High genetic heterogeneity of Premature Ovarian Insufficiency

From DNA replication and repair to hormonal regulation

 Abstract 

Primary ovarian insufficiency greatly influences a woman’s fertility potential and her overall health. The condition affects about 1–2 % of women and in most cases, the cause is undefined. Primary ovarian insufficiency (POI) may be caused by any process that results in dysfunction or depletion of ovarian follicles, reducing the number of oocytes within the ovary. The tendency for POI to run in families implies a strong genetic component underlying the condition. The most common single gene mutation to cause POI is the premutation of the fragile-X mental retardation gene 1 (FMR1), located on Xq27.3. Many other candidate genes have been suggested to play a role in the POI etiology, with mutations identified in genes involving follicle function and oogenesis, such as FOXL2, BMP15, NR5A1, Inhibin A, LHR, FSHR and the phenotype. In addition, variations in genes involved in meiosis and DNA repair have been hypothesized to affect the normal process of follicle formation and diminish ovarian reserve resulting in infertility. An alternative approach to identify novel POI candidate genes is the genome-wide analysis and we also report on a few studies that might have identified novel susceptibility genes for POI. 

Introduction 

A woman’s ovary has several million potential oocytes at around five months of gestational age. These are held in a quiescent state until required for ovulation, years later. Most of these potential oocytes are destroyed by the body before birth presumably as part of a quality control mechanism. Between infancy and the age of 40 years, the potential oocytes are gradually reduced from approximately one million to 10,000 in each ovary and around the age of 40, the process of egg destruction accelerates with normal aging. Unfortunately, some women can experience irregular menstrual cycles and stop producing oocytes in their early 30’s leading to the condition called Premature Ovarian Insufficiency (POI). Genetic analysis has identified aberrations in several biological pathways that can result in this condition. This review summarizes the evidence for involvement of multiple developmental genes, as well as highlights the role of known oncogenes in POI.

Disease Definition 

A woman, through her reproductive life, uses fewer than 500 eggs, a tiny proportion of the original millions (Hsueh 1994, Tilly 2001). Primary Ovarian Insufficiency (POI) or Premature Ovarian Failure (POF) may be caused by any process that results in dysfunction or depletion of ovarian follicles, reducing the number of oocytes within the ovary. It is defined as early menopause with elevated levels of serum gonadotrophins before the age of 40 (Coulam 1982). Various terms have been used to describe this deviation from healthy ovarian function, including ‘premature menopause’. Albright (1942) coined the term ‘primary ovarian insufficiency’ to emphasise that the primary defect was within, rather than outside the ovary. Other conditions involving endocrine disturbances outside the ovary can also result in abnormal ovulation including pituitary disorders, adrenal dysfunction, or polycystic ovary syndrome. The term ‘ovarian insufficiency’ is regarded as more scientifically accurate than ‘ovarian failure’ (De Vos 2010) as insufficiency indicates impaired ovarian function suggesting that follicular activity of the ovary might intermittently recover, years after diagnosis leading to pregnancy in some women (Nelson 2005).

Disease Diagnosis 

Primary ovarian insufficiency (POI) affects about 1–2 % of women (Vegetti 2000) and in most cases, the cause is undefined. Destruction of primordial follicles by toxic agents, autoimmune response, activation of proapoptotic pathways, or accelerated follicular recruitment might result in premature depletion of the pool of primordial follicles. Accurate and timely diagnosis of POI poses challenges as hormonal and biochemical tests do not show the monthly follicle loss and thus do not indicate the true biological age of ovaries. Direct evidence of depletion of the resting pool of follicles can be reliably provided only through assessment of the total number of follicles in whole ovaries. Testing of biopsy samples of ovaries has been suggested as a diagnostic method to measure ovarian follicular reserve (Massin 2008), with other investigators concluding that analysis of laparoscopic biopsy samples cannot be used to predict follicular distribution in ovarian cortex (Lambalk 2004).

Genetics of POI 

Chromosomal abnormalities account for 12% of cases (Jiao 2012), and the familial aggregation often associated with POI indicating a significant genetic contribution. Incidence of familial cases among women with POI has been reported to be as low as 4% (Conway, 1996), but it might be an underestimation and epidemiological studies have indicated incidence of familial POI as high as 30% (Cramer 1995, Torgerson 1997). In a large Italian study, Vegetti et al. (1998) found that the condition was inherited in one-third of the idiopathic POI patients. Pedigree studies on affected families showed a mode of inheritance suggestive of autosomal dominant sex-limited transmission or X-linked inheritance with incomplete penetrance (van Kasteren 1999). Using family history can help distinguish between familial or sporadic primary ovarian insufficiency as the risk of female relatives developing this condition may be as high as 100% in familial primary ovarian insufficiency, or as low as 1% in sporadic cases (van Kasteren 1999).

In rare cases, sufficient ovarian follicles are present but they do not function i.e. oocytes do not mature in regular cycles. However, in a large proportion of cases no cause is found and they are classified as idiopathic or karyotypically normal spontaneous ovarian failure (Laml 2000).

Unraveling the genetic causes of POI 

Several methods have been used to elucidate the role of genetic contributors in the pathogenesis of POI — transgenic ‘knockout’ animals, mutation screening in affected women, analysing pedigree data in linkage analysis. Genetic association studies aim to identify candidate genes or genome regions that contribute to a specific trait or disease by identifying a correlation between disease status and genetic variation (Cordell 2005) and we report on several candidate genes that are believed to contribute to POI.

POI genes on the X-chromosome 

Premature ovarian senescence is many times associated with abnormalities in the X chromosome. Women with structural and numerical abnormalities in the X chromosome make up the largest subgroup with POI. During early embryonic development, one of the X chromosomes is randomly inactivated by methylation in female somatic cells (Sato 2004). In some women with X chromosome structural abnormalities, such as large deletions and unbalanced translocations, skewed patterns of X chromosome inactivation (SXCI) may result with the abnormal inactive X chromosome in most of the cells. Other women may inherit only one X chromosome (45,X) leading to congenital Turner’s syndrome (Sybert 2004). Although one X chromosome is sufficient to allow the normal development of most organs and initial differentiation of ovaries, oocytes need two active X chromosomes. Defective X chromosome leads to insufficient gene dosage of many genes, and haploinsufficiency of the X chromosome results in depletion of the oocyte pool in the first 10 years of life.

Link between Fragile X and POI 

Mutations in the FMR1 gene can also lead to the expansion of a CGG trinucleotide repeat located at the 5’ UTR region of the gene. Long repeats of 200 CGG trineucleotides lead to reduced gene expression and Fragile X mental retardation syndrome. Repeat lengths between 59 and 199 of the CGG repeat confer an unstable premutation state. Women with the premutation allele have a substantially increased risk of POI. Besides Turner’s syndrome, premutation in the FMR1 gene is the most common known congenital cause of POI. Cryptic deletions in FMR2 gene, located near the FMR1, have also been suggested as an X chromosome-linked cause of primary ovarian insufficiency (Murray 1999).

Multiple rare mutations in oocyte development and hormone regulation genes contribute to the risk of POI 

FOXL2 is a member of the forkhead /hepatocyte nuclear factor 3 gene family of transcription factors that plays a role in sex determination. Mutations in FOXL2 cause congenital blepharophimosis–ptosis–epicanthus inversus syndrome (BPES) that is characterized by premature death of egg cells (Crisponi 2001). Foxl2 knockout mice were shown to replicate the findings in humans (Schmidt 2004). Reduced Foxl2 expression resulted in the characteristic cranio-facial alterations and infertility with folliculogenesis being blocked at the early stages. A functional study supporting the role of FOXL2 mutations in nonsyndromic POI was reported by Laissue et al. (2009). A novel FOXL2 missense mutation p.G187N was found in a case of POI without BPES. The subcellular localization of the mutant protein was normal, but its functional activity was significantly lower than that of normal FOXL2 protein.

NR5A1 

NR5A1 gene, also called steroidogenic factor 1, plays a key role in ovarian development and function. Mutations in the gene were detected in members of four families with a history of POI but not in the 700 control alleles (Lourenco 2009). Mutations were associated with a range of ovarian anomalies, with functional analysis revealing that mutant proteins had altered transcriptional activity that is important for follicle growth and maturation.

Members of the TGF superfamily 

Hetrozygous mutations in BMP15 (Bone Morphogenetic Protein 15), an oocyte-specific growth/differentiation factor that stimulates folliculogenesis and is expressed in oocytes during early folliculogenesis, has been implicated in POI (Di Pasquale 2004). It is presumably expressed from both X chromosomes in oocytes, and could potentially show a gene dosage effect. BMP15 maps to a locus on the short arm of X chromosome (Xp11.2), within a ‘POI critical region’ (Persani 2009). In humans, mutations in BMP15 gene have been found in POI cohorts. Rossetti et. al. (2009) demonstrated that BMP15 protein coding variations resulted in reduced production of bioactive BMP15 proteins in comparison with wild type, thus functional effects of these mutation is consistent with a mechanism of haploinsufficiency. Mature BMP15 proteins with missense variations also showed significant reduction in their biological effects in human cell-lines (Rossetti 2009).

Besides BMP15, other TGFβ family members have a relevant role in the progression of folliculogenesis. GDF9 is also expressed in the oocyte. Several studies reported that variations in GDF9 gene (p.K67E; p.V216M; p.S186Y; p.P103S; and p.T238A) were found in women with POI but were not detected in the control samples (Laissue 2006, Kovanci 2007).

Inhibin A, NOBOX 

Inhibin A plays an important role in regulating ovarian function either as a negative modulator of pituitary FSH synthesis. Inhibin A (INHA) gene knockout mice have raised FSH levels, are infertile and develop tumors in the gonads at an early age with nearly 100% penetrance (Matzuk 1992). Therefore, Inhibin A was regarded as a candidate gene for mutational studies. One missense variation of INHA gene (p.A257T) was found to be associated with POI in several populations: the INHA variant was identified in Indian, New Zealand and Slovenian patients (Shelling 2000, Dixit 2004). An Italian study also reported a significant association between the p.A257T allele in INHA and sporadic (4.5%) and familial (7.7%) POI cases (Marozzi 2002). However, other studies have found no differences in variant frequency between POI cases and controls (Corre 2009).

NOBOX and FIGLA are oocyte-specific transcription factors, and deletion of either of these genes could accelerate post-natal oocyte loss. Mutations in NOBOX seem to occur more frequently in the Caucasian POI population. The NOBOX missense variant, p.R355H, first identified in 1 of 96 Caucasian POI subjects, could disrupt the binding of the NOBOX homeodomain to DNA (Qin 2007). Bouilly et al. (2011) subsequently demonstrated that loss-of-function NOBOX mutations accounted for 6.2% of POI cases in a Caucasian cohort of 178 participants.

Gonadotropin Receptors 

FSHR and LHR are glycoprotein hormone receptors which together with their binding hormones, LH and FSH, are essential for normal reproductive function. A linkage analysis in a Finnish population revealed a significant association between a locus containing both FSHR and LHR genes and ovarian developmental disorder. Sequencing of the entire FSHR gene revealed a homozygous missense mutation, p.A189V (Aittomaki 1995) that has been observed only in the Finnish population suggesting a founder effect. From in vitro studies it was observed that the p.A189V mutation had altered receptor folding and it failed to reach the plasma membrane, causing complete FSH resistance.

STAG3 

Using a combination of genome wide linkage analysis and exome sequencing in a consanguineous (people descended from the same ancestor) family with POI, Caburet et al. (2014) identified a homozygous 1-bp deletion in the gene encoding stromal antigen 3 (STAG3). All affected family members analyzed were homozygous for the mutation. This finding was supported by the phenotype of female mice with a homozygous disruption in Stag3. These mice were sterile and their fetal oocytes were arrested at early prophase I, leading to oocyte depletion at one week of age.

Genes involved in meiosis and DNA repair 

It has been proposed that genetic defects in meiotic genes are involved in POI as several meiotic-gene knockout mice have phenotypes resembling human POI. Wang et al (2014) identified a heterozygous mutation in a meiotic gene, HFM1, which encodes a protein necessary for homologous recombination of chromosomes, in two sisters suffering from POI. Variants in genes that affect the normal processes of primordial germ-cell proliferation, oocyte meiosis, and follicle formation are plausible candidates in the pathogenesis of POI. Also, Hfm1-deficient mice are infertile (Guiraldelli 2013).

BRCA1 mutations, fertility treatments and POI 

As infertility is associated with breast and ovarian cancer risks, Oktay et al (2010) hypothesized that mutations in the BRCA1 and BRCA2 genes may be associated with low response to fertility treatments. Low response to ovarian stimulation is a strong indication of diminished ovarian reserve and infertility. As DNA repair is deficient in patients with BRCA mutations, their oocytes may be more prone to DNA damage, and when DNA damage cannot be repaired, apoptotic pathways are activated. Thus, oocytes with deficient BRCA function may be prematurely eliminated, resulting in early depletion of oocyte pool and, as a consequence, POI. Oktay et al (2010) found that in BRCA mutation-positive patients, the incidence of low ovarian response was significantly higher compared to BRCA mutation-negative patients. Of note, all BRCA mutation-positive low responders to fertility treatment had BRCA1 mutations, but not BRCA2 mutations. These finding can explain, in part, the link between infertility and breast/ovarian cancer risks.

Genome Wide Association Studies in POI 

Genes mentioned above were chosen as candidates in the context of POI because they are known to be associated with folliculogenesis or other related biological pathways. Genome Wide Association Studies (GWAS), on the other hand, is unbiased and discovery-driven, providing a comprehensive approach that is based on a case-control design.

PTHB1 and ADAMTS19 

In a two-stage association study in a Korean population (101 cases and 87 controls), Kang et al. (2008) showed a strong association of POI with the PTHB1 gene. PTHB1 was first identified in osteoblastic cells and then in other tissues, but not the ovary, and its physiological function remains unknown. PTHB1 variants have been described in a subset of patients with Bardet–Biedl syndrome who sometimes exhibit POI. It is possible that the study has identified PTHB1 as a novel susceptibility gene for POI.

Knauff et al. (2009) conducted a GWAS involving 309 158 SNPs in 99 unrelated idiopathic Caucasian POI patients and 235 unrelated controls, focusing on chromosomal areas and candidate genes previously implicated in POI. A genome-wide significant association was observed for a SNP (rs246246) which maps to an intron of ADAMTS19, a gene encoding a zinc-dependent metalloprotease, known to be up-regulated in the female mouse gonads during sexual differentiation. Although limited by sample size, this proof-of-principle study’s findings did reveal ADAMTS19 as a biologically plausible candidate gene for POI.

Early Menopause and Primary Ovarian Insufficiency 

Early menopause (EM) affects up to 10% of the female population. Perry et al (2013) undertook a meta-analysis of GWAS in 3493 EM cases and 13 598 controls from 10 independent studies. Although no novel genetic variants were discovered, 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT), were found to be associated with both EM and POI. This included genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG, PRIM1) and immune function (IL11, NLRP11, BAT2) suggesting common biological and genetic mechanism for these two related phenotypes. The 17 alleles associated with younger menopause age were also associated with increased risk of EM and POI. Their data supported the hypothesis that EM and POI have overlapping polygenic aetiology, with individuals who carry more risk variants for lower-age-at-menopause having an increased risk of EM and POI.

In GWAS, genetic variations are investigated in unrelated affected individuals compared to matched controls by means of single nucleotide polymorphisms (SNPs). The drawback is that the SNPs are not chosen on the basis of their possible functional effect. The approach follows the common disease-common variant hypothesis and would fail to identify rare and novel variations in genes involved in oocyte development and maturation.

A rapid decline in the cost of sequencing is enabling effective mutational analysis for rare and common variations along with chromosomal deletions and copy number analysis. Application of genome or exome sequencing to identify variants can confirm and validate the role of candidate genes described in this overview and reveal the function of new genes which have a role in the etiology of POI.

Genetic heterogeneity 

The genetic studies described above demonstrate the high genetic heterogeneity of POI. It is likely that most severe familial cases of early onset (before age of 30) are caused by rare, highly penetrant mutations, while POI of later onset are caused by a large number of less penetrant alleles. It is also possible that different genes play a role in the development of familial and sporadic POI. The condition should be regarded as a complex genetic disease and as with other complex genetic disorders; it is characterized by familial clustering without an obvious Mendelian pattern of inheritance because several genes, their mutations and environmental factors contribute to the etiology of the disease.

Can genetic testing impact on POI management? 

Considering that 1% of women suffer from primary ovarian insufficiency, the underlying mechanism is unknown in 90% of the cases, and that an even a larger fraction of infertile women may be suffering from occult primary ovarian insufficiency, discovery of susceptibility genes for POI will have positive implications for understanding the link between infertility and the pathogenic mechanism. However, as the pathogenic mechanism remains unknown in most cases of POI, should women with idiopathic POI be screened for genetic alterations?

Screening for the most prevalent alterations i.e. X chromosome abnormalities, FMR1 premutations and the BRCA1 alleles would not only identify the cause of disease but also help affected women make more informed reproductive decisions. Also, when a genetic alteration is observed in one of the POI candidate genes in a woman suffering from idiopathic POI, it can be useful for family counselling, and to help predict other female relatives who might be at higher risk for POI and fertility loss at a young age. This information is particularly important now, as many women choose to conceive in their late thirties and early forties, when the risk of POI is highest. Women who experience irregular menstrual cycles should be concerned and consider not deferring child bearing to a later age due to an increasing risk of POI.

Genome sequencing can identify potential cause of both female and male infertility, as well as carrier status for multiple genetic disorders, helping couples make more informed reproductive decisions. Important limitations of genomic sequencing to predict disease risk include its potential use in genetic selection. While for a condition such as POI, information gathered from genetic screening may allow those at risk to start trying to conceive at a younger age, and increase chances of a healthy pregnancy; screening for genetic diseases may influence the decision to carry pregnancies to term. For example, there is robust data indicating that well over 50% of Down’s syndrome pregnancies detected by antenatal screening are selectively terminated (Natoli 2012, Wu 2013). For healthcare providers, the ethical consequences of applying genetic screening should be evaluated on a case-by-case basis.

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PCOS Natural Alternatives

Abstract 

Polycystic ovarian syndrome (PCOS) affects 5-10% of women across all ethnicities and its clinical manifestation varies widely among individuals. The presence of insulin resistance, hyperinsulinemia, and obesity are associated with reproductive symptoms, and these metabolic disturbances place those affected at greater risk for developing cardiovascular disease and diabetes. Women with PCOS often seek care for menstrual disturbances, androgen excess, and infertility. Conventional treatment of PCOS is largely symptom-based with therapies aimed at these categories. While conventional pharmaceutical treatments may offer benefit in PCOS, they present risks for adverse effects such as hepatotoxicity, renal toxicity, teratogenicity, and multiple pregnancies. Numerous natural treatments exist that are commonly used as alternatives to prescription medications, such as inositol, cinnamon, chromium, and N-acetyl-cysteine (NAC). The evidence primarily indicates that natural alternatives may be used to address the insulin resistance and hyperinsulinemia seen in many patients with PCOS. Inositol has shown to be effective in improving the hormonal and metabolic profiles in PCOS. Cinnamon and chromium have shown to have benefit by improving insulin signalling and glucose control. NAC has been shown to significantly increase both ovulation rate and pregnancy rate.

Polycystic ovarian syndrome (PCOS) was first reported in 1935, when Stein and Leventhal described a series of seven women who presented with oligo/amenorrhea, hirsutism, obesity (BMI > 25), infertility, and enlarged ovaries with multiple cysts (Madnani 2013, Sirmans 2013). This condition is now recognized as a common heterogeneous disorder affecting women of reproductive age and can be hereditary (Ebejer 2013, Sirmans 2013). It affects 5-10% of women across all ethnicities and its clinical manifestation varies widely among individuals (Madnani 2013). Stein and Leventhal originally observed a primary ovarian defect in the women studied, classifying this disorder as polycystic ovarian disease (Madnani 2013). It has become clear in recent years that the disorder is associated with major metabolic and reproductive morbidities and as such is now known as PCOS (Gerli 2007). The presence of insulin resistance, hyperinsulinemia, and obesity are associated with the reproductive symptoms, and recent data provide evidence that these metabolic disturbances place those affected at greater risk for developing cardiovascular disease and diabetes (Fulghesu 2002, Sirmans 2013).

Women with PCOS often seek care for menstrual disturbances, androgen excess, and infertility (Sirmans 2013). Although 30% of women with PCOS have normal menses, the majority report oligomenorrhea, amenorrhea, and prolonged erratic menstrual bleeding (Sirmans 2013). Hirsutism is a common symptom of androgen excess prevalent in up to 70% of women with PCOS. A modified Ferriman- Gallwey scoring system is used to evaluate hair growth at seven sites with a total score of eight or more being indicative of hirsutism (Sirmans 2013). More than 90% of normally menstruating women with hirsutism present with polycystic ovaries through ultrasound. Other markers of hyperandrogenism are acne, oily skin, and certain virilisation patterns such as a deep voice or alopecia (Ciotta 2011, Madnani 2013). Acne is less prevalent than hirsutism, possibly due to higher dihydrotestosterone levels resulting from the expression activity of 5α-reductase in the sebaceous glands and hair follicles (Madnani 2013).

PCOS is the most common cause of anovulatory infertility where follicular growth is halted due to disturbances in normal follicular development (Sirmans 2013). A normal ovulatory cycle comprises a complex interplay of hormones from the pituitary, hypothalamus, adrenals, and ovaries where eventually the secretion of FSH and LH target the follicles in the ovary, allowing only one to undergo maturation to become the dominant or graffian follicle (Madnani 2013). The LH surge that takes place mid-cycle then stimulates ovulation. In PCOS however, a dominant follicle does not develop and ovulation does not ensue (Sirmans 2013).

Obesity is a common feature of PCOS with 70% of these women exhibiting exaggerated insulin secretion (Fulghesu 2002). There is a decreased sensitivity to circulating insulin (possibly due to a defect in phosphorylation of tyrosine kinase in the insulin receptor), resulting in hyperinsulinemia which in turn increases androgen production (Madnani 2013). Hepatic production of sex hormone binding globulins (SHBG) is reduced thereby increasing concentrations of free androgens (Sirmans 2013). Insulin resistance occurs independently of obesity, however it is consistent with metabolic syndrome common in women with PCOS (Sirmans 2013). Impaired glucose tolerance and type 2 diabetes are also highly prevalent in these women, who are also at risk for developing dyslipidemia (Latha 2012). Studies reveal that elevated plasma insulin levels enhance VLDL synthesis and triglyceride levels, resulting in atherogenic effects in arteries (Latha 2012, Sirmans 2013).

A relationship between oxidative stress and PCOS has been shown to influence the cardiovascular system as a result of lipid peroxidation, as well as the reproductive system through its effects on oocyte maturation, ovarian steroidogenesis, corpus luteum functions and other fertilization processes (De Leo 2012, Latha 2012). Equally interesting is the finding that women with PCOS have significantly higher levels of C-reactive protein (CRP) when compared to healthy weight controls, suggesting that this is an inflammatory condition (Ebejer 2013). CRP levels can predict risk of coronary heart disease and other elevated cytokines suggesting an immune component in the pathogenesis of PCOS (Ebejer 2013).

Conventional treatment of PCOS is largely symptom-based with therapies aimed at three categories: menstruation-related disorders, androgen-related symptoms, and infertility (Madnani 2013, Sirmans 2013). Low dose combined hormonal contraceptives are the primary treatment choice for PCOS-related menstrual disorders, as well as hirsutism and acne for patients avoiding pregnancy (Sirmans 2013). Anti-androgens such as spironolactone and finesteride are also prescribed, but with great caution due to their ability to feminize a male fetus if pregnancy occurs, and so are typically combined with oral contraceptive pills (Sirmans 2013). The oral contraceptives do not correct the underlying ovulatory defect and also possibly worsen insulin sensitivity. Agents for improving insulin sensitivity include metformin and thiazolidinediones (eg. Rosiglitazone) which may also aid in restoring ovulation and improving metabolic disturbances (Ebejer 2013). Clomiphene citrate is the drug of first choice for anovulatory infertility and acts as an anti-estrogen to stimulate FSH (Ciotta 2011). Although clomiphene citrate is the gold-standard drug for ovulation induction in those with PCOS, resistance is seen in as much as 40% of women (Saha 2013). While these treatments may offer benefit in PCOS, they present risks for adverse effects such as hepatotoxicity, renal toxicity, teratogenicity, and multiple pregnancies (Madnani 2013). Numerous natural treatments exist that are commonly used as alternatives to prescription medications. These treatments include inositol, cinnamon, chromium, and N-acetyl-cysteine (NAC). The evidence for these natural therapies is reviewed.

Inositol 

Mounting evidence points to the central role of insulin resistance (IR) and compensatory hyperinsulinemia in the pathogenesis of PCOS (Dona 2012, Nordio 2012). These conditions predispose patients towards the development of dyslipidemia, impaired glucose tolerance, type 2 diabetes mellitus, and cardiovascular disease (Dona 2012). Several studies show that an altered insulin transduction induces abnormal ovarian steroidogenesis (Nordio 2012). Reducing serum insulin and androgen levels and restoring ovulation are typically treated with insulin-sensitizing drugs such as metformin (Nordio 2012). Metformin is generally well tolerated, however common side effects of metformin may include reduced vitamin B12 levels and gastrointestinal upset (Sato 2013). There is a good body of evidence to suggest that inositol functions as a natural insulin sensitizer, and may improve the effectiveness of metformin.

Inositol is a six carbon polyalcohol which has also been characterized as an insulin-sensitizer, with reported improvements in glucose tolerance, ovulation and androgen concentration (Galletta 2011). It exists as nine different stereoisomers, two of which have been shown to be insulin mediators; namely myo-inositol (MI) and D-chiro-inositol (DCI) (Galletta 2011, Nordio 2012). The history of inositol treatment stems from studies performed by Larner et al. in 1993, who originally sought to unravel the causes of type 2 diabetes mellitus (Galletta 2011). Larner undeniably showed that administration of these two inositol phosphoglycans (IPG), MI and DCI reduced hyperglycemia in a dose-dependent manner (Galletta 2011). Subsequent studies suggested that a deficiency in tissue availability, or an altered metabolism of IPG mediators may contribute to insulin resistance (Dona 2012, Nordio 2012).

In 1999, Nestler et al. reported the efficacy of DCI in treating 22 obese PCOS women where 50% of subjects ovulated after four weeks of treatment (Nestler 1999). An increase in insulin sensitivity and a reduction in serum androgen levels were also reported and similar effects were produced in later studies (Galletta 2011). Inspired by the results obtained by Nestler, a research group at the AGUNCO Obstetrics and Gynecology Center in Italy began to study the effects of MI in PCOS patients and results showed a similarity in effectiveness between MI and DCI in treating metabolic disturbances and ovarian dysfunction. The study, conducted over 16 weeks, demonstrated regular menstrual cycles and a 40% pregnancy rate (Papaleo 2007). Another 16-week randomized placebo-controlled trial by Gerli et al. of 92 women with oligomenorrhea and PCOS showed a significant reduction in the mean time until the first ovulation in the myo-inositol-treated group (Gerli 2007). During the first week of treatment, a significant increase in E2 concentrations was also observed, indicating a relatively rapid effect of treatment. Considerable reductions in weight were also noted, along with lower circulating leptin and higher HDL levels (Gerli 2007).

Although MI and DCI exert similar effects on insulin resistance, a direct comparison between the two molecules has been elucidated with respect to oocyte quality and maturation (Galletta 2011, Nordio 2012). It appears that elevated concentrations of MI in follicular fluid play a specific role in follicular maturation, while DCI may be more involved with enhancing insulin response (Dona 2012). MI is converted into DCI via “epimerization”, a process that is dependent on insulin. The MI/DCI physiological ratio is specific in each tissue (Nordio 2012). In particular, DCI concentrations are present in insulin sensitive tissues that are responsible for glycogen synthesis and storage such as the liver, muscles, and fat (Galletta 2011). The ovaries however, never become insulin resistant leading to hyperinsulinemia in these organs (Nordio 2012, Galletta 2011). During insulin resistance, the MI/DCI conversion rate is affected resulting in an overproduction of DCI and a reduction of MI and this ensuing MI depletion in tissues is a possible cause for poor oocyte quality (Galletta 2011). On this basis, a combination treatment due to synergistic effects, has shown efficacy in improving the hormonal and metabolic profiles in PCOS (Nordio 2012).

Oxidative stress is another factor involved in PCOS, where reactive oxygen species are produced faster than the endogenous antioxidant systems can neutralize (Dona 2012). Hyperglycemia increases the generation of reactive oxygen species, which eventually attack certain proteins creating an inflammatory state (De Leo 2012). This in turn induces insulin resistance, hyperandrogenism and increases the risk of cardiovascular disease in women with this disorder. A dosage of 1200 mg/day of inositol has yielded therapeutic effects in lowering inflammation, serum androgens, and insulin levels (Dona 2012). Inositol belongs to the B-Complex group of vitamins and is present in phospholipids in human cells (Ciotta 2011). Increasing evidence supports its effectiveness in reducing hormonal, metabolic and oxidative abnormalities in patients with PCOS (Dona 2012). Inositol is promising as a safe and beneficial first-line and adjunctive treatment for women with this disorder.

Cinnamon and Chromium 

Cinnamon (Cinnamomon cassia) and chromium are two supplemental therapies that have been studied and shown to have benefit in the treatment of PCOS (Anderson 2007). Both appear to have similar effects on insulin signalling and glucose control. In an eight-week pilot study, fifteen women with PCOS were randomized to a daily 500mg cinnamon extract or placebo (Wang 2007). The results of this study showed significant reductions in insulin resistance as measured by fasting and two-hour oral glucose tolerance tests (OGTT) in the cinnamon group as compared to the placebo group. The proposed mechanism of action is that cinnamon extract may potentiate insulin action by enhancing the insulin signaling pathways, leading to increased phosphatidylinositol 3-kinase activity, which in turn regulates insulin-stimulated glucose uptake and glycogen synthesis, as seen in in vivo rat studies (Qin 2003). In particular, the polyphenol type-A polymer procyanidin (which can be extracted from cinnamon), appears to be particularly helpful in enhancing the insulin signalling pathways. In addition, cinnamon has been demonstrated to have antioxidant effects in people with impaired fasting glucose who are overweight or obese, which may also partially explain how it benefits those with PCOS (Roussel 2009).

In a pilot study of chromium supplementation in women with PCOS, 200mcg daily of chromium picolinate improved glucose tolerance compared with placebo, but did not improve ovulatory frequency or other hormonal parameters (Lucidi 2005). In a separate trial with five obese subjects who had PCOS, trivalent chromium (also as chromium picolinate) was supplemented at a dose of 1000mcg and given without change in diet or activity level. The results showed that the chromium caused a 38% mean improvement in glucose disposal rate (as tested with a euglycemic hyperinsulinemic clamp technique) (Lydic 2006). Finally, there was a double-blind randomized clinical trial comparing 200mcg daily of chromium picolinate versus metformin for three months (Amooee 2013). The results showed that chromium significantly decreased fasting blood sugar and serum levels of fasting insulin. There were no significant differences in ovulation and pregnancy rates. In this study, only metformin was associated with decreased hyperandrogenism, but overall chromium was better tolerated. Together these studies represent the totality of recently published trials on these two supplements in the treatment of PCOS.

N-acetyl-cysteine (NAC) 

There is research showing that NAC can play a role in insulin secretion in pancreatic beta-cells (Santini 1997). NAC also increases cellular levels of the antioxidant glutathione, which can itself influence insulin receptor activity (Ammon 1992). One trial used this information as justification for seeing if NAC would improve insulin sensitivity in women with PCOS (Fulghesu 2002). In this trial, 37 women with PCOS were assessed. Insulin sensitivity was measured by using the hyperinsulinemic euglycemic clamp technique and other measurements were also obtained at baseline and after treatment (including oral glucose tolerance test, lipid blood profile, and hormonal assay). Trial participants were administered 1.8g of NAC orally for five to six weeks. The results showed that although many parameters were unchanged (fasting glucose, fasting insulin, and glucose area under the curve), insulin area under the curve after the OGTT was significantly reduced and the peripheral insulin sensitivity increased. A significant improvement was observed in hyperinsulinemic subjects.

A set of trials has also examined NAC supplementation in PCOS patients who were clomiphene citrate resistant. In the earliest of these studies, 150 women undergoing therapy for infertility were assigned randomly to receive either 1.2g daily of NAC or placebo with 100mg daily of clomiphene citrate for five days starting at day 3 of the cycle (Rizk 2005). The results showed that the combination of NAC and clomiphene citrate significantly increased both ovulation rate and pregnancy rate (49.3% vs 1.3% and 21.3% vs 0%, respectively). A more recent study that included 180 PCOS infertile patients showed that NAC was safe and well-tolerated as an adjuvant therapy to clomiphene citrate (Salehpour 2012). NAC improved ovulation and pregnancy rates and may have had some beneficial impacts on endometrial thickness.

A recent review of the evidence on the topic showed that three separate studies (a 2006 prospective controlled pilot study, a 2007 prospective randomized controlled study, and a 2010 randomized controlled trial) were all unable to replicate the results found by the first study (Saha 2013). In the most recent of these studies, 192 women were similarly randomized to receive either clomiphene citrate combined with either 1.8g NAC or metformin for three treatment cycles (Abu Hashim 2010). The results of this study showed that over a three-month follow-up period, the women who received the metformin combination had higher ovulation and pregnancy rates compared to the NAC group (69.1% vs 20.0% and 22.7% vs 5.3%). The authors concluded that the efficacy of the metformin combination therapy is higher than that of NAC combination for inducing ovulation and achieving pregnancy. The evidence on NAC remains mixed, which means it may or may not help women with PCOS, but at the very least is well-tolerated.

Conclusion 

PCOS is characterized by the presence of hyperandrogenism, insulin resistance, hyperinsulinemia, and obesity and is associated with an increased risk for developing cardiovascular disease and diabetes. Conventional approaches to management of PCOS often involve used of the oral contraceptive pill, which can regulate menstrual bleeding but fails to correct ovulatory defects and may worsen insulin sensitivity, and metformin, which is generally well tolerated although it may deplete vitamin B12 levels. Natural medicines such as inositol, cinnamon, chromium, and NAC have been studied as natural alternatives or adjunctive treatments. Inositol has shown efficacy in improving the hormonal and metabolic profiles in PCOS, as well as possibly providing anti-inflammatory and anti-oxidant actions. Cinnamon and chromium have shown to have benefit by purportedly improving insulin signalling and glucose control. The data on NAC is mixed but may help with ovulation and pregnancy rates. Overall, the safety profile of natural supplements is excellent and together, they provide patients with additional viable treatment options.

References 

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Diet in inflammatory bowel disease prevention and management A review

Abstract

As a result of inconsistent health improvement and severe adverse effects associated with the use of current drug therapies, inflammatory bowel disease (IBD) patients have turned to alternative treatments such as diet modification to help alleviate IBD disease symptoms. This review discusses the role of diet in preventing and managing IBD symptoms. Specifically, the influences of dietary intake of gluten, fiber, Fermentable Olio-, Di-, and Mono-saccharides and Polyols (FODMAPs), dairy, meat, and polyunsaturated fats are elucidated. This review concludes that though substantial evidence exists for each of these topics and their role in IBD, more research should be conducted in order to further delineate the role of diet in IBD symptom development and control. Recommendations include careful monitoring and coordination of diet on a case-per-case basis in patients with IBD in order to decrease adverse IBD-associated symptoms. This can be achieved through elimination and reintroduction diets, which may allow practitioners to identify dietary sources of IBD flare-ups.

Introduction

Inflammatory bowel disease (IBD) is a chronic disorder characterized by inflammation within the gastrointestinal (GI) tract as a result of dysregulated interactions between the mucosal immune system and intestinal microorganisms in genetically predisposed individuals (Hyun 2006, Neuman 2007). IBD manifests itself as either ulcerative colitis (UC), with localized inflammation and ulcerative lesions occurring in superficial layers of the colon, or Crohn’s disease (CD), with inflammation and lesions occurring transmurally and sporadically along the entire length of the GI tract (Hyun 2006, Neuman 2007). Chronic inflammation leads to clinical symptoms such as weight loss, abdominal pain, and bloody diarrhea, all of which can negatively impact patients’ quality of life (Hendrickson 2002).

IBD can affect individuals of all ages, but is most commonly diagnosed in the second or third decade of life. In 2012, the prevalence of individuals with IBD was 233,000 in Canada, with an approximate incidence rate of 10,200 cases per year. The economic cost of IBD in Canada has been estimated at $2.8 billion per year, considering both the direct and indirect costs of healthcare (Rocchi 2012).

There is currently no cure for IBD (Mulder 2013). Instead, treatment approaches focus on symptom management, with the predominant therapy being 5-aminosalicyclic acid, a mild anti-inflammatory, in combination with steroids (Panaccione 2008). Following the failure of this therapy option, stronger immunosuppressive therapies such as thiopurine analogues, methotrexate, and calcineurin inhibitors are prescribed in order to ameliorate disease symptoms (Panaccione 2008). However, data on these immunosuppressive therapies has either been inconclusive or has demonstrated the drugs’ lack of ability to induce and maintain remission (Khan 2011). Although there is evidence that one thiopurine analogue, azathioprine, is moderately effective at preventing relapse, this effect disappears after four years of use (Bouhnik 1996, Khan 2011). The numerous side effects of these drugs prevent this class of treatment from being an ideal option for long-term management (de Boer 2007, Haslam 2000, Loftus 2004, Mason 2013). For example, severe adverse effects such as hypertension, lethargy, and lower respiratory tract infection have been found in 51% of participants taking the immunosuppressant cyclosporin for long term treatment of IBD (Haslam 2000).

As a result of inconsistent health improvement and the aforementioned severe adverse effects of current drug therapies, IBD patients have turned to alternative treatments, such as diet modification, to help alleviate disease symptoms (Hendrickson 2002). These altered diets can include or exclude many items, such as gluten, fiber, FODMAP carbohydrates, dairy, meat, and polyunsaturated fats. Though no one diet has been proven to help treat all cases of IBD, the focus of this literature review will be to collect and summarize current research on diet-based approaches to IBD prevention and treatment.

Gluten

Though celiac disease is not an IBD, studies have shown an increased incidence of non-celiac gluten sensitivity (NCGS) (Watanabe 2013) and celiac disease (Oxford 2013, Tavakkoli 2012) in IBD patients compared to non-IBD patients (13% vs. 1% and 9% vs. 1%, respectively). NCGS and celiac disease often present with similar symptoms, which can be ameliorated by the adoption of a gluten-free diet; however, the two are differentiated by distinct clinical features (Kabbani 2014). Celiac disease is often characterized by the presence of three elements: 1) a genetic predisposition to the disease, determined by the expression of HLA-DQ2 or HLA-DQ8 proteins, 2) gluten as the precipitating factor to symptoms, and 3) autoantibodies against tissue transglutaminase (tTG) (Schuppan 2013). The presence of tTG leads to structural changes to a-gliadin, a protein component of gluten, which is then presented on HLA-DQ2 or HLA-DQ8 to cytotoxic CD8+ T cells in the lamina propria of the gut (Schuppan 2013). Additionally, helper CD4+ T cells in the lamina propria release pro-inflammatory cytokines, which leads to intestinal inflammation, similar to that observed in IBD (Schuppan 2013).

Gluten-containing foods have been linked to worsened symptoms in IBD patients (Asakura 2008, Brown 2010, Mishkin 1997, Riordan 1993, Triggs 2010). In cases of IBD patients with NCGS, one study found that eliminating gluten from the diet significantly reduced liquid stools per day (from 6.2 to 1.5) compared to gluten-eating controls (from 4.0 to 4.7) (Watanabe 2013). Though this evidence pertains to NCGS IBD patients, research has shown that gluten consumption is linked to increased intestinal permeability and inflammation. Due to the association between intestinal permeability and diseases such as rheumatoid arthritis, multiple sclerosis, and depression (de Punder 2013), it may be beneficial for non-gluten-sensitive IBD patients to also exclude gluten from their diets to reduce the risk of developing the aforementioned comorbidities.

Dietary Fiber

The efficacy of fiber intake as a dietary intervention for IBD has been of interest due to prospective studies showing decreased CD risk in patients with high vs. low (24.3g/d, 11.6g/d) fibre consumption (Ashwin 2013). One study following 170,000 women over 26 years found a 40% CD risk decrease in those with high fibre intake, especially fiber derived from fruits (6.4g/d) (Ashwin 2013). These results are supported by additional studies (Hou 2011). Although dietary fiber has been associated with decreased UC incidence in some studies, few trials have yielded statistically significant results (Ashwin 2013, Hou 2011).

A retrospective study conducted on patients with CD demonstrated that individuals treated with a fiber-rich (32.6g/d), unrefined-carbohydrate diet and conventional medication experienced a reduction in hospital visits (total 111 vs. 533) and surgeries required (1 vs. 5) when compared to patients in a drug-only treatment group (Heaton 1979). More recently, a study administering 20g of fiber per day through oat bran in bread to quiescent UC patients displayed improvement in abdominal pain and gastroesophageal reflux with no adverse effects or relapse activity observed (Hallert 2003). Open label studies where patients with mild to moderate UC consumed 20g/d of germinated barley foodstuff (GBF) in conjunction with standard drug treatments resulted in various clinical activity improvements including decreased diarrhea, less blood in stool, and lower cumulative recurrence rates (Bamba 2002, Hanai 2004).

Though the mechanisms through which these foods benefit IBD is not fully elucidated, possible explanations suggest that fiber can indirectly affect IBD through interacting with the intestinal microbiome and increasing production of butyrate (Flint 2008). Fiber intake results in residential bacteria fermentation, which increase short chain fatty acid (SCFA) production in the colon (Viladomiu 2013). SCFAs, such as butyrate, down-regulate and modulate intestinal inflammatory factors, cytokines interleukin-6 (IL-6), IL-8, and tumor necrosis factor-α (TNF-α), all of which play a role in intensifying inflammation and aggravating intestinal tissue; SCFAs therefore indirectly prevent damage to colonic mucosa (Galvez 2005, Rodríguez-Cabezas 2002, Viladomiu 2013). Dietary fiber intake is also associated with promoting anti-inflammatory actions, as it increases the percentage of Treg immune cells in the gut and decreases interferon-y (IFNy) production (Galvez 2005, Viladomiu 2013). The therapeutic effects of dietary fiber may also be due to shifting microbiota profiles through favouring the survival of bacteria capable of SCFA fermentation. This is suggested by research reporting that vegans and vegetarians, who may consume more fibre through fruits and vegetables, have lowered bifidobacterium compared to omnivores (Zimmer 2012). In contrast, ulcerative colitis patients have increased bifidobacterium, as well as increased bacteriodes, enterococcus, and clostridium species in the gut compared to controls (Wang 2014, Zhang 2013).

FODMAPs

A diet with decreased amounts of highly fermentable, but poorly absorbed short chain carbohydrates and polyols consumed, known as the FODMAPs diet (Fermentable Olio-, Di-, and Mono-saccharides and Polyols) is a relatively new method of treating IBD (Gibson 2005). FODMAPs include fructooligosaccharides (wheat, legumes), lactose (milk), fructose (fruits, honey), galactans (legumes) and sorbitol (artificial sweetener) (Gearry 2009, Gibson 2005). It has been found that a diet rich in FODMAPs causes elevated intestinal permeability, which is a biomarker of susceptibility for CD (Gibson 2005). FODMAPs in the small intestine are poorly absorbed, and exert an osmotic effect by drawing water into the large intestine due to their small molecular size (Barrett 2010, Gearry 2009). The FODMAPs are then fermented by the colonic microflora in the large intestine, producing hydrogen and/or methane gas (Barrett 2010, Gearry 2009). The increase in fluid and gas in the intestines results in diarrhea, bloating, gas, abdominal pain, and distention (Barrett 2010). A diet low in FODMAPs can lead to a decrease in these gastrointestinal symptoms in individuals with CD and UC (Gearry 2009). However, this diet has been shown to have no or a negative effect on constipation in study subjects (Gearry 2009, Gibson 2005). This diet requires time and dedication to achieve desirable outcomes, and is more favorable for individuals with higher education and who have more time to spend on food shopping (Gearry 2009).

In addition to FODMAPs, an older diet popularized by Elaine Gottschall’s book Breaking the Vicious Cycle: Intestinal Health Through Diet, called the Specific Carbohydrate Diet (SCD), has been used in the treatment of IBD. Like FODMAPs, the SCD limits the use of certain complex carbohydrates such as disaccharides and polysaccharides, on the basis that these may not be completely digested by the body, and may serve as fuel for overgrowth of bacteria and yeast instead. Although most evidence is anecdotal, and there is limited scientific evaluation of the SCD, a recent study assessed the effectiveness of the SCD in children with Crohn’s disease (Suskind 2014). A retrospective chart analysis, this study included seven children aged seven to 16 years of age with Crohn’s disease receiving the SCD for an average of 14.6 months, and no immunosuppressive medications. Disease severity ranged from mild to severe. The authors stated that “Although the exact time of symptom resolution could not be determined through chart review, all symptoms were notably resolved at a routine clinic visit three months after initiating the diet. Each patient’s laboratory indices, including serum albumin, C-reactive protein, hematocrit, and stool calprotectin, either normalized or significantly, improved during follow-up clinic visits” (Suskind 2014).

Dairy

In countries adopting “Western-style” diets, which include more high-fat dairy consumption, the prevalence of IBD has also increased (Asakura 2008). This suggests that increased dairy consumption can lead to greater IBD incidence, though this relationship is not observed in all countries (Jantchou 2010). As with other self-reported food intolerances in IBD, dairy has not been shown to have consistent effects in all IBD patients. Some studies (Brown 2010, Cohen 2013, Mishkin 1997, Riordan 1993, Triggs 2010, Wright 1965) have reported that dairy milk is associated with worsened diarrhea, bloating, and gas in many patients. Conversely, dairy yoghurt has been seen to ameliorate these symptoms in many patients (Cohen 2013, Triggs 2010), highlighting the possibility that the positive effects of introducing beneficial gut bacteria surpass the negative effects of dairy. Dairy should be avoided with caution, as it has been shown that patients who perceive dairy to be harmful for them do not meet their recommended daily allowance (RDA) for calcium intake as frequently as dairy-consumers (87.6% vs. 105.8% RDA) (Vernia 2013).

Meat

Animal protein has been shown to have an effect on both IBD incidence and IBD health outcomes (Hou 2011, Jantchou 2010, Jowett 2004, Mishkin 1997, Triggs 2010). One prospective study comprised of 67,581 female participants showed that high animal protein consumption including meat and fish was associated with a significantly increased risk of being diagnosed with IBD (HR 3.31 and 3.03 for total and animal protein, respectively) (Jantchou 2010). Regarding clinical activity, a study conducted on UC patients demonstrated that high intake of meat (OR compared with low intake 3.74), particularly red and processed meat (OR 6.88), was associated with IBD relapse (Jowett 2004). Additionally, many studies point to a link between red meat and worsened symptoms (Cohen 2013, Hou 2011, Jantchou 2010, Jowett 2004, Triggs 2010). Current research does not provide conclusive evidence on the effects of fish. Some note that fish is beneficial to many patients (Hou 2011, Triggs 2010) while others claim it is not (Hou 2011, Mishkin 1997).

Polyunsaturated Fats

Epidemiological evidence has illustrated a link between dietary fat intake and the incidence of IBD. Studies have shown a lowered incidence of IBD in the Eskimo population, whose diet is rich in omega-3 n-3 polyunsaturated fats (PUFA) (Kromann 1980), and an increased risk of IBD in Western populations with a diet characterized by high n-6 PUFA and a decreased ratio of n-3:n-6 fat consumption (Hou 2011, Lupien 1994, Simopoulos 1994). In addition, higher intake of linoleic acid (n-6 PUFA) is associated with increased UC risk, while oleic (n-9 MonoUFA) and docosahexaenoic acids (DHA n-3 PUFA) have been associated with a decreased UC risk (Tjonneland 2009).

A 2010 study by Uchiyama et al. investigated the impact of dietary omega-3 and -6 intake ratios on maintaining remission in individuals with IBD. These fats were of particular interest as N-6 PUFAs are considered to be pro-inflammatory given that linoleic acid, the major n-6 PUFA, increases inflammatory mediators, including prostaglandin E2 and leukotriene B4 (Rachmilewitz 1982, Sharon 1984). In addition, animal studies have shown that n-3 PUFAs, which include a-linolenic acid, DHA, and eicosapentaenoic acid, are generally antiinflammatory (Hassan 2010, Ibrahim 2011). The study used 230 individuals with UC and CD who had achieved remission from drug therapy and prescribed them a dietary regimen that provided a n-3:n-6 fat intake ratio of 1:1. All steroids and immunosuppressants were gradually removed after achievement of remission, except for 5-ASA and thiopurines. The results showed that the dietary regimen resulted in changes of n-3:n-6 ratios in the patients’ erythrocyte membranes. Consequently, remission rates after 12-18 months were 79.7% and 54.3% in patients who maintained a n-3:n-6 membrane ratio of greater than 0.65, and less than 0.65, respectively (Uchiyama 2010).

Discussion

This review highlights the implications gluten, fiber, FODMAP carbohydrates, dairy, meat, and polyunsaturated fats have on IBD (Appendix I). Effective dietary strategies for IBD seem to decrease existing GI inflammation (high fiber, GBF and n-3 PUFA, or low FODMAPs), or decrease food-induced immune activation (low gluten, dairy, or meat).

Conclusions for clinical consideration are difficult to draw due to various limitations present in the research. For instance, though studies on dietary fibre indicate fruits as a preferred source of fibre in controlling IBD symptoms, the FODMAPs diet calls for the exclusion of certain fruits, given their potential for adverse IBD-related outcomes. The emerging evidence in these two areas suggest that the therapeutic effect of high-fiber diets may be limited by the inclusion of high FODMAP containing foods. Thus, further studies on the effect of high-fiber, low- FODMAP diets are needed. Another limitation of dietary studies lies in the inherent difficulty of adherence to dietary interventions; patients may introduce bias into observed results if diet regimens are not properly followed.

Although there are challenges to the use of dietary interventions to treat IBD, there is compelling evidence for the use of these treatments in practice. The use of diet alone has been shown to reduce the incidence of flare-ups (Wild 2007), increase remission time (7.5 vs. 3.8 months) and decrease relapse rates at 2 years (62% vs. 79%) when compared to 40 mg doses of prednisone daily (Riordan 1993). Administration of diet in conjunction with standard anti-inflammatory treatment can also lead to greater symptom alleviation.

Ultimately, dietary modulation in the prevention and control of IBD should be tailored to individual patients. This may be accomplished through the use of elimination and reintroduction diets, which allow practitioners to identify the food sources causing IBD flare-ups (Candy 1995). This review provides a starting point for such interventions.

Conclusion

This review has discussed the role of diet in managing IBD symptoms, specifically, the influences of gluten, fiber, FODMAP carbohydrates, dairy, meat, and polyunsaturated fat consumption. Though much evidence exists for each of the topics discussed herein, more research should be conducted in order to further delineate the role of diet in IBD symptom development and control. Given the studies explored in this review, it is evident that ingestion of these foods should be carefully monitored and coordinated in patients with IBD in order to decrease and modulate adverse IBD-associated symptoms.

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