Aim: The responses of 10 patients with long-standing, symptomatic, intractable drug-refractory histories of irritable bowel syndrome with diarrhea (IBS-D) and with abdominal pain, gas/bloating and distention, termed IBS undefined (IBS-U), were evaluated when administering a medical food product containing serum-derived bovine immunoglobulin/protein isolate (SBI). Methods: Patients in this case series were chosen based on their lack of satisfactory response to a variety of drugs, including antidiarrheal and antispasmodic medications, serotonin 5-HT3 receptor antagonists, selective serotonin re-uptake inhibitors (SSRIs), proton pump inhibitors (PPIs), antibiotics, and antidepressive drugs. Patients met Rome III criteria and were administered 5 g/day of SBI as standard-of-care nutritional support. A scale of 0% - 25%, 25% - 50%, 50% - 75%, 75% - 100% response to SBI was used for patient-reported improvement in overall IBS symptoms following administration for one month. Exact methods for calculating confidence intervals and p-values were used to assess complete management of symptoms and response to therapy. Adverse events were also monitored for this nutritional product. Results: The onset of gastrointestinal (GI) symptom reduction utilizing nutritional management with SBI occurred within an average time of 2-4 weeks with improved or near complete management in all 10 patients who were refractory to previous drug therapies by 4 weeks. When prompted, patients reported significant IBS symptom improvement which averaged between 50% - 100% (p = 0.002) with an average for complete management in all patients of 69%. No side effects were reported after SBI administration even when taken for up to 28 weeks. Conclusion: Based on the safety profile and reported outcomes in this case report, SBI should be considered as a nutritional option for management in IBS-D and IBS-U.
The etiology of irritable bowel syndrome (IBS) is complex and not fully understood. Since there are no established bio-markers for IBS, diagnosis is via exclusion of underlying pathology and every “red flag” symptom. Irritable bowel syndrome is often a difficult to treat and an intractable problem for patients. Though the exact occurrence in developed countries is challenging to determine, it is estimated that 10% - 20% of the population has IBS [
Dietary modification, by reducing the ingestion of fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP diet), has been shown to improve gastrointestinal (GI) symptoms [
SBI is a specially formulated protein mixture which provides for a distinctive dietary requirement in the management of enteropathy in patients with chronic loose or frequent stools in such conditions as IBS-D and HIV-associated enteropathy under physician supervision [
We present a retrospective case series of 10 IBS patients previously refractory to multiple drug therapies who were subsequently administered SBI and experienced significant improvement in overall symptoms, thereby corroborating the effectiveness of this nutritional product in a “real world” setting.
The Rome Foundation has defined three classes of IBS including irritable bowel syndrome with constipation (IBS-C), IBS-D, and alternating or mixed populations termed IBS-M [
| Case | Age (yrs) | Race | Sex (M/F) | Case History | Gastrointestinal Symptoms | Attempted Treatments without Resolution of Symptoms |
|---|---|---|---|---|---|---|
| 1 | 71 | C | F | History of ischemic colitis, IBS-D esophageal spasms/hypersensitivity, Schatzki’s ring, anxiety, and chronic atypical chest pains, complaints of hemorrhoids and irritation, rare rectal bleeding from hemorrhoids, rheumatoid arthritis | Worsening epigastric pain, general abdominal pain, bloating/distension, diarrhea | Pantoprazole, omeprazole, sildenafil, atropine/ hyoscyamine/scopolamine/ phenobarbital, pantoprazole, hyoscyamine, ondansetron, promethazine, topical hydrocortisone acetate (2.5%) |
| 2 | 53 | C | F | History of IBS-U, nausea, acid indigestion, foul smelling flatus, anemia, multiple somatic complaints | Chronic abdominal pain, bloating/distention, flatus, epigastric pain, nausea | Dicyclomine, omeprazole |
| 3 | 37 | H | F | Lactose intolerance, small intestinal bacterial overgrowth, IBS-U symptoms | Chronic abdominal pain, bloating/distention, diarrhea, positive H2 breath test | Pantoprazole, hyoscyamine, polyethylene glycol 3350 NF, probiotic, flaxseed, subsequent monthly courses of rifaximin followed by dicyclomine |
| 4 | 62 | C | F | History lactose intolerance, IBS-U, dyspesia/tachygastria, GERD, reflux esophagitis, recurrent polycythemia vera | Chronic and severe abdominal pain, bloating/distention, with occasional dyspepsia | Aluminum hydroxide, magnesium hydroxide and simethicone, milk supplemented with lactase, dicyclomine (discontinued due to blurred vision) |
| 5 | 59 | B | F | History of IBS-D, GERD, insomnia, sleep apnea | Watery BMs with urgency, abdominal pain and distention relieved by defecation, “bubbling” followed by nausea/ vomiting | Escitalopram, amitriptyline, alosetron caused nausea |
| 6 | 63 | C | M | Long history of IBS-D, GERD, dyspesia/tachgastria, gastritis, gastroparesis, anal fissure, hiatal hernia, renal cell carcinoma | Abdominal pain, bloating/distention, diarrhea | Omeprazole (discontinued), diphenoxylate/atropine, dicyclomine (discontinued), tamsulosin, simvastatin, losartan, simethicone |
| 7 | 54 | H | F | History of IBS-U, gastritis, GERD, reflux esophagitis, hemorrhoids | Chronic abdominal pain, bloating/ distention, nonulcer dyspepsia, moderate epigastric pain after meals | Dicyclomine, hyoscyamine, omeprazole, bisacodyl, phenobarbital, PEG-3350 |
| 8 | 52 | C | F | History of gastroparesis and IBS-D multiple somatic and joint complaints | Generalized abdominal pain, bloating, early satiety, chronic diarrhea, foul smelling gas and flatulence, bloating/distention, nausea, vomiting | Pantoprazole, ondansetron, propranolol, chlordiazepoxide/clidinium, topiramate, quetiapine, lamotrigine, sumatriptan, trazodone |
| 9 | 66 | H | F | Long history of IBS-D, GERD, gastritis, fundic gland gastric polyps, avoids dairy | Quit her part time job due to symptoms, urgent exploding diarrhea mainly in morning with abdominal cramping, fecal incontinence | Citalopram, bismuth subsalicylate |
| 10 | 63 | H | F | Long history of IBS-D, GERD, gastritis | Chronic watery, non-bloody diarrhea with urgency occurring 2 - 3 times a day | Mesalamine (resulted in rash), sulfasalazine, metronidazole, methylprednisolone |
C—Caucasian; B—Black (African American); GERD—Gastrointestinal Reflux Disease; H—Hispanic; IBS-D—Irritable Bowel Syndrome with Diarrhea; IBS-U—Irritable Bowel Syndrome Undefined (Abdominal Pain, Gas/Bloating/Distention); PEG—Polyethylene Glycol.
Most patients had additional GI complications as well as other comorbidities which complicated their conditions detailed below.
Case 1 had a two-year history of IBS-D with worsening intermittent epigastric pain and ischemic colitis in addition to esophageal spasms and atypical chest pain. Case 2, in addition to being diagnosed as IBS-U for over one year, had multiple somatic complaints as well as nausea, epigastric pain and some flatus with a chronic history of stable anemia. Case 3 had a positive hydrogen breath test with lactose intolerance concurrent with small intestinal bacterial overgrowth (SIBO). The patient reported diarrhea, bloating, distention and gas pain and was diagnosed with IBS-D. During rifaximin (550 mg PO TID) treatment continuously for 5 weeks, symptoms were 50% better, but all symptoms returned with the same intensity after discontinuing the rifaximin course within 2 weeks. The patient then had a hydrogen breath test after the rifaximin course which was negative but symptoms continued. Case 4 had a two-year history of IBS-U complicated by lactose intolerance, dyspepsia/tachygastria, gastrointestinal reflux disease (GERD), reflux esophagitis, and had been treated with interferon for recurrent polycythemia vera. Case 5 had a one and a half-year history of IBS-D and GERD exacerbated by insomnia and sleep apnea. The patient reported the following symptoms after eating: cramping and abdominal pain followed by extreme urgency. Both cramping and abdominal pain were relieved by defecation, but the patient’s quality of life continued to be severely altered because of the severity of symptoms. Case 6 had a three-year history of IBS-D along with GERD, dyspepsia/tachygastria, gastritis, gastroparesis, and anal fissures. In addition, this male patient, the only one in this case series, had a history of benign prostatic hyperplasia, hyperlipidemia, and hyperthyroidism as well as a history of renal cell carcinoma, which was fully encapsulated and removed without further treatment. Case 7 was diagnosed with IBS-U two years earlier, along with ongoing epigastric pain, GERD, reflux esophagitis, and non-ulcer dyspepsia. The patient also had comorbid liver/pancreas cystic nonmalignant neoplasms and multiple somatic and joint complaints. Case 8 was diagnosed with IBS-D over a year earlier, but also had gastrointestinal comorbidities of gastroparesis and ongoing rectal bleeding from hemorrhoids. The patient was additionally diagnosed with generalized anxiety, depression, bipolar disorder, fibromyalgia, hypertension, asthma and chronic obstructive pulmonary disease (COPD). Case 9 had a 10-year history of IBS-D complicated by GERD, gastritis, and fundic gland gastric polyps. Furthermore, the patient had comorbid hyperlipidemia, breast cancer (the treatment for breast cancer was successful and there was no evidence of disease upon follow up), and mitral valve prolapse. Finally, Case 10 had a 7-year history of IBS-D, GERD, and gastritis. Case 10 also had comorbid chronic non-specific colitis (previously diagnosed but unconfirmed by the current treating physician with follow up colonoscopy), a large cecal polyp (flat, benign, tubular adenoma, no high grade dysplasia or malignancy on pathology) which required a right hemicolectomy, hyperthyroidism, and hyperlipidemia. Because these patients had been refractory to multiple drug therapies, they were placed on SBI as a nutritional agent in an attempt to help manage their IBS. None of the treatments noted in
Retrospective chart analysis was used to assess patient response to SBI administration as part of standard-of-care in patients diagnosed with drug-refractory histories for relief of symptoms for IBS-D and IBS-U. Patients were administered 5 g/d for 4 weeks before being seen to assess the impact on management of IBS-D or IBS-U. After 4 weeks, patients were asked to report their overall response for symptom improvement to SBI as a nutritional support pro- duct using a tiered scale between 0% and 100%. This scale was divided into four ranges (0% - 25%, 25% - 50%, 50% - 75%, 75% - 100%) to assess patient-reported improvement in overall IBS symptoms (i.e., abdominal pain, diarrhea, gas/bloating/distention, flatulence) following administration of SBI for one month. Patients continued on product after 4 weeks to assess long term exposure and to assess adverse events in a few cases longer than 20 weeks. An exact method for calculating confidence intervals and p-values was used for the case series data with a lower bound 95% confidence interval to assess relative management of their condition and statistical response to this nutritional therapy. The cost of drugs patients were on before and after SBI administration was determined using a commercial site (www.goodrx.com) that provides the range of retail prices in the location where patients live. These prices were averaged to give the retail cost for patients around the practice where patients were seen by physicians.
Three patients reported a response to nutritional management with SBI in the first 2 weeks. Seven others were not determined until the 4-week time point. All 10 patients responded to therapy within 4 weeks of receiving the first dose of 1 packet daily of EnteraGam™ (5 g/d of SBI). Four of 6 patients with IBS-D reported a 75% - 100% improvement in overall symptoms, while 2 out of 6 reported 50% - 75% improvement at 4 weeks. One out of 4 patients with IBS-U reported a 75% - 100% improvement in overall symptoms, while 3 out of 4 reported 50% - 75% improvement at 4 weeks. Average time on SBI for all patients was 13.6 weeks (median = 10 weeks). Using for calculating confidence intervals and the Fischer Exact test (two-sided) to calculate p-values for the case series data, the lower bound of the 95% confidence interval for the improved or near complete management rate among the cases in this study is 69%. Testing of the overall rate against a null population proportion of 50% resulted in a significant reduction in gastrointestinal (GI) symptoms in these 10 refractory patients with a p-value of 0.002. This represents a significant difference between patient responses to previous drugs vs. the response to nutritional management with SBI (
| Case | Dose of SBI (g/d) | Initial Response and Total Time on Therapy (wks) | Symptom Response | Overall Symptom Improvement |
|---|---|---|---|---|
| 1 | 5 | nd, 10 | Significantly decreased symptoms including bloating/distention, and diarrhea | 75% - 100 % |
| 2 | 5 | nd, 24 | Decreased bloating/distention and abdominal pain | 50% - 75% |
| 3 | 5 | nd, 8 | Improved abdominal pain, bloating/distention, and diarrhea | 50% - 75% |
| 4 | 5 | nd, 4 | Significant improvement in bloating and distention | 75% - 100% |
| 5 | 5 | nd, 6 | Decreased bloating, frequency, and urgency sensation in less than one month on therapy. One watery stool first followed by 2 soft stools per day. Metronidazole 10-day course and dicyclomine as needed were prescribed along with SBI. Now the patient is managed continuously on SBI with loperamide as needed. | 75% - 100% |
| 6 | 5 | 2, 10 | In one week, bloating and diarrhea improved. Continued improvement of bloating, diarrhea, and symptoms of GERD over a 9 week period. When patient stopped SBI for Nissen Fundoplication, symptoms of bloating and diarrhea returned. Re-initiation of SBI therapy resolved symptoms once again after 2-weeks. | 75% - 100% |
| 7 | 5 | nd, 12 | Significant decrease in bloating and distention | 50% - 75% |
| 8 | 5 | nd, 24 | Significant decrease in bloating in 8 wks with continued improvement in abdominal pain, bloating/distention and diarrhea thereafter. Patient still has recurrent nausea with vomiting and could not tolerate PPI therapy. Patient was also placed on dicyclomine to manage condition. | 50% - 75% |
| 9 | 5 | 2, 10 | Bowel movements were formed after morning meal with no urgency. Bismuth subsalicylate was discontinued. No abdominal cramping was reported after SBI administration. | 75% - 100% |
| 10 | 5 | 2, 28 | Normally formed bowel movements with notably reduced urgency. Patient self trial off SBI resulted in watery loose stool several times a day. This was resolved with re-initiation of SBI therapy within 2-weeks. | 50% - 75% |
GERD—Gastrointestinal Reflux Disease; nd—Not Determined; PPI—Proton Pump Inhibitor; SBI—Serum-Derived Bovine Immunoglobulin/Protein Isolate.
Two patients completed an initial 4-week course of SBI (Cases 6 and 10) and had a return of IBS-D symptoms when they decided to discontinue product. When they re-initiated SBI, the symptoms subsided in approximately 2 weeks. Two patients (Cases 5 and 8) required co-administration with other agents to manage symptoms fully following the initial 4 weeks of SBI, suggesting a reduction in overall utilization of drug therapies to treat this real world population. Cost analysis utilizing an online tool for retail pricing (www.goodrx.com) demonstrated that these patients, on average, saved more than $300 per month in direct drug costs and over $200 in medical costs while on SBI in reduced office visits. Finally, all patients reported improved quality of life while on nutritional management with SBI.
Wilson et al. [
Patients with IBS represent a challenge not only to physicians in treating their condition, but also to healthcare systems in terms of cost of care. The financial burden this illness places on the United States is upwards of $10 billion in direct medical costs and over $20 billion in indirect medical costs, totaling greater than $30 billion in combined costs per year [
IBS patients have disturbances in microbiota, minor inflammation in the lamina propria, barrier disruption and malabsorption of water [
The cases presented here are characteristic of IBS patients as a whole with food intolerances, somatic complaints, and sleep disturbance (
Despite this being a small retrospective chart analysis of patients that had not responded to previous treatments, it still resulted in a statistically significant decrease in IBS symptoms (p = 0.002) as well as pharmacoeconomic benefits with no reported side effects. Weaknesses of this case series report included that it was a retrospective chart analysis with a small sample size of patients (N = 10) and not a prospective evaluation. It is encouraging to note, however, that all patients responded to therapy by reporting improvement in their IBS symptoms, whereas they had experienced poor responses to traditional drug interventions.
Based on these results in a geographically separated, racially diverse population with comorbid disease complications and long histories of taking multiple agents for IBS, SBI was consistently effective in providing nutritional support to improve symptoms and the patients’ quality of life. While additional research may be needed, SBI should be considered as a viable nutritional option for managing patients with IBS.
B.P.B wishes to acknowledge Douglas A. Drossman, M.D. for his critical reading of this manuscript and recommended edits.