A Roadmap for Advancing Women's Health in Disorders of the Gut-Brain Interaction.

Despite progress such as the NIH's “Sex as Biological Variable” policy and the 21 Century Cures Act mandating sex‐disaggregated reporting [ 89 ], challenges for conducting sex‐based research for GI conditions remain given the ever‐evolving sociopolitical climate. Debates globally surrounding gender identity, reproductive health and inclusion of underrepresented populations have led to uncertainty in research design and funding priorities from some government sources [ 90 ]. Continued and intentional support from our professional societies, philanthropic foundations and industry is needed to move potentially “controversial” research priorities forward. Given multiple mechanistic pathways linking sex‐specific comorbidities to DGBI (especially surrounding shared visceral and central sensitization pathways), renewed emphasis on innovative approaches with interdisciplinary colleagues is also needed. For example, therapeutic targets being studied for pelvic pain should be examined for potential benefits for IBS and vice versa [ 91 ]. To advance women's health in DGBI, further animal‐ and human‐based mechanistic investigations are needed to elucidate sex‐based differences in gastrointestinal physiology and symptom generation to guide the development of new clinical therapies or new applications of established therapies. Future clinical studies should focus on the following: Development and standardized use of sex‐specific normative data Prioritize phenotyping hormonal status of female participants in clinical trials Intentional inclusion of prevalent sex‐specific comorbidities which can impact overlapping GI symptoms (such as endometriosis, PCOS, interstitial cystitis, hEDS, eating disorders) in baseline demographics to identify if comorbid conditions impact treatment outcomes Collaboration between gastroenterologists and other women's health professionals such as gynecologists and urogynecologists to design interdisciplinary trials, including incorporation of cross‐disciplinary outcomes (e.g., abdominopelvic pain) Development and standardized use of sex‐specific normative data Prioritize phenotyping hormonal status of female participants in clinical trials Intentional inclusion of prevalent sex‐specific comorbidities which can impact overlapping GI symptoms (such as endometriosis, PCOS, interstitial cystitis, hEDS, eating disorders) in baseline demographics to identify if comorbid conditions impact treatment outcomes Collaboration between gastroenterologists and other women's health professionals such as gynecologists and urogynecologists to design interdisciplinary trials, including incorporation of cross‐disciplinary outcomes (e.g., abdominopelvic pain) Deliberate integration of sex‐informed trial design, comorbidity assessment, and cross‐disciplinary collaboration will be essential to advance tailored care for women with DGBI across their lifespan.

The authors have nothing to report.

There are several comorbid conditions which are highly prevalent in women and influence the mechanisms, presentation and treatment responses of overlapping DGBI (Table  1 ), but remain underrecognized in clinical practice and are rarely incorporated into trial design or therapeutic algorithms [ 6 ]. Notably, most studies investigating this overlap are almost exclusively focused on IBS from both epidemiological and therapeutic lens. Impact of sex‐specific comorbidities on disorders of the gut‐brain interaction disease states. Abbreviation: IBS, irritable bowel syndrome. Endometriosis affects approximately 10% of women of reproductive age [ 43 ] and is associated with a lengthy diagnostic delay in many patients [ 44 , 45 ]. Up to 90% of patients with endometriosis have chronic GI symptoms, including constipation, bloating, nausea, and abdominal pain though there are no recommendations to screen for endometriosis in patients with chronic GI symptoms [ 46 ]. One meta‐analysis found that the risk of IBS in women with endometriosis (compared to women without) was OR 3.26 (95% CI 1.97–5.3) [ 47 ]. This aligns with another meta‐analysis which found a similar risk of IBS to be OR 2.39 (95% CI 1.83–3.11) [ 44 ]; however, the authors noted that the Rome criteria may be insufficient to distinguish IBS from the visceral hypersensitivity often noted in patients with endometriosis [ 44 ]. Studies have explored the pathophysiologic links between intestinal microbiome dysbiosis in both IBS and endometriosis as alterations in gut microbiome can also influence estrogen metabolism [ 46 ]. Several recent studies have found that a low FODMAP diet provides greater symptom relief in women with both IBS and endometriosis compared with those with IBS alone [ 48 , 49 ], suggesting that this subgroup may represent a unique phenotype with distinct therapeutic implications. Furthermore, in animal studies, linaclotide, which is approved for IBS‐C, has been shown to reduce endometriosis‐associated pain, [ 50 ], indicating the potential for more research on treatments that may have overlapping benefits for women. PCOS affects approximately 9.2% of women [ 51 ] and has been associated with an increased risk of IBS [ 52 ]. A recent meta‐analysis of case‐controlled studies found that the risk of IBS was significantly higher in patients with PCOS than controls (OR 2.23, 95% CI 1.58–3.14) [ 52 ]. Potential therapeutic avenues in patients with PCOS and IBS could explore modification of insulin resistance or the microbiome as has been shown in animal studies for PCOS alone; however, therapeutic human studies are lacking [ 53 , 54 , 55 , 56 ]. IBS and interstitial cystitis/bladder pain syndrome (IC/BPS) frequently co‐occur with substantial symptom overlap. One case‐control study found that women with IC/BPS had markedly higher odds of also carrying an IBS diagnosis (OR 11, 95% CI 2.7–52) [ 57 ], with another cohort study showing that patients with IBS were more likely (HR 1.599, 95% CI 1.344–1.903) to be diagnosed with IC/BPS in the next decade than patients without IBS [ 58 ]. This may be secondary to common anatomic comorbidities such as pelvic floor dysfunction [ 59 ]. While far less common, one study found that patients with IC/BPS also reported more upper GI symptoms including worsening nausea than age matched controls, possibly related to a global visceral sensitization [ 60 , 61 ]. Another French study of patients with functional dyspepsia found that IC/BPS was present in 26.9% of patients with reduced quality of life [ 62 ]. Ehlers‐Danlos Syndrome (EDS), particularly the hypermobile subtype (hEDS), is significantly more prevalent in women [ 63 , 64 , 65 ], with a population study reporting a point prevalence of 194.2 per 100 000 of which 75% were women [ 65 ]. Emerging evidence suggests an extraordinarily strong association between hEDS and overlapping DGBI spanning the entire GI tract [ 66 , 67 , 68 ]. One study of 680 women with hEDS in the United Kingdom found that nearly all patients (99%) screened positive for a DGBI using Rome IV criteria, with functional dyspepsia (62.2%) being the most common followed by IBS (45.4%) [ 69 ]. A recent clinical practice update by the American Gastroenterological Association advises gastroenterologists seeing patients with DGBI to screen for hEDS, especially those with refractory symptoms [ 70 ]. Hypermobile EDS frequently co‐occurs within a “triad” of comorbid conditions including postural orthostatic tachycardia syndrome and mast cell activation syndrome with a clear female predominance (although the true prevalence is likely overestimated in studies using less rigorous diagnostic definitions), all of which can exacerbate chronic GI symptoms [ 71 ]. Studies using Rome criteria and objective anorectal physiology testing have demonstrated hEDS patients also have higher rates of chronic constipation, rectal hyposensitivity and abnormal anorectal pressure profiles compared to patients with functional constipation without hEDS [ 72 , 73 ]. Many large‐scale epidemiological studies and meta‐analyses have shown that women with DGBI have a higher prevalence of anxiety and depression than men, with odds ratios ranging from 1.5 to 1.7 and overall prevalence ranging from 25% to 50% depending on the disorder, correlating with greater severity of symptoms [ 74 , 75 ]. While understudied in comparison to depression or anxiety, eating disorders occur substantially more frequently in women than in men (ranging from three to twelve times more likely depending on the diagnosis) and operate as both biological and psychosocial drivers of sex‐based differences in a subset of DGBI [ 76 ]. There is a bidirectional relationship; disordered eating behaviors can induce alterations in motility and visceral sensitivity, whereas chronic GI symptoms can reinforce maladaptive eating patterns such as avoidant‐restrictive food intake disorder (ARFID), which is increasingly recognized as highly prevalent in patients with DGBI [ 77 ]. The prevalence of IBS amongst patients with eating disorders ranges from 30.5% to 64% depending on the population studied [ 78 ]. Consideration for routine screening for eating disorders should precede recommendations for dietary restriction (e.g., low‐FODMAP in IBS), especially in female patients with chronic GI symptoms [ 79 ]. Interdisciplinary management is important, as in some patients, weight restoration may alleviate GI symptoms [ 80 ].

Sex‐based differences in gastrointestinal disorders are well established, encompassing variations in prevalence, physiology, and symptom burden [ 1 , 2 ]. This is particularly pertinent for the highly prevalent disorders of the gut‐brain interaction (DGBI) [ 1 , 3 ], though nomenclature for these disorders continues to evolve [ 4 ]. For the purposes of this review, we will use DGBI to refer to the Rome criteria diagnoses such as irritable bowel syndrome (IBS) [ 5 ]. However, it is important to note that there is significant overlap in symptoms and occasionally mechanisms between DGBI, primary motility disorders such as gastroparesis, and “organic” gastrointestinal disorders such as inflammatory bowel disease [ 6 ]. There is increasing recognition of the disproportionate impact of DGBI on women in terms of higher prevalence as well as greater burden on quality of life [ 1 ]. Proposed mechanisms for these differences span hormonal influences, anatomical factors, sex‐specific microbiome alterations, psychosocial determinants, altered central and autonomic nervous system pathways, visceral perception, epithelial permeability, immune regulation, inflammation, genetics and epigenetics [ 1 , 3 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. While the underlying mechanisms of sex differences are a subject of ongoing investigations, research on treatments and outcomes in women's health and its intersection with DGBI symptoms and severity remain limited with no guidelines on sex‐specific management strategies [ 14 , 15 ]. This scoping review aims to shed light on how symptoms of DGBI and management may be affected by women's hormonal status across the lifespan and common sex‐specific comorbidities from both an epidemiologic as well as patient outcomes standpoint in the last decade [ 6 ]. Of note, although the Rome IV criteria were released in 2016, [ 5 ], many studies included in this review employ older Rome criteria, subjective patient reported diagnoses, or ICD codes to identify patients with DGBI and other conditions of interest, which introduces significant heterogeneity and reflects a substantial limitation in the current literature. At the conclusion of this review, we also suggest future directions for clinical studies and review.

Dr. Yuying Luo has an investigator‐initiated grant with Ardelyx.

Although numerous epidemiological studies have described the prevalence and symptom burden of sex‐specific comorbidities which commonly overlap with DGBI, there is still little guidance on how treatment approaches in DGBI should differ by sex. As highlighted in this review, this is largely due to the lack of patient‐focused outcomes research focusing specifically on sex‐specific DGBI management as well as studies on the intersection of DGBI and sex‐specific comorbidities; thus, the quality of these studies is variable. While there are sex‐specific IBS agents available such as alosteron and tegaserod (respectively approved for women with IBS‐D and IBS‐C), they are no longer used or widely available. However, studies on treatments for DGBI also frequently suffer from insufficient representation of men in the cohort and low power. For example, lubiprostone was approved for IBS‐C only in women due to inadequate efficacy in men [ 81 ], but the study population comprised only 8% men [ 82 ]. Another recent example of a study demonstrating sex‐specific treatment differences was metoclopramide nasal spray for gastroparesis (which often overlaps or exists on a spectrum with DGBI such as functional dyspepsia and functional constipation); based on these preliminary findings of efficacy differences, the Phase 3 randomized controlled trial was conducted only in women [ 83 ]. Most clinical trials in the realm of DGBI have sufficient representation of women (based on higher prevalence), but they are inadequately powered to detect sex or hormonal status differences in treatment outcomes as described above and do not account for highly prevalent comorbidities which may impact severity of GI symptoms. Two of the most recently approved modalities for IBS‐C and chronic idiopathic constipation included mostly women (a Phase 3 trial of tenapor included 82.1% women [ 84 ]; the Phase 3 trial of vibrant capsules included 86.2% women [ 85 ]), but did not explore differences based on hormonal status or other comorbidities. Two other recent randomized control trials for non‐pharmacologic interventions (low FODMAP diet and yoga) for IBS also included mostly women, greater than 90% in both studies, and did not assess hormonal status [ 86 , 87 ]. One randomized controlled trial in Italy found that leuprolide acetate was an effective treatment for menstrual cycle related IBS symptoms, but used Rome II criteria [ 88 ]. There are no clinical trials published even in the last 5 years on potential treatments for pregnant or post‐menopausal women with DGBI. Similarly, there are no contemporary clinical trials investigating the effectiveness of new and approved treatment for DGBI in women with common sex‐specific comorbidities. The presence of the comorbidities highlighted in this review in women with DGBI may impact the effectiveness of guideline‐directed treatment.