be involved in growth regulation and stress
response in M. tuberculosis [38]. Recently it
was observed that water soluble vitamins of
which vitamin C is one, can prevent the
progression of a disease causing organism
because of its antioxidant activity. According
to Khameneh et al. 2016, vitamin c has shown
to selectively improve the antibacterial
activity of anti-tuberculosis drugs against
M.tuberculosis [39].
D. VITAMIN D
Vitamin D also called calciferol plays a role
in maintaining calcium homeostasis and bone
mineral density in human beings. It comes in
two major forms namely ergocalciferol
(Vitamin D2) and cholecalciferol (Vitamin
D3). This Vitamin is obtained either through
diet or exposure of epidermis to sunlight
(ultraviolet B radiation-UVB). However, its
role as a protective agent against various
diseases is being researched [40]. Studies
have found some relationship between
vitamin D deficiency and its susceptibility to
Tuberculosis since 1651, when the deficiency
of vitamins was found to be associated with
signs and symptoms of Tuberculosis for the
first time. Later, heliotherapy became a
common practice for patients with
Tuberculosis and this formed the basis of
treatment in sanatoria [41]. Meanwhile,
Stead et al. showed racial differences in the
incidence of Tuberculosis which was
associated with the levels of 25 hydroxy
Vitamin D [42]. Although conflicting results
which emerged from clinical trials, in one of
the studies carried out by Salahuddin et al.,
observed high doses of vitamin D
supplementation which enhanced clinical and
radiographic improvement in Tuberculosis
patients [43]. In a contrast, studies carried
out by Ralph et al.[44], and Daley et
al.[45] observed no significant improvement
in the culture conversion rate in vitamin D
supplemented patients. There is a debate
whether culture conversion rate can be a
parameter while studying the effect of
vitamin D supplementation. Tissue damage
prevention may be an appropriate method
during the study of vitamin D
supplementation effects [46].
Reports has shown that vitamin D
concentration in human beings depend on the
season and latitude which indirectly has a
8
relationship with Tuberculosis outbreak. A
study carried out at Birmingham having data
from 9739 patients over a period of 28 years
pointed to the fact that Tuberculosis
outbreaks increased by 24.1%, during the
winters there is low incidence of sunshine
with decreased vitamin D concentration
which led to higher Tuberculosis outbreak in
the winter season. A similar study was also
conducted in South Africa having the same
results [47]. Concentration of vitamin D in
humans depends on various factors that
include biosynthesis by human body,
pigmentation, latitude, dietary
supplementation, obesity, genetics, and
disease status. Deficiency of vitamin D (<50
nmol/l 25(OH)D) is a global problem, and
areas such as Middle East and South Asia
have severe deficiency which in turn may
increase the susceptibility to various diseases
[48].
Vitamins
Names
Scientific
Name
Solubility of
Vitamins
Food Sources
Plant Sources Animal Sources
Vitamin A
Retinol Fat Soluble Riped yellow
fruits, Yellow corn,
Carrots, pumpkin,
Squash, Spinach
Liver, Fish, Milk
Vitamin D Cholecalciferol Fat soluble Mushrooms Fish, Eggs, Liver
Vitamin
B1
Thiamine Water Soluble Oat meal, brown
rice, potatoes
Eggs, Liver
Vitamin
B7
Biotin Water Soluble Leafy green
vegetable, peanuts
Raw egg yolk, Liver
Vitamin C Ascorbic acid Water soluble Fruits and
vegetable
Liver
Table 2: Showing the sources of vitamins discussed in the Review Article [49].
4. PROTEIN-ENERGY
MALNUTRITION AND
TUBERCULOSIS
Proteins are large complex molecules that
play an important role in the body. They
perform mostly structural and regulatory
function in the tissues and organs. Proteins
9
are made up of thousands of smaller units
called amino acids which have been found to
have a link with tuberculosis infection.
According to WHO, protein energy
malnutrition is defined as an imbalance
between the supply of protein and energy and
the bodies demand for them to ensure optimal
growth and function. In india, Protein Energy
Malnutrition is one of the major concerns
among other healths disorders because of its
dire consequences ranging from physical to
cognitive growth and susceptibility to
infections [50]. The salvage cycle of
infection and undernutrition go hand in hand.
With inadequate dietary intake, the immune
response gets weaker and increases
susceptibility to infections [51]. A research
study conducted by the University of
California [UCLA] group of scientist
discovered that protein play a key role in
protecting people infected with
Mycobacteruim tuberculosis from
developing the active form of the disease.
The protein interleukin-32 which is a
protective protein was discovered to be one
biomarker that has an adequate host defense
against tuberculosis; it can induce killing of
the TB bacterium only in the presence of
vitamin D [52]. The in depth study of proteins
and its interactions has given a clearer
understanding with regards to tuberculosis
disease through proteomics study [53].
Undernutrion is observed with patients who
have tuberculosis infection and this is seen in
the form of wasting which is decrease in the
circulation of body protein mass, decreased
fat mass and a reduced protein and energy
intake. Protein energy malnutrition occurs as
a result of insufficient protein essential for
creating and regenerating body tissues; which
greatly compromises the body’s immune
functions [54]. Protein energy malnutrition
could be seen in the following forms (i) acute
malnutrition which is a precursor to wasting.
(ii) chronic Malnutrition which leads to
stunting [55]. Taking a critical observation at
the feeding patterns or behaviour of a
particular group of people; it can be deduced
that their feeding behaviours or pattern goes
a very long way in preventing malnutrition
and infection like tuberculosis [56]. Poverty
and income is more common to population
with lower income and even if malnutrition is
present in the upper income population, it is
limited to the milder forms [57]. There is a
disproportionate large number of
impoverished and socially excluded groups
in the society among the poor people, which
exposes them to further deprivable poverty,
food insecurity and undernutrition [58].
Though 26% of people live below the poverty
line in India, 46% of under three children are
10
suffering from undernutrition [59]. This
shows that the prevalence of poverty solely
cannot be responsible for undernutrition but
is an underlying cause of factors like
inadequate dietary intake, large family,
infection, unhygienic environment and
illiteracy which contributes to undernutrition
among low income group and when they are
undernourished, the immune system gets
weaken which pre-exposes them to getting
infected with tuberculosis.
Figure 1: Showing the cycle relationship between Protein Energy Malnutrition and Tuberculosis
When there is no steady source of income or
the income is very small, and the possibilities
of getting a well paid job is highly
competitive which is the case senario in the
indian setting, food insecurity sets in, the
people are not able to buy qualitative food that
Poverty
1
Worsened problem
of food insecurity
and nutrition
6
Active TB
7
Food Insecurity
2
Undernutrition
3
Reduced
Resistance to TB
4
Reduced inability
of people to work
5
Protein Energy Malnutrition and Tuberculosis Cycle
11
will be sufficient for the entire household.
When these continue for a long period of time,
undernutrition begins, members of the
household begin to lack some vital nutrients
that are required to build up the immune
system; causing the immune system to be
weak and become less resistant to primary
infections like tuberculosis that will want to
invade the imune system. Once the immune
system is weak, the strength to work and look
for sources to earn a living is greatly
compromised which worsens the problem of
food insecurity leading to a full
disease(tuberculosis) as a result of lack of
vital nutrients required by the body.
5. MICRONUTRIENTS AND
TUBERCULOSIS
Micronutrient deficiency happens as a result
of increased metabolic demands and
decreased intake of micronutrients which
worsen the disease and delay recovery by
supressing immune functions [60]. The
following micronutrients have shown to be of
great importance in improve immune
response when there is tuberculosis infection;
and these include Zinc, iron, copper, calcuim
and selenium [61]. Zinc- Various studies on
patients with tuberculosis had shown
significantly lower plasma zinc level than
those without tuberculosis, irrespective of
their nutritional status. There was significant
rise in zinc level at the end of six- months of
antituberculosis therapy (ATT). Thus, it may
be suggested that plasma zinc status is likely
a marker for monitoring the severity of
disease and response to therapy [62]. Zinc
supplementation of patients with pulmonary
tuberculosis helps to increase immunity and
thereby speed up the recovery process [63].
An adequate supply of zinc needs to be
ensured through foods such as seafood, meat,
seeds, and cooked dried beans, peas and
lentils [64]. Selenium- The essential trace
element selenium has an important function in
maintaining the immune processes and thus
may have a critical role in clearance of the
bacteria related to TB. Sea-foods and organ
meats are the richest food sources of
selenium. Other sources include muscle
meats, cereals and other grains, and dairy
products [65]. Anemia is highly prevalent
among adults with pulmonary tuberculosis. In
a study, concentration of hemoglobin was
lower in tuberculosis patients than that in
normal healthy subjects. There are two
reasons for the association of low iron status
and infection. One is that anemia which
results from chronic infection and the other is
that iron deficiency which increases the
susceptibility of a person or group of
individuals to infection like tuberculosis [66].
12
6. CONCLUSION
In summary there is a very close relationship
between macro nutrients and micro nutrients
and the prevention, treatment and control of
tuberculosis disease. Adequate nutrition plays
a vital role in building up the immune system.
If proper care and attention is paid to the
classes of food nutrients we consume, this
deadly disease tuberculosis will be a thing of
the past. A healthy immune system is
adequately fortified with food nutrients.
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