GI and Hepatology News

Helicobacter pylori (HP) eradication reduced the risk of gastric noncardia adenocarcinoma in five Scandinavian countries, a population-based study in Gastroenterology reported. Risk became virtually similar to the background population from 11 years after treatment onward.

HP infection of the stomach is the main established risk factor for this tumor, but not much was known about the impact of eradication on long-term risk, particularly in Western populations, noted investigators led by Jesper Lagengren, MD, a gastrointestinal surgeon and professor at the Karolinksa Institutet in Stockholm, Sweden. Research with longer follow-up has reported contradictory results.

The study cohort included all adults treated for HP from 1995 to 2019 in Denmark, Finland, Iceland, Norway, and Sweden. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were calculated by comparing the gastric noncardia adenocarcinoma incidence in the study cohort with the incidence in the background population of the same age, sex, calendar period, and country.

The 659,592 treated participants were 54.3% women, 61.5% age 50 or younger, and had no serious comorbidities. They contributed to 5,480,873 person-years at risk with a mean follow-up of 8.3 years. Treatment consisted of a minimum one-week antibiotic regimen with two of amoxicillin, clarithromycin, or metronidazole, in combination with a proton pump inhibitor. This is the recommended regimen in the Nordic countries, where it achieves successful eradication in 90% of infected individuals.

Among these patients, 1311 developed gastric noncardia adenocarcinoma. Over as many as 24 years of follow-up, the SIR in treated HP patients was initially significantly higher than in the background population at 2.27 (95% confidence interval [CI], 2.10-2.44) at 1 to 5 years after treatment. By 6 to 10 years the SIR had dropped to 1.34 (1.21-1.48) and by 11 to 24 years it further fell to 1.11 (.98-1.27). In terms of observed vs expected cases, that translated to 702 vs 310 at 1 to 5 years, 374 vs 270 at 6 to 10 years, and 235 vs 211 from 11 to 24 years.

The results of the Nordic study align with systematic reviews from Asian populations indicating that eradication reduces the risk of gastric cancer, the authors said. 

They noted gastric HP infection is the most prevalent bacterial infection worldwide, found in approximately 50% of the global population but with striking geographical variations in prevalence and virulence. The highest prevalence (>80%) and virulence are found in countries with low socioeconomic status and sanitation standards such as regions in Africa and Western Asia. 

Gastric adenocarcinoma is the fourth-commonest cause of cancer-related death globally, leading to 660,000 deaths in 2022. 

Lagergren and colleagues cited the need for research to delineate high-risk individuals who would benefit rom HP screening and eradication.

This study was supported by the Sjoberg Foundation, Nordic Cancer Union, Stockholm County Council, and Stockholm Cancer Society. The authors had no conflicts of interest to disclose.

Helicobacter pylori (HP) eradication reduced the risk of gastric noncardia adenocarcinoma in five Scandinavian countries, a population-based study in Gastroenterology reported. Risk became virtually similar to the background population from 11 years after treatment onward.

HP infection of the stomach is the main established risk factor for this tumor, but not much was known about the impact of eradication on long-term risk, particularly in Western populations, noted investigators led by Jesper Lagengren, MD, a gastrointestinal surgeon and professor at the Karolinksa Institutet in Stockholm, Sweden. Research with longer follow-up has reported contradictory results.

The study cohort included all adults treated for HP from 1995 to 2019 in Denmark, Finland, Iceland, Norway, and Sweden. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were calculated by comparing the gastric noncardia adenocarcinoma incidence in the study cohort with the incidence in the background population of the same age, sex, calendar period, and country.

The 659,592 treated participants were 54.3% women, 61.5% age 50 or younger, and had no serious comorbidities. They contributed to 5,480,873 person-years at risk with a mean follow-up of 8.3 years. Treatment consisted of a minimum one-week antibiotic regimen with two of amoxicillin, clarithromycin, or metronidazole, in combination with a proton pump inhibitor. This is the recommended regimen in the Nordic countries, where it achieves successful eradication in 90% of infected individuals.

Among these patients, 1311 developed gastric noncardia adenocarcinoma. Over as many as 24 years of follow-up, the SIR in treated HP patients was initially significantly higher than in the background population at 2.27 (95% confidence interval [CI], 2.10-2.44) at 1 to 5 years after treatment. By 6 to 10 years the SIR had dropped to 1.34 (1.21-1.48) and by 11 to 24 years it further fell to 1.11 (.98-1.27). In terms of observed vs expected cases, that translated to 702 vs 310 at 1 to 5 years, 374 vs 270 at 6 to 10 years, and 235 vs 211 from 11 to 24 years.

The results of the Nordic study align with systematic reviews from Asian populations indicating that eradication reduces the risk of gastric cancer, the authors said. 

They noted gastric HP infection is the most prevalent bacterial infection worldwide, found in approximately 50% of the global population but with striking geographical variations in prevalence and virulence. The highest prevalence (>80%) and virulence are found in countries with low socioeconomic status and sanitation standards such as regions in Africa and Western Asia. 

Gastric adenocarcinoma is the fourth-commonest cause of cancer-related death globally, leading to 660,000 deaths in 2022. 

Lagergren and colleagues cited the need for research to delineate high-risk individuals who would benefit rom HP screening and eradication.

This study was supported by the Sjoberg Foundation, Nordic Cancer Union, Stockholm County Council, and Stockholm Cancer Society. The authors had no conflicts of interest to disclose.

Helicobacter pylori (HP) eradication reduced the risk of gastric noncardia adenocarcinoma in five Scandinavian countries, a population-based study in Gastroenterology reported. Risk became virtually similar to the background population from 11 years after treatment onward.

HP infection of the stomach is the main established risk factor for this tumor, but not much was known about the impact of eradication on long-term risk, particularly in Western populations, noted investigators led by Jesper Lagengren, MD, a gastrointestinal surgeon and professor at the Karolinksa Institutet in Stockholm, Sweden. Research with longer follow-up has reported contradictory results.

The study cohort included all adults treated for HP from 1995 to 2019 in Denmark, Finland, Iceland, Norway, and Sweden. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were calculated by comparing the gastric noncardia adenocarcinoma incidence in the study cohort with the incidence in the background population of the same age, sex, calendar period, and country.

The 659,592 treated participants were 54.3% women, 61.5% age 50 or younger, and had no serious comorbidities. They contributed to 5,480,873 person-years at risk with a mean follow-up of 8.3 years. Treatment consisted of a minimum one-week antibiotic regimen with two of amoxicillin, clarithromycin, or metronidazole, in combination with a proton pump inhibitor. This is the recommended regimen in the Nordic countries, where it achieves successful eradication in 90% of infected individuals.

Among these patients, 1311 developed gastric noncardia adenocarcinoma. Over as many as 24 years of follow-up, the SIR in treated HP patients was initially significantly higher than in the background population at 2.27 (95% confidence interval [CI], 2.10-2.44) at 1 to 5 years after treatment. By 6 to 10 years the SIR had dropped to 1.34 (1.21-1.48) and by 11 to 24 years it further fell to 1.11 (.98-1.27). In terms of observed vs expected cases, that translated to 702 vs 310 at 1 to 5 years, 374 vs 270 at 6 to 10 years, and 235 vs 211 from 11 to 24 years.

The results of the Nordic study align with systematic reviews from Asian populations indicating that eradication reduces the risk of gastric cancer, the authors said. 

They noted gastric HP infection is the most prevalent bacterial infection worldwide, found in approximately 50% of the global population but with striking geographical variations in prevalence and virulence. The highest prevalence (>80%) and virulence are found in countries with low socioeconomic status and sanitation standards such as regions in Africa and Western Asia. 

Gastric adenocarcinoma is the fourth-commonest cause of cancer-related death globally, leading to 660,000 deaths in 2022. 

Lagergren and colleagues cited the need for research to delineate high-risk individuals who would benefit rom HP screening and eradication.

This study was supported by the Sjoberg Foundation, Nordic Cancer Union, Stockholm County Council, and Stockholm Cancer Society. The authors had no conflicts of interest to disclose.

Exocrine pancreatic insufficiency (EPI) is a recognized condition in patients with underlying pancreatic disease. However, it is a disease state that requires a meticulous approach to diagnose, as misdiagnosis can lead to inappropriate testing and unnecessary treatment.

EPI has been defined as “a near total decline in the quantity and/or activity of endogenous pancreatic enzymes to a level that is inadequate to maintain normal digestive capacity leading to steatorrhea.”¹ It can lead to complications including malnutrition, micronutrient deficiencies, metabolic bone disease and have significant impact on quality of life. In this article, we will review the approach to diagnosis of EPI, differential diagnosis considerations, the approach to treatment of EPI, and screening for complications.
 

EPI Diagnosis

EPI results from ineffective or insufficient pancreatic digestive enzyme secretion. In 2021, a group of experts from the American Gastroenterological Association (AGA) and PancreasFest met and proposed a new mechanistic definition of EPI. This suggests that EPI is the failure of sufficient pancreatic enzymes to effectively reach the intestine in order to allow for optimal digestion of ingested nutrients, leading to downstream macronutrient and micronutrient deficiencies with symptoms of maldigestion including post-prandial abdominal pain, bloating, steatorrhea, loose stools, or weight loss.²

A more pragmatic definition by Khan, et al in 2022 utilized a staging system to distinguish exocrine pancreatic dysfunction (EDP) from EPI. As such EPD occurs when there is a decline in pancreatic function without impaired digestive capacity, while EPI requires digestive capacity impairment leading to objective steatorrhea (coefficient of fat absorption <93 %).³Differential Diagnosis: There are many factors that can impact normal digestion. In approaching EPI, symptoms are often the most common reason to test for disease state in the appropriate clinical context. There can be pancreatic causes of EPI and non-pancreatic (secondary) causes of EPI (see Figure 1), though the latter can be challenging to detect.

The most common parenchymal etiologies for EPI include chronic pancreatitis, recurrent acute pancreatitis, cystic fibrosis, pancreatic cancer or prior pancreatic resections. Non-pancreatic conditions that impact synchronous mixing of endogenous pancreatic enzymes with meals (i.e., Roux-en-Y gastric bypass, short bowel syndrome, delayed gastric emptying), mucosal barriers causing decrease endogenous pancreatic stimulation despite intact parenchyma, such as celiac disease, foregut Crohn’s disease, intraluminal inactivation of pancreatic enzymes (Zollinger-Ellison syndrome), and bile salts de-conjugation with small intestinal bacterial overgrowth (SIBO) can predispose to EPI.^4-6 The true prevalence of EPI is difficult to ascertain due to a variety of factors including challenges in diagnosis and misdiagnosis.

Some of the major challenges in the diagnosis and treatment of EPI is that the symptoms of EPI overlap with many other GI conditions including celiac disease, diabetes mellitus, SIBO, irritable bowel syndrome (IBS), bile acid diarrhea, and other functional GI syndromes. These non-pancreatic conditions can also be associated with falsely low FE-1. Hence, ordering FE-1 should be employed with caution when the pretest probability is low. Patients with EPI will generally have a significant response to pancreatic enzyme replacement therapy (PERT) if it is adequately dosed and a lack of response should prompt consideration of an alternative diagnosis. A framework to factors which contribute to EPI is outlined in Figure 2.

Symptoms Screening and Signs: Pancreatic enzymes output estimation is the most reliable indicator for pancreatic digestive capacity. However, EPI diagnosis requires a combination of symptoms screening, stool-based (indirect pancreatic function) testing or direct pancreatic function testing (PFT).

Although symptoms might not correlate with objective disease state, in screening for symptoms of steatorrhea or maldigestion, it is important to ask specific questions regarding bloating, abdominal pain, stool frequency, consistency, and quality. Screening questions should be specific and include question such as, “Is there oil in the toilet bowl or is the stool greasy/shiny?”, “Is the stool sticky and difficult to flush or wipe?”, “Is there malodorous flatus?” If patients screen positive for EPI symptoms and there is a high pre-test probability of EPI such as the presence of severe chronic pancreatitis or significant pancreatic resection (> 90% loss of pancreatic parenchyma), then cautious trial of PERT and assessment for treatment response can be considered without additional stool-based testing. However, this practice end points are unclear and mainly based on subjective response.

Patients with EPI are at increased risk for malnutrition and micronutrient deficiencies. While not required for the diagnosis, low levels of fat-soluble vitamins (vitamin AEDK) or other minerals (zinc, selenium, magnesium, phosphorus) can suggest issues with malabsorption. Once the diagnosis of EPI is made, micronutrient screening should occur annually.

Stool Based Testing: The gold standard clinical test for steatorrhea is measuring coefficient of fat absorption (CFA). With a normal range of 93% fat absorption, the test is performed on a 72-hours fecal fat collection kit. To ensure accurate results, a patient must adhere to a diet with a minimum of 100 grams of fat per day in the three days leading up to the test and during the duration of the test. Patients must also abstain from taking PERT during the duration of the test. This can be incredibly challenging for someone with underlying steatorrhea but can reliably distinguish between EPD and EPI.

A more commonly used stool test is fecal elastase (FE-1). While easier to perform, the test often results in many false positives and false negatives. FE-1 is an ELISA based test, which measures the concentration of the specific isoform CELA3 (chymotrypsin-like elastase family) in the stool sample. The test must be run on a solid stool sample as soft or liquid stool will dilute down elastase concentration falsely. One test advantage is that a patient can continue PERT if needed. FE-1 test measures the concentration of patients’ elastase and PERT is porcine derived. As such, there is no interaction between porcine lipase and human elastase in stool. FE-1 sensitivity and specificity are high for severe disease (<100 mcg/g) if the test is performed properly on patients with a high pretest probability. However, the sensitivity and specificity are poor in mild to moderate pancreatic disease and in the absence of known pancreatic disease.⁷

Our suggested approach to utilizing FE-1 test is to reserve it for patients with known severe chronic pancreatitis or prior pancreatic surgery in patients with symptoms. In patients without pancreatic disease who are at low risk of EPI, a positive FE-1 can lead to misdiagnosis, further diagnostic testing, and unnecessary treatment. Currently, there is no stool-based test that is accurate, reproducible, and reliable.

Direct Pancreatic Function testing: Secretin stimulated PFT is highly reliable in measuring ductal function with bicarbonate concentration. However, it cannot reliably estimate acinar function as both do not decline at the same rate, unless in severe pancreatic disease. A much more robust test should include cholecystokinin analog to measure pancreatic enzymes concentration. This test involves endoscopy, administration of secretin, and/or a cholecystokinin analog, and subsequent measurement of bicarbonate and digestive enzymes in the pancreatic juice. This test is not routinely offered as it is invasive, cumbersome, and difficult to repeat for reassessment of pancreatic function over time.⁸

Treatment

The primary goal of treatment is to improve symptoms and nutritional status of the patient. EPI treatment consists of PERT and nutritional counseling. In the United States, there are multiple FDA approved PERT preparations, which include Creon, Zenpep, Pancreaze, Pertzye, Viokase, and Relizorb. While dosing is dependent on lipase concentration, all PERT (aside from Relizorb) preparations have a combination of lipase, proteases, and amylase. All but Viokace and Relizorb are enteric-coated formulations.⁹

In patients with an inadequate response to enteric coated PERT, non-enteric coated PERT can be added as it may provide a more immediate effect than enteric coated formulations, specially if concern about rapid gut transit with inadequate mixing is raised. If a non-enteric formations is used, acid suppression should be added to prevent inactivation of the PERT. Relizorb is a cartridge system which delivers lipase directly to tube feeds. This cartridge is only utilized in patients receiving enteral nutrition and allows for treatment of EPI even when patients are unable to tolerate oral feeding.

PERT dosing is intended to at least compensate for 10% of the physiologically secreted amount of endogenous lipase after a normal meal (approximately 30,000 IU). Hence, dosing is primarily weight-based. In symptomatic adults, PERT dose of 500-1000 units/kg/meal and half of the amount with snacks is appropriate. Although higher doses of 1500-2000 units/kg/meal may be needed when there is significant steatorrhea, weight loss, or micronutrient deficiencies, PERT doses exceeding 2500 units/kg/meal are not recommended and warrant further investigation.¹⁰

Proper counseling is important to ensure compliance with pancreatin preparations. PERT will generally be effective in improving steatorrhea, weight loss, bowel movement frequency, and reversal of nutritional deficiencies, but it does not reliably help symptoms of bloating or abdominal pain. If a patient’s steatorrhea does not respond to PERT, then alternative diagnoses such as SIBO, or diarrhea-predominant IBS should be considered.

PERT must be taken with meals. There are studies that support split dosing as a more effective way of absorbing fat.¹¹ If PERT is ineffective or minimally effective, review of appropriate dosing and timing of PERT to a meal is recommended. Addition of acid suppression may be required to improve treatment efficacy, especially in patients with abnormal intestinal motility or prior pancreatic surgery as PERT is effective at a pH of 4.5. Cost, pill burden, and persistence of certain symptoms may impact adherence to PERT and thus pre-treatment counseling and close follow-up after initiation is important. This aids in assessment of patients’ response to therapy, ensure appropriate PERT administration, and identifying any barriers to therapy adherence.

Nutritional management of EPI consists of an assessment of nutritional status, diet, and lifestyle. An important component of nutritional management is the assessment of micronutrient deficiencies. Patients with a confirmed diagnosis of EPI should be screened for the following micronutrients annually: Vitamins (A, E, D, K, B12), folate, zinc, selenium, magnesium, and iron. Patients with chronic pancreatitis and EPI should also be screened for metabolic bone disease once every two years and for diabetes mellitus annually.^{4, 12}

Conclusion

EPI is a challenging diagnosis as many symptoms overlap with other GI conditions. Pancreas exocrine function is rich with significant reserve to allow for proper digestive capacity, yet EPI occurs when an individual’s pancreatic digestive enzymes are insufficient to meet their nutritional needs. In patients with high likelihood of having EPI, such as those with pre-existing pancreatic disease, diagnosing EPI combines clinical evidence based on subjective symptoms and stool-based testing to support a disease state.

Appropriate dosing and timing of PERT is critical to improve nutritional outcomes and improve certain symptoms of EPI. Failure of PERT requires evaluating for proper dosing/timing, and consideration of additional or alternative diagnosis. EPI morbidity can lead to significant impact on patients’ quality of life, but with counseling, proper PERT use, nutritional consequences can be mediated, and quality of life can improve.

Dr. Hernandez-Barco is based in the Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts. Dr. Ashkar is based in the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Dr. Hernandez-Barco disclosed consulting for AMGEN and served as a scientific advisor for Nestle Health Science. She had project-related funding support or conflicts of interest to disclose. Dr. Ashkar disclosed consulting for AMGEN. He had no project-related funding support or conflicts of interest to disclose.

References

1. Othman MO, et al. Introduction and practical approach to exocrine pancreatic insufficiency for the practicing clinician. Int J Clin Pract. 2018 Feb. doi: 10.1111/ijcp.13066.

2. Whitcomb DC, et al. AGA-PancreasFest Joint Symposium on Exocrine Pancreatitic Insufficiency. Gastro Hep Adv. 2022 Nov. doi: 10.1016/j.gastha.2022.11.008.

3. Khan A, et al. Staging Exocrine Pancreatic Dysfunction. Pancreatology. 2022 Jan. doi: 10.1016/j.pan.2021.11.005.

4. Whitcomb DC, et al. AGA Clinical Practice Update on the Epidemiology, Evaluation, and Management of Exocrine Pancreatitis insufficiency: Expert Review. Gastroenterology. 2023 Nov. doi: 10.1053/j.gastro.2023.07.007.

5. Kunovský L, et al. Causes of Exocrine Pancreatic Insufficiency Other than Chronic Pancreatitis. J Clin Med. 2021 Dec. doi: 10.3390/jcm10245779.

6. Singh VK, et al. Less common etiologies of exocrine pancreatic insufficiency. World J Gastroenterol. 2017 Oct. doi: 10.3748/wjg.v23.i39.7059.

7. Lankisch PG, et al. Faecal elastase 1: not helpful in diagnosing chronic pancreatitis associated with mid to moderate exocrine pancreatic insufficiency. Gut. 1998 Apr. doi: 10.1136/gut.42.4.551.

8. Gardner TB, et al. ACG Clinical Guideline: Chronic Pancreatitis. Am J Gastroenterol. 2020 Mar. doi: 10.14309/ajg.0000000000000535.

9. Lewis DM, et al. Exocrine Pancreatic Insufficiency Dosing Guidelines for Pancreatic Enzyme Replacement Therapy Vary Widely Across Disease Types. Dig Dis Sci. 2024 Feb. doi: 10.1007/s10620-023-08184-w.

10. Borowitz DS, et al. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Consensus Committee. J Pediatr. 1995 Nov. doi: 10.1016/s0022-3476(95)70153-2.

11. Domínguez-Muñoz JE, et al. Effect of the Administration Schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: a randomized, three-way crossover study. Aliment Pharmacol Ther. 2005 Apr. doi: 10.1111/j.1365-2036.2005.02390.x.

12. Hart PA and Conwell DL. Chronic Pancreatitis: Managing a Difficult Disease. Am J Gastroenterol. 2020 Jan. doi: 10.14309/ajg.0000000000000421.

Exocrine pancreatic insufficiency (EPI) is a recognized condition in patients with underlying pancreatic disease. However, it is a disease state that requires a meticulous approach to diagnose, as misdiagnosis can lead to inappropriate testing and unnecessary treatment.

EPI has been defined as “a near total decline in the quantity and/or activity of endogenous pancreatic enzymes to a level that is inadequate to maintain normal digestive capacity leading to steatorrhea.”¹ It can lead to complications including malnutrition, micronutrient deficiencies, metabolic bone disease and have significant impact on quality of life. In this article, we will review the approach to diagnosis of EPI, differential diagnosis considerations, the approach to treatment of EPI, and screening for complications.
 

EPI Diagnosis

EPI results from ineffective or insufficient pancreatic digestive enzyme secretion. In 2021, a group of experts from the American Gastroenterological Association (AGA) and PancreasFest met and proposed a new mechanistic definition of EPI. This suggests that EPI is the failure of sufficient pancreatic enzymes to effectively reach the intestine in order to allow for optimal digestion of ingested nutrients, leading to downstream macronutrient and micronutrient deficiencies with symptoms of maldigestion including post-prandial abdominal pain, bloating, steatorrhea, loose stools, or weight loss.²

A more pragmatic definition by Khan, et al in 2022 utilized a staging system to distinguish exocrine pancreatic dysfunction (EDP) from EPI. As such EPD occurs when there is a decline in pancreatic function without impaired digestive capacity, while EPI requires digestive capacity impairment leading to objective steatorrhea (coefficient of fat absorption <93 %).³Differential Diagnosis: There are many factors that can impact normal digestion. In approaching EPI, symptoms are often the most common reason to test for disease state in the appropriate clinical context. There can be pancreatic causes of EPI and non-pancreatic (secondary) causes of EPI (see Figure 1), though the latter can be challenging to detect.

The most common parenchymal etiologies for EPI include chronic pancreatitis, recurrent acute pancreatitis, cystic fibrosis, pancreatic cancer or prior pancreatic resections. Non-pancreatic conditions that impact synchronous mixing of endogenous pancreatic enzymes with meals (i.e., Roux-en-Y gastric bypass, short bowel syndrome, delayed gastric emptying), mucosal barriers causing decrease endogenous pancreatic stimulation despite intact parenchyma, such as celiac disease, foregut Crohn’s disease, intraluminal inactivation of pancreatic enzymes (Zollinger-Ellison syndrome), and bile salts de-conjugation with small intestinal bacterial overgrowth (SIBO) can predispose to EPI.^4-6 The true prevalence of EPI is difficult to ascertain due to a variety of factors including challenges in diagnosis and misdiagnosis.

Some of the major challenges in the diagnosis and treatment of EPI is that the symptoms of EPI overlap with many other GI conditions including celiac disease, diabetes mellitus, SIBO, irritable bowel syndrome (IBS), bile acid diarrhea, and other functional GI syndromes. These non-pancreatic conditions can also be associated with falsely low FE-1. Hence, ordering FE-1 should be employed with caution when the pretest probability is low. Patients with EPI will generally have a significant response to pancreatic enzyme replacement therapy (PERT) if it is adequately dosed and a lack of response should prompt consideration of an alternative diagnosis. A framework to factors which contribute to EPI is outlined in Figure 2.

Symptoms Screening and Signs: Pancreatic enzymes output estimation is the most reliable indicator for pancreatic digestive capacity. However, EPI diagnosis requires a combination of symptoms screening, stool-based (indirect pancreatic function) testing or direct pancreatic function testing (PFT).

Although symptoms might not correlate with objective disease state, in screening for symptoms of steatorrhea or maldigestion, it is important to ask specific questions regarding bloating, abdominal pain, stool frequency, consistency, and quality. Screening questions should be specific and include question such as, “Is there oil in the toilet bowl or is the stool greasy/shiny?”, “Is the stool sticky and difficult to flush or wipe?”, “Is there malodorous flatus?” If patients screen positive for EPI symptoms and there is a high pre-test probability of EPI such as the presence of severe chronic pancreatitis or significant pancreatic resection (> 90% loss of pancreatic parenchyma), then cautious trial of PERT and assessment for treatment response can be considered without additional stool-based testing. However, this practice end points are unclear and mainly based on subjective response.

Patients with EPI are at increased risk for malnutrition and micronutrient deficiencies. While not required for the diagnosis, low levels of fat-soluble vitamins (vitamin AEDK) or other minerals (zinc, selenium, magnesium, phosphorus) can suggest issues with malabsorption. Once the diagnosis of EPI is made, micronutrient screening should occur annually.

Stool Based Testing: The gold standard clinical test for steatorrhea is measuring coefficient of fat absorption (CFA). With a normal range of 93% fat absorption, the test is performed on a 72-hours fecal fat collection kit. To ensure accurate results, a patient must adhere to a diet with a minimum of 100 grams of fat per day in the three days leading up to the test and during the duration of the test. Patients must also abstain from taking PERT during the duration of the test. This can be incredibly challenging for someone with underlying steatorrhea but can reliably distinguish between EPD and EPI.

A more commonly used stool test is fecal elastase (FE-1). While easier to perform, the test often results in many false positives and false negatives. FE-1 is an ELISA based test, which measures the concentration of the specific isoform CELA3 (chymotrypsin-like elastase family) in the stool sample. The test must be run on a solid stool sample as soft or liquid stool will dilute down elastase concentration falsely. One test advantage is that a patient can continue PERT if needed. FE-1 test measures the concentration of patients’ elastase and PERT is porcine derived. As such, there is no interaction between porcine lipase and human elastase in stool. FE-1 sensitivity and specificity are high for severe disease (<100 mcg/g) if the test is performed properly on patients with a high pretest probability. However, the sensitivity and specificity are poor in mild to moderate pancreatic disease and in the absence of known pancreatic disease.⁷

Our suggested approach to utilizing FE-1 test is to reserve it for patients with known severe chronic pancreatitis or prior pancreatic surgery in patients with symptoms. In patients without pancreatic disease who are at low risk of EPI, a positive FE-1 can lead to misdiagnosis, further diagnostic testing, and unnecessary treatment. Currently, there is no stool-based test that is accurate, reproducible, and reliable.

Direct Pancreatic Function testing: Secretin stimulated PFT is highly reliable in measuring ductal function with bicarbonate concentration. However, it cannot reliably estimate acinar function as both do not decline at the same rate, unless in severe pancreatic disease. A much more robust test should include cholecystokinin analog to measure pancreatic enzymes concentration. This test involves endoscopy, administration of secretin, and/or a cholecystokinin analog, and subsequent measurement of bicarbonate and digestive enzymes in the pancreatic juice. This test is not routinely offered as it is invasive, cumbersome, and difficult to repeat for reassessment of pancreatic function over time.⁸

Treatment

The primary goal of treatment is to improve symptoms and nutritional status of the patient. EPI treatment consists of PERT and nutritional counseling. In the United States, there are multiple FDA approved PERT preparations, which include Creon, Zenpep, Pancreaze, Pertzye, Viokase, and Relizorb. While dosing is dependent on lipase concentration, all PERT (aside from Relizorb) preparations have a combination of lipase, proteases, and amylase. All but Viokace and Relizorb are enteric-coated formulations.⁹

In patients with an inadequate response to enteric coated PERT, non-enteric coated PERT can be added as it may provide a more immediate effect than enteric coated formulations, specially if concern about rapid gut transit with inadequate mixing is raised. If a non-enteric formations is used, acid suppression should be added to prevent inactivation of the PERT. Relizorb is a cartridge system which delivers lipase directly to tube feeds. This cartridge is only utilized in patients receiving enteral nutrition and allows for treatment of EPI even when patients are unable to tolerate oral feeding.

PERT dosing is intended to at least compensate for 10% of the physiologically secreted amount of endogenous lipase after a normal meal (approximately 30,000 IU). Hence, dosing is primarily weight-based. In symptomatic adults, PERT dose of 500-1000 units/kg/meal and half of the amount with snacks is appropriate. Although higher doses of 1500-2000 units/kg/meal may be needed when there is significant steatorrhea, weight loss, or micronutrient deficiencies, PERT doses exceeding 2500 units/kg/meal are not recommended and warrant further investigation.¹⁰

Proper counseling is important to ensure compliance with pancreatin preparations. PERT will generally be effective in improving steatorrhea, weight loss, bowel movement frequency, and reversal of nutritional deficiencies, but it does not reliably help symptoms of bloating or abdominal pain. If a patient’s steatorrhea does not respond to PERT, then alternative diagnoses such as SIBO, or diarrhea-predominant IBS should be considered.

PERT must be taken with meals. There are studies that support split dosing as a more effective way of absorbing fat.¹¹ If PERT is ineffective or minimally effective, review of appropriate dosing and timing of PERT to a meal is recommended. Addition of acid suppression may be required to improve treatment efficacy, especially in patients with abnormal intestinal motility or prior pancreatic surgery as PERT is effective at a pH of 4.5. Cost, pill burden, and persistence of certain symptoms may impact adherence to PERT and thus pre-treatment counseling and close follow-up after initiation is important. This aids in assessment of patients’ response to therapy, ensure appropriate PERT administration, and identifying any barriers to therapy adherence.

Nutritional management of EPI consists of an assessment of nutritional status, diet, and lifestyle. An important component of nutritional management is the assessment of micronutrient deficiencies. Patients with a confirmed diagnosis of EPI should be screened for the following micronutrients annually: Vitamins (A, E, D, K, B12), folate, zinc, selenium, magnesium, and iron. Patients with chronic pancreatitis and EPI should also be screened for metabolic bone disease once every two years and for diabetes mellitus annually.^{4, 12}

Conclusion

EPI is a challenging diagnosis as many symptoms overlap with other GI conditions. Pancreas exocrine function is rich with significant reserve to allow for proper digestive capacity, yet EPI occurs when an individual’s pancreatic digestive enzymes are insufficient to meet their nutritional needs. In patients with high likelihood of having EPI, such as those with pre-existing pancreatic disease, diagnosing EPI combines clinical evidence based on subjective symptoms and stool-based testing to support a disease state.

Appropriate dosing and timing of PERT is critical to improve nutritional outcomes and improve certain symptoms of EPI. Failure of PERT requires evaluating for proper dosing/timing, and consideration of additional or alternative diagnosis. EPI morbidity can lead to significant impact on patients’ quality of life, but with counseling, proper PERT use, nutritional consequences can be mediated, and quality of life can improve.

Dr. Hernandez-Barco is based in the Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts. Dr. Ashkar is based in the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Dr. Hernandez-Barco disclosed consulting for AMGEN and served as a scientific advisor for Nestle Health Science. She had project-related funding support or conflicts of interest to disclose. Dr. Ashkar disclosed consulting for AMGEN. He had no project-related funding support or conflicts of interest to disclose.

References

1. Othman MO, et al. Introduction and practical approach to exocrine pancreatic insufficiency for the practicing clinician. Int J Clin Pract. 2018 Feb. doi: 10.1111/ijcp.13066.

2. Whitcomb DC, et al. AGA-PancreasFest Joint Symposium on Exocrine Pancreatitic Insufficiency. Gastro Hep Adv. 2022 Nov. doi: 10.1016/j.gastha.2022.11.008.

3. Khan A, et al. Staging Exocrine Pancreatic Dysfunction. Pancreatology. 2022 Jan. doi: 10.1016/j.pan.2021.11.005.

4. Whitcomb DC, et al. AGA Clinical Practice Update on the Epidemiology, Evaluation, and Management of Exocrine Pancreatitis insufficiency: Expert Review. Gastroenterology. 2023 Nov. doi: 10.1053/j.gastro.2023.07.007.

5. Kunovský L, et al. Causes of Exocrine Pancreatic Insufficiency Other than Chronic Pancreatitis. J Clin Med. 2021 Dec. doi: 10.3390/jcm10245779.

6. Singh VK, et al. Less common etiologies of exocrine pancreatic insufficiency. World J Gastroenterol. 2017 Oct. doi: 10.3748/wjg.v23.i39.7059.

7. Lankisch PG, et al. Faecal elastase 1: not helpful in diagnosing chronic pancreatitis associated with mid to moderate exocrine pancreatic insufficiency. Gut. 1998 Apr. doi: 10.1136/gut.42.4.551.

8. Gardner TB, et al. ACG Clinical Guideline: Chronic Pancreatitis. Am J Gastroenterol. 2020 Mar. doi: 10.14309/ajg.0000000000000535.

9. Lewis DM, et al. Exocrine Pancreatic Insufficiency Dosing Guidelines for Pancreatic Enzyme Replacement Therapy Vary Widely Across Disease Types. Dig Dis Sci. 2024 Feb. doi: 10.1007/s10620-023-08184-w.

10. Borowitz DS, et al. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Consensus Committee. J Pediatr. 1995 Nov. doi: 10.1016/s0022-3476(95)70153-2.

11. Domínguez-Muñoz JE, et al. Effect of the Administration Schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: a randomized, three-way crossover study. Aliment Pharmacol Ther. 2005 Apr. doi: 10.1111/j.1365-2036.2005.02390.x.

12. Hart PA and Conwell DL. Chronic Pancreatitis: Managing a Difficult Disease. Am J Gastroenterol. 2020 Jan. doi: 10.14309/ajg.0000000000000421.

Exocrine pancreatic insufficiency (EPI) is a recognized condition in patients with underlying pancreatic disease. However, it is a disease state that requires a meticulous approach to diagnose, as misdiagnosis can lead to inappropriate testing and unnecessary treatment.

EPI has been defined as “a near total decline in the quantity and/or activity of endogenous pancreatic enzymes to a level that is inadequate to maintain normal digestive capacity leading to steatorrhea.”¹ It can lead to complications including malnutrition, micronutrient deficiencies, metabolic bone disease and have significant impact on quality of life. In this article, we will review the approach to diagnosis of EPI, differential diagnosis considerations, the approach to treatment of EPI, and screening for complications.
 

EPI Diagnosis

EPI results from ineffective or insufficient pancreatic digestive enzyme secretion. In 2021, a group of experts from the American Gastroenterological Association (AGA) and PancreasFest met and proposed a new mechanistic definition of EPI. This suggests that EPI is the failure of sufficient pancreatic enzymes to effectively reach the intestine in order to allow for optimal digestion of ingested nutrients, leading to downstream macronutrient and micronutrient deficiencies with symptoms of maldigestion including post-prandial abdominal pain, bloating, steatorrhea, loose stools, or weight loss.²

A more pragmatic definition by Khan, et al in 2022 utilized a staging system to distinguish exocrine pancreatic dysfunction (EDP) from EPI. As such EPD occurs when there is a decline in pancreatic function without impaired digestive capacity, while EPI requires digestive capacity impairment leading to objective steatorrhea (coefficient of fat absorption <93 %).³Differential Diagnosis: There are many factors that can impact normal digestion. In approaching EPI, symptoms are often the most common reason to test for disease state in the appropriate clinical context. There can be pancreatic causes of EPI and non-pancreatic (secondary) causes of EPI (see Figure 1), though the latter can be challenging to detect.

The most common parenchymal etiologies for EPI include chronic pancreatitis, recurrent acute pancreatitis, cystic fibrosis, pancreatic cancer or prior pancreatic resections. Non-pancreatic conditions that impact synchronous mixing of endogenous pancreatic enzymes with meals (i.e., Roux-en-Y gastric bypass, short bowel syndrome, delayed gastric emptying), mucosal barriers causing decrease endogenous pancreatic stimulation despite intact parenchyma, such as celiac disease, foregut Crohn’s disease, intraluminal inactivation of pancreatic enzymes (Zollinger-Ellison syndrome), and bile salts de-conjugation with small intestinal bacterial overgrowth (SIBO) can predispose to EPI.^4-6 The true prevalence of EPI is difficult to ascertain due to a variety of factors including challenges in diagnosis and misdiagnosis.

Some of the major challenges in the diagnosis and treatment of EPI is that the symptoms of EPI overlap with many other GI conditions including celiac disease, diabetes mellitus, SIBO, irritable bowel syndrome (IBS), bile acid diarrhea, and other functional GI syndromes. These non-pancreatic conditions can also be associated with falsely low FE-1. Hence, ordering FE-1 should be employed with caution when the pretest probability is low. Patients with EPI will generally have a significant response to pancreatic enzyme replacement therapy (PERT) if it is adequately dosed and a lack of response should prompt consideration of an alternative diagnosis. A framework to factors which contribute to EPI is outlined in Figure 2.

Symptoms Screening and Signs: Pancreatic enzymes output estimation is the most reliable indicator for pancreatic digestive capacity. However, EPI diagnosis requires a combination of symptoms screening, stool-based (indirect pancreatic function) testing or direct pancreatic function testing (PFT).

Although symptoms might not correlate with objective disease state, in screening for symptoms of steatorrhea or maldigestion, it is important to ask specific questions regarding bloating, abdominal pain, stool frequency, consistency, and quality. Screening questions should be specific and include question such as, “Is there oil in the toilet bowl or is the stool greasy/shiny?”, “Is the stool sticky and difficult to flush or wipe?”, “Is there malodorous flatus?” If patients screen positive for EPI symptoms and there is a high pre-test probability of EPI such as the presence of severe chronic pancreatitis or significant pancreatic resection (> 90% loss of pancreatic parenchyma), then cautious trial of PERT and assessment for treatment response can be considered without additional stool-based testing. However, this practice end points are unclear and mainly based on subjective response.

Patients with EPI are at increased risk for malnutrition and micronutrient deficiencies. While not required for the diagnosis, low levels of fat-soluble vitamins (vitamin AEDK) or other minerals (zinc, selenium, magnesium, phosphorus) can suggest issues with malabsorption. Once the diagnosis of EPI is made, micronutrient screening should occur annually.

Stool Based Testing: The gold standard clinical test for steatorrhea is measuring coefficient of fat absorption (CFA). With a normal range of 93% fat absorption, the test is performed on a 72-hours fecal fat collection kit. To ensure accurate results, a patient must adhere to a diet with a minimum of 100 grams of fat per day in the three days leading up to the test and during the duration of the test. Patients must also abstain from taking PERT during the duration of the test. This can be incredibly challenging for someone with underlying steatorrhea but can reliably distinguish between EPD and EPI.

A more commonly used stool test is fecal elastase (FE-1). While easier to perform, the test often results in many false positives and false negatives. FE-1 is an ELISA based test, which measures the concentration of the specific isoform CELA3 (chymotrypsin-like elastase family) in the stool sample. The test must be run on a solid stool sample as soft or liquid stool will dilute down elastase concentration falsely. One test advantage is that a patient can continue PERT if needed. FE-1 test measures the concentration of patients’ elastase and PERT is porcine derived. As such, there is no interaction between porcine lipase and human elastase in stool. FE-1 sensitivity and specificity are high for severe disease (<100 mcg/g) if the test is performed properly on patients with a high pretest probability. However, the sensitivity and specificity are poor in mild to moderate pancreatic disease and in the absence of known pancreatic disease.⁷

Our suggested approach to utilizing FE-1 test is to reserve it for patients with known severe chronic pancreatitis or prior pancreatic surgery in patients with symptoms. In patients without pancreatic disease who are at low risk of EPI, a positive FE-1 can lead to misdiagnosis, further diagnostic testing, and unnecessary treatment. Currently, there is no stool-based test that is accurate, reproducible, and reliable.

Direct Pancreatic Function testing: Secretin stimulated PFT is highly reliable in measuring ductal function with bicarbonate concentration. However, it cannot reliably estimate acinar function as both do not decline at the same rate, unless in severe pancreatic disease. A much more robust test should include cholecystokinin analog to measure pancreatic enzymes concentration. This test involves endoscopy, administration of secretin, and/or a cholecystokinin analog, and subsequent measurement of bicarbonate and digestive enzymes in the pancreatic juice. This test is not routinely offered as it is invasive, cumbersome, and difficult to repeat for reassessment of pancreatic function over time.⁸

Treatment

The primary goal of treatment is to improve symptoms and nutritional status of the patient. EPI treatment consists of PERT and nutritional counseling. In the United States, there are multiple FDA approved PERT preparations, which include Creon, Zenpep, Pancreaze, Pertzye, Viokase, and Relizorb. While dosing is dependent on lipase concentration, all PERT (aside from Relizorb) preparations have a combination of lipase, proteases, and amylase. All but Viokace and Relizorb are enteric-coated formulations.⁹

In patients with an inadequate response to enteric coated PERT, non-enteric coated PERT can be added as it may provide a more immediate effect than enteric coated formulations, specially if concern about rapid gut transit with inadequate mixing is raised. If a non-enteric formations is used, acid suppression should be added to prevent inactivation of the PERT. Relizorb is a cartridge system which delivers lipase directly to tube feeds. This cartridge is only utilized in patients receiving enteral nutrition and allows for treatment of EPI even when patients are unable to tolerate oral feeding.

PERT dosing is intended to at least compensate for 10% of the physiologically secreted amount of endogenous lipase after a normal meal (approximately 30,000 IU). Hence, dosing is primarily weight-based. In symptomatic adults, PERT dose of 500-1000 units/kg/meal and half of the amount with snacks is appropriate. Although higher doses of 1500-2000 units/kg/meal may be needed when there is significant steatorrhea, weight loss, or micronutrient deficiencies, PERT doses exceeding 2500 units/kg/meal are not recommended and warrant further investigation.¹⁰

Proper counseling is important to ensure compliance with pancreatin preparations. PERT will generally be effective in improving steatorrhea, weight loss, bowel movement frequency, and reversal of nutritional deficiencies, but it does not reliably help symptoms of bloating or abdominal pain. If a patient’s steatorrhea does not respond to PERT, then alternative diagnoses such as SIBO, or diarrhea-predominant IBS should be considered.

PERT must be taken with meals. There are studies that support split dosing as a more effective way of absorbing fat.¹¹ If PERT is ineffective or minimally effective, review of appropriate dosing and timing of PERT to a meal is recommended. Addition of acid suppression may be required to improve treatment efficacy, especially in patients with abnormal intestinal motility or prior pancreatic surgery as PERT is effective at a pH of 4.5. Cost, pill burden, and persistence of certain symptoms may impact adherence to PERT and thus pre-treatment counseling and close follow-up after initiation is important. This aids in assessment of patients’ response to therapy, ensure appropriate PERT administration, and identifying any barriers to therapy adherence.

Nutritional management of EPI consists of an assessment of nutritional status, diet, and lifestyle. An important component of nutritional management is the assessment of micronutrient deficiencies. Patients with a confirmed diagnosis of EPI should be screened for the following micronutrients annually: Vitamins (A, E, D, K, B12), folate, zinc, selenium, magnesium, and iron. Patients with chronic pancreatitis and EPI should also be screened for metabolic bone disease once every two years and for diabetes mellitus annually.^{4, 12}

Conclusion

EPI is a challenging diagnosis as many symptoms overlap with other GI conditions. Pancreas exocrine function is rich with significant reserve to allow for proper digestive capacity, yet EPI occurs when an individual’s pancreatic digestive enzymes are insufficient to meet their nutritional needs. In patients with high likelihood of having EPI, such as those with pre-existing pancreatic disease, diagnosing EPI combines clinical evidence based on subjective symptoms and stool-based testing to support a disease state.

Appropriate dosing and timing of PERT is critical to improve nutritional outcomes and improve certain symptoms of EPI. Failure of PERT requires evaluating for proper dosing/timing, and consideration of additional or alternative diagnosis. EPI morbidity can lead to significant impact on patients’ quality of life, but with counseling, proper PERT use, nutritional consequences can be mediated, and quality of life can improve.

Dr. Hernandez-Barco is based in the Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts. Dr. Ashkar is based in the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Dr. Hernandez-Barco disclosed consulting for AMGEN and served as a scientific advisor for Nestle Health Science. She had project-related funding support or conflicts of interest to disclose. Dr. Ashkar disclosed consulting for AMGEN. He had no project-related funding support or conflicts of interest to disclose.

References

1. Othman MO, et al. Introduction and practical approach to exocrine pancreatic insufficiency for the practicing clinician. Int J Clin Pract. 2018 Feb. doi: 10.1111/ijcp.13066.

2. Whitcomb DC, et al. AGA-PancreasFest Joint Symposium on Exocrine Pancreatitic Insufficiency. Gastro Hep Adv. 2022 Nov. doi: 10.1016/j.gastha.2022.11.008.

3. Khan A, et al. Staging Exocrine Pancreatic Dysfunction. Pancreatology. 2022 Jan. doi: 10.1016/j.pan.2021.11.005.

4. Whitcomb DC, et al. AGA Clinical Practice Update on the Epidemiology, Evaluation, and Management of Exocrine Pancreatitis insufficiency: Expert Review. Gastroenterology. 2023 Nov. doi: 10.1053/j.gastro.2023.07.007.

5. Kunovský L, et al. Causes of Exocrine Pancreatic Insufficiency Other than Chronic Pancreatitis. J Clin Med. 2021 Dec. doi: 10.3390/jcm10245779.

6. Singh VK, et al. Less common etiologies of exocrine pancreatic insufficiency. World J Gastroenterol. 2017 Oct. doi: 10.3748/wjg.v23.i39.7059.

7. Lankisch PG, et al. Faecal elastase 1: not helpful in diagnosing chronic pancreatitis associated with mid to moderate exocrine pancreatic insufficiency. Gut. 1998 Apr. doi: 10.1136/gut.42.4.551.

8. Gardner TB, et al. ACG Clinical Guideline: Chronic Pancreatitis. Am J Gastroenterol. 2020 Mar. doi: 10.14309/ajg.0000000000000535.

9. Lewis DM, et al. Exocrine Pancreatic Insufficiency Dosing Guidelines for Pancreatic Enzyme Replacement Therapy Vary Widely Across Disease Types. Dig Dis Sci. 2024 Feb. doi: 10.1007/s10620-023-08184-w.

10. Borowitz DS, et al. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Consensus Committee. J Pediatr. 1995 Nov. doi: 10.1016/s0022-3476(95)70153-2.

11. Domínguez-Muñoz JE, et al. Effect of the Administration Schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: a randomized, three-way crossover study. Aliment Pharmacol Ther. 2005 Apr. doi: 10.1111/j.1365-2036.2005.02390.x.

12. Hart PA and Conwell DL. Chronic Pancreatitis: Managing a Difficult Disease. Am J Gastroenterol. 2020 Jan. doi: 10.14309/ajg.0000000000000421.

Effective ways to combat harmful viruses, bacteria, fungi, and parasitic worms have driven major advances in medicine and contributed to a significant increase in human life expectancy over the past century. However, as knowledge about the role of these microorganisms in promoting and maintaining health deepens, there is a need for a new look at the impact of these treatments.

The list of drugs that can directly alter the gut microbiota is long. In addition to antibiotics, antivirals, antifungals, anthelmintics, proton pump inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), laxatives, oral antidiabetics, antidepressants, antipsychotics, statins, chemotherapeutics, and immunosuppressants can trigger dysbiosis.

A 2020 study published in Nature Communications, which analyzed the impact of common medications on the composition and metabolic function of the gut bacteria, showed that of the 41 classes of medications, researchers found that 19 were associated with changes in the microbiome, most notably antibiotics, proton pump inhibitors, laxatives, and metformin.

“There are still no protocols aimed at preserving the microbiota during pharmacological treatment. Future research should identify biomarkers of drug-induced dysbiosis and potentially adapt live biotherapeutics to counteract it,” said Maria Júlia Segantini, MD, a coloproctologist at the University of São Paulo, Brazil.

 

Known Facts

Antibiotics, antivirals, antifungals, and anthelmintics eliminate pathogens but can also disrupt the microbiota across the gut, skin, mouth, lungs, and genitourinary tract.

“This ecosystem is part of the innate immune system and helps to balance inflammation and homeostasis. Loss of microbial diversity alters interspecies interactions and changes nutrient availability, which can undermine the ability to fend off pathogens,” said Segantini, noting the role of microbiota in vitamin K and B-complex production.

“The microbiome may lose its ability to prevent pathogens from taking hold. This is due to the loss of microbial diversity, changes in interactions between species, and the availability of nutrients,” she added.

Antibiotics, as is well known, eliminate bacterial species indiscriminately, reduce the presence of beneficial bacteria in the gut, and, therefore, favor the growth of opportunistic pathogenic microorganisms. However, in addition to their direct effects on microorganisms, different medications can alter the intestinal microbiota through various mechanisms linked to their specific actions. Here are some examples:

Proton pump inhibitors: These can facilitate the translocation of bacteria from the mouth to the intestine and affect the metabolic functions of the intestinal microbiota. “In users of these medications, there may be an enrichment of pathways related to carbohydrate metabolism, such as glycolysis and pyruvate metabolism, indicating possible changes in intestinal metabolism,” Segantini explained.

NSAIDs: NSAIDs can modify the function and composition of the intestinal microbiota, favor the growth of pathogenic species, and reduce the diversity of preexisting bacteria by reducing the presence of beneficial commensal bacteria, such as Lactobacillus and Bifidobacterium. “This is due to changes in the permeability of the intestinal wall, due to the inhibition of prostaglandins that help maintain the integrity of the intestinal barrier, enteropathy induced by NSAIDs, and drug interactions,” said Segantini.

Laxatives: Accelerated intestinal transit using laxatives impairs the quality of the microbiota and alters bile acid. Osmotic agents, such as lactulose and polyethylene glycol, may decrease resistance to infection.

“Studies in animal models indicate that polyethylene glycol can increase the proportion of Bacteroides and reduce the abundance of Bacteroidales bacteria, with lasting repercussions on the intestinal microbiota. Stimulant laxatives, in addition to causing an acceleration of the evacuation flow, can lead to a decrease in the production of short-chain fatty acids, which are important for intestinal health,” Segantini explained.

Chemotherapeutics: Chemotherapeutic agents can significantly influence the intestinal microbiota and affect its composition, diversity, and functionality, which in turn can affect the efficacy of treatment and the occurrence of adverse effects. “5-fluorouracil led to a decrease in the abundance of beneficial anaerobic genera, such as Blautia, and an increase in opportunistic pathogens, such as Staphylococcus and Escherichia coli, during chemotherapy. In addition, it can lead to an increase in the abundance of Bacteroidetes and Proteobacteria while reducing Firmicutes and Actinobacteria. These changes can affect the function of the intestinal barrier and the immune response. Other problems related to chemotherapy-induced dysbiosis are the adverse effects themselves, such as diarrhea and mucositis,” said Segantini.

Statins: Animal studies suggest that treatment with statins, including atorvastatin, may alter the composition of the gut microbiota. “These changes include the reduction of beneficial bacteria, such as Akkermansia muciniphila, and the increase in intestinal pathogens, resulting in intestinal dysbiosis. The use of statins can affect the diversity of the intestinal microbiota, although the results vary according to the type of statin and the clinical context.”

“Statins can activate intestinal nuclear receptors, such as pregnane X receptors, which modulate the expression of genes involved in bile metabolism and the inflammatory response. This activation can contribute to changes in the intestinal microbiota and associated metabolic processes. Although statins play a fundamental role in reducing cardiovascular risk, their interactions with the intestinal microbiota can influence the efficacy of treatment and the profile of adverse effects,” said Segantini.

Immunosuppressants: The use of immunosuppressants, such as corticosteroids, tacrolimus, and mycophenolate, has been associated with changes in the composition of the intestinal microbiota. “Immunosuppressant-induced dysbiosis can compromise the intestinal barrier, increase permeability, and facilitate bacterial translocation. This can result in opportunistic infections by pathogens and post-transplant complications, such as graft rejection and post-transplant diabetes,” Segantini stated.

“Alteration of the gut microbiota by immunosuppressants may influence the host’s immune response. For example, tacrolimus has been associated with an increase in the abundance of Allobaculum, Bacteroides, and Lactobacillus, in addition to elevated levels of regulatory T cells in the colonic mucosa and circulation, suggesting a role in modulating gut immunity,” she said.

Antipsychotics: Antipsychotics can affect gut microbiota in several ways, influencing bacterial composition and diversity, which may contribute to adverse metabolic and gastrointestinal effects.

“Olanzapine, for example, has been shown in rodent studies to increase the abundance of Firmicutes and reduce that of Bacteroidetes, resulting in a higher Firmicutes/Bacteroidetes ratio, which is associated with weight gain and dyslipidemia,” said Segantini.

She stated that risperidone increased the abundance of Firmicutes and decreased that of Bacteroidetes in animal models, correlating with weight gain and reduced basal metabolic rate. “Fecal transfer from risperidone-treated mice to naive mice resulted in decreased metabolic rate, suggesting that the gut microbiota would mediate these effects.”

Treatment with aripiprazole increased microbial diversity and the abundance of Clostridium, Peptoclostridium, Intestinibacter, and Christensenellaceae, in addition to promoting increased intestinal permeability in animal models.

“Therefore, the use of these medications can lead to metabolic changes, such as weight gain, hyperglycemia, dyslipidemia, and hypertension. This is due to a decrease in the production of short-chain fatty acids, which are important for maintaining the integrity of the intestinal barrier. Another change frequently observed in clinical practice is constipation induced by these medications. This functional change can also generate changes in the intestinal microbiota,” she said.

Oral antidiabetic agents: Oral antidiabetic agents influence the intestinal microbiota in different ways, depending on the therapeutic class. However, not all drug interactions in the microbiome are harmful. Liraglutide, a GLP-1 receptor agonist, promotes the growth of beneficial bacteria associated with metabolism.

“Exenatide, another GLP-1 agonist, has varied effects and can increase both beneficial and inflammatory bacteria,” explained Álvaro Delgado, MD, a gastroenterologist at Hospital Alemão Oswaldo Cruz in São Paulo, Brazil.

“In humans, an increase in bacteria such as Faecalibacterium prausnitzii has been observed, with positive effects. However, more studies are needed to evaluate the clinical impacts,” he said, and that, in animal models, these changes caused by GLP-1 agonists are linked to metabolic changes, such as greater glucose tolerance.

Metformin has been linked to increased abundance of A muciniphila, a beneficial bacterium that degrades mucin and produces short-chain fatty acids. “These bacteria are associated with improved insulin sensitivity and reduced inflammation,” he said.

Segantini stated that studies in mice have shown that vildagliptin also plays a positive role in altering the composition of the intestinal microbiota, increasing the abundance of Lactobacillus and Roseburia, and reducing Oscillibacter. “This same beneficial effect is seen with the use of sitagliptin,” she said.

Studies in animal models have also indicated that empagliflozin and dapagliflozin increase the populations of short-chain fatty acid-producing bacteria, such as Bacteroides and Odoribacter, and reduce the populations of lipopolysaccharide-producing bacteria, such as Oscillibacter.

“There are still not many studies regarding the use of sulfonylureas on the intestinal microbiota, so their action on the microbiota is still controversial,” said Segantini.

Antivirals: Antiviral treatment can influence gut microbiota in complex ways, depending on the type of infection and medication used.

“Although many studies focus on the effects of viral infection on the microbiota, there is evidence that antiviral treatment can also restore the healthy composition of the microbiota, promoting additional benefits to gut and immune health,” said Segantini.

In mice with chronic hepatitis B, entecavir restored the alpha diversity of the gut microbiota, which was reduced due to infection. In addition, the recovery of beneficial bacteria, such as Akkermansia and Blautia, was observed, which was associated with the protection of the intestinal barrier and reduction of hepatic inflammation.

Studies have indicated that tenofovir may aid in the recovery of intestinal dysbiosis induced by chronic hepatitis B virus infection and promote the restoration of a healthy microbial composition.

“Specifically, an increase in Collinsella and Bifidobacterium, bacteria associated with the production of short-chain fatty acids and modulation of the immune response, was observed,” said Segantini.

The use of antiretrovirals, such as lopinavir and ritonavir, has been associated with changes in the composition of the intestinal microbiota in patients living with HIV.

“A decrease in Lachnospira, Butyricicoccus, Oscillospira, and Prevotella, bacteria that produce short-chain fatty acids that are important in intestinal health and in modulating the immune response, was observed.”

Antifungals: As a side effect, antifungals also eliminate commensal fungi, which “share intestinal niches with microbiota bacteria, balancing their immunological functions. When modified, they culminate in dysbiosis, worsening of inflammatory pathologies — such as colitis and allergic diseases — and can increase bacterial translocation,” said Segantini. 

For example, fluconazole reduces the abundance of Candida spp. while promoting the growth of fungi such as Aspergillus, Wallemia, and Epicoccum.

“A relative increase in Firmicutes and Proteobacteria and a decrease in Bacteroidetes, Deferribacteres, Patescibacteria, and Tenericutes were also observed,” she explained.

Anthelmintics: These also affect the intestinal bacterial and fungal microbiota and alter the modulation of the immune response, in addition to having specific effects depending on the type of drug used.

 

Clinical Advice

Symptoms of dysbiosis include abdominal distension, flatulence, constipation or diarrhea, pain, fatigue, and mood swings. “The diagnosis is made based on the clinical picture, since tests such as small intestinal bacterial overgrowth, which indicate metabolites of bacteria associated with dysbiosis, specific stool tests, and microbiota mapping with GI-MAP [Gastrointestinal Microbial Assay Plus], for example, are expensive, difficult to access, and often inconclusive for diagnosis and for assessing the cause of the microbiota alteration,” explained Fernando Seefelder Flaquer, MD, a gastroenterologist at Albert Einstein Israelite Hospital in São Paulo.

When caused by medication, dysbiosis tends to be reversed naturally after discontinuation of the drug. “However, in medications with a high chance of altering the microbiota, probiotics can be used as prevention,” said Flaquer.

“To avoid problems, it is important to use antibiotics with caution and prefer, when possible, those with a reduced spectrum,” advised Delgado.

“Supplementation with probiotics and prebiotics can help maintain the balance of the microbiota, but it should be evaluated on a case-by-case basis, as its indications are still restricted at present.”

Currently, dysbiosis management relies on nutritional support and lifestyle modifications. “Physical exercise, management of psychological changes, and use of probiotics and prebiotics. In specific cases, individualized treatment may even require the administration of some types of antibiotics,” explained Segantini.

Although fecal microbiota transplantation (FMT) has been widely discussed and increasingly studied, it should still be approached with caution. While promising, FMT remains experimental for most conditions, and its use outside research settings should be carefully considered, particularly in patients who are immunocompromised or have compromised intestinal barriers.

“Currently, the treatment has stood out as promising for cases of recurrent Clostridioides difficile infection, being the only consolidated clinical indication,” said Segantini.

 

Science Hype

The interest in gut microbiome research has undoubtedly driven important scientific advances, but it also risks exaggeration. While the field holds enormous promise, much of the research remains in its early stages.

“The indiscriminate use of probiotics and reliance on microbiota analysis tests for personalized probiotic prescriptions are growing concerns,” Delgado warned. “We need to bridge the gap between basic science and clinical application. When that translation happens, it could revolutionize care for many diseases.”

Flaquer emphasized a broader issue: “There has been an overvaluation of dysbiosis and microbiota-focused treatments as cure-alls for a wide range of conditions — often subjective or lacking solid scientific correlation — such as depression, anxiety, fatigue, cancer, and even autism.”

With ongoing advances in microbiome research, understanding the impact of this complex ecosystem on human health has become essential across all medical specialties. In pediatrics, for instance, microbiota plays a critical role in immune and metabolic development, particularly in preventing conditions such as allergies and obesity.

In digestive surgery, preoperative use of probiotics has been shown to reduce complications and enhance postoperative recovery. Neurological research has highlighted the gut-brain axis as a potential factor in the development of neurodegenerative diseases. In gynecology, regulating the vaginal microbiota is key to preventing infections and complications during pregnancy.

“Given the connections between the microbiota and both intestinal and systemic diseases, every medical specialist should understand how it relates to the conditions they treat daily,” concluded Flaquer.

This story was translated from Medscape’s Portuguese edition.

Effective ways to combat harmful viruses, bacteria, fungi, and parasitic worms have driven major advances in medicine and contributed to a significant increase in human life expectancy over the past century. However, as knowledge about the role of these microorganisms in promoting and maintaining health deepens, there is a need for a new look at the impact of these treatments.

The list of drugs that can directly alter the gut microbiota is long. In addition to antibiotics, antivirals, antifungals, anthelmintics, proton pump inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), laxatives, oral antidiabetics, antidepressants, antipsychotics, statins, chemotherapeutics, and immunosuppressants can trigger dysbiosis.

A 2020 study published in Nature Communications, which analyzed the impact of common medications on the composition and metabolic function of the gut bacteria, showed that of the 41 classes of medications, researchers found that 19 were associated with changes in the microbiome, most notably antibiotics, proton pump inhibitors, laxatives, and metformin.

“There are still no protocols aimed at preserving the microbiota during pharmacological treatment. Future research should identify biomarkers of drug-induced dysbiosis and potentially adapt live biotherapeutics to counteract it,” said Maria Júlia Segantini, MD, a coloproctologist at the University of São Paulo, Brazil.

 

Known Facts

Antibiotics, antivirals, antifungals, and anthelmintics eliminate pathogens but can also disrupt the microbiota across the gut, skin, mouth, lungs, and genitourinary tract.

“This ecosystem is part of the innate immune system and helps to balance inflammation and homeostasis. Loss of microbial diversity alters interspecies interactions and changes nutrient availability, which can undermine the ability to fend off pathogens,” said Segantini, noting the role of microbiota in vitamin K and B-complex production.

“The microbiome may lose its ability to prevent pathogens from taking hold. This is due to the loss of microbial diversity, changes in interactions between species, and the availability of nutrients,” she added.

Antibiotics, as is well known, eliminate bacterial species indiscriminately, reduce the presence of beneficial bacteria in the gut, and, therefore, favor the growth of opportunistic pathogenic microorganisms. However, in addition to their direct effects on microorganisms, different medications can alter the intestinal microbiota through various mechanisms linked to their specific actions. Here are some examples:

Proton pump inhibitors: These can facilitate the translocation of bacteria from the mouth to the intestine and affect the metabolic functions of the intestinal microbiota. “In users of these medications, there may be an enrichment of pathways related to carbohydrate metabolism, such as glycolysis and pyruvate metabolism, indicating possible changes in intestinal metabolism,” Segantini explained.

NSAIDs: NSAIDs can modify the function and composition of the intestinal microbiota, favor the growth of pathogenic species, and reduce the diversity of preexisting bacteria by reducing the presence of beneficial commensal bacteria, such as Lactobacillus and Bifidobacterium. “This is due to changes in the permeability of the intestinal wall, due to the inhibition of prostaglandins that help maintain the integrity of the intestinal barrier, enteropathy induced by NSAIDs, and drug interactions,” said Segantini.

Laxatives: Accelerated intestinal transit using laxatives impairs the quality of the microbiota and alters bile acid. Osmotic agents, such as lactulose and polyethylene glycol, may decrease resistance to infection.

“Studies in animal models indicate that polyethylene glycol can increase the proportion of Bacteroides and reduce the abundance of Bacteroidales bacteria, with lasting repercussions on the intestinal microbiota. Stimulant laxatives, in addition to causing an acceleration of the evacuation flow, can lead to a decrease in the production of short-chain fatty acids, which are important for intestinal health,” Segantini explained.

Chemotherapeutics: Chemotherapeutic agents can significantly influence the intestinal microbiota and affect its composition, diversity, and functionality, which in turn can affect the efficacy of treatment and the occurrence of adverse effects. “5-fluorouracil led to a decrease in the abundance of beneficial anaerobic genera, such as Blautia, and an increase in opportunistic pathogens, such as Staphylococcus and Escherichia coli, during chemotherapy. In addition, it can lead to an increase in the abundance of Bacteroidetes and Proteobacteria while reducing Firmicutes and Actinobacteria. These changes can affect the function of the intestinal barrier and the immune response. Other problems related to chemotherapy-induced dysbiosis are the adverse effects themselves, such as diarrhea and mucositis,” said Segantini.

Statins: Animal studies suggest that treatment with statins, including atorvastatin, may alter the composition of the gut microbiota. “These changes include the reduction of beneficial bacteria, such as Akkermansia muciniphila, and the increase in intestinal pathogens, resulting in intestinal dysbiosis. The use of statins can affect the diversity of the intestinal microbiota, although the results vary according to the type of statin and the clinical context.”

“Statins can activate intestinal nuclear receptors, such as pregnane X receptors, which modulate the expression of genes involved in bile metabolism and the inflammatory response. This activation can contribute to changes in the intestinal microbiota and associated metabolic processes. Although statins play a fundamental role in reducing cardiovascular risk, their interactions with the intestinal microbiota can influence the efficacy of treatment and the profile of adverse effects,” said Segantini.

Immunosuppressants: The use of immunosuppressants, such as corticosteroids, tacrolimus, and mycophenolate, has been associated with changes in the composition of the intestinal microbiota. “Immunosuppressant-induced dysbiosis can compromise the intestinal barrier, increase permeability, and facilitate bacterial translocation. This can result in opportunistic infections by pathogens and post-transplant complications, such as graft rejection and post-transplant diabetes,” Segantini stated.

“Alteration of the gut microbiota by immunosuppressants may influence the host’s immune response. For example, tacrolimus has been associated with an increase in the abundance of Allobaculum, Bacteroides, and Lactobacillus, in addition to elevated levels of regulatory T cells in the colonic mucosa and circulation, suggesting a role in modulating gut immunity,” she said.

Antipsychotics: Antipsychotics can affect gut microbiota in several ways, influencing bacterial composition and diversity, which may contribute to adverse metabolic and gastrointestinal effects.

“Olanzapine, for example, has been shown in rodent studies to increase the abundance of Firmicutes and reduce that of Bacteroidetes, resulting in a higher Firmicutes/Bacteroidetes ratio, which is associated with weight gain and dyslipidemia,” said Segantini.

She stated that risperidone increased the abundance of Firmicutes and decreased that of Bacteroidetes in animal models, correlating with weight gain and reduced basal metabolic rate. “Fecal transfer from risperidone-treated mice to naive mice resulted in decreased metabolic rate, suggesting that the gut microbiota would mediate these effects.”

Treatment with aripiprazole increased microbial diversity and the abundance of Clostridium, Peptoclostridium, Intestinibacter, and Christensenellaceae, in addition to promoting increased intestinal permeability in animal models.

“Therefore, the use of these medications can lead to metabolic changes, such as weight gain, hyperglycemia, dyslipidemia, and hypertension. This is due to a decrease in the production of short-chain fatty acids, which are important for maintaining the integrity of the intestinal barrier. Another change frequently observed in clinical practice is constipation induced by these medications. This functional change can also generate changes in the intestinal microbiota,” she said.

Oral antidiabetic agents: Oral antidiabetic agents influence the intestinal microbiota in different ways, depending on the therapeutic class. However, not all drug interactions in the microbiome are harmful. Liraglutide, a GLP-1 receptor agonist, promotes the growth of beneficial bacteria associated with metabolism.

“Exenatide, another GLP-1 agonist, has varied effects and can increase both beneficial and inflammatory bacteria,” explained Álvaro Delgado, MD, a gastroenterologist at Hospital Alemão Oswaldo Cruz in São Paulo, Brazil.

“In humans, an increase in bacteria such as Faecalibacterium prausnitzii has been observed, with positive effects. However, more studies are needed to evaluate the clinical impacts,” he said, and that, in animal models, these changes caused by GLP-1 agonists are linked to metabolic changes, such as greater glucose tolerance.

Metformin has been linked to increased abundance of A muciniphila, a beneficial bacterium that degrades mucin and produces short-chain fatty acids. “These bacteria are associated with improved insulin sensitivity and reduced inflammation,” he said.

Segantini stated that studies in mice have shown that vildagliptin also plays a positive role in altering the composition of the intestinal microbiota, increasing the abundance of Lactobacillus and Roseburia, and reducing Oscillibacter. “This same beneficial effect is seen with the use of sitagliptin,” she said.

Studies in animal models have also indicated that empagliflozin and dapagliflozin increase the populations of short-chain fatty acid-producing bacteria, such as Bacteroides and Odoribacter, and reduce the populations of lipopolysaccharide-producing bacteria, such as Oscillibacter.

“There are still not many studies regarding the use of sulfonylureas on the intestinal microbiota, so their action on the microbiota is still controversial,” said Segantini.

Antivirals: Antiviral treatment can influence gut microbiota in complex ways, depending on the type of infection and medication used.

“Although many studies focus on the effects of viral infection on the microbiota, there is evidence that antiviral treatment can also restore the healthy composition of the microbiota, promoting additional benefits to gut and immune health,” said Segantini.

In mice with chronic hepatitis B, entecavir restored the alpha diversity of the gut microbiota, which was reduced due to infection. In addition, the recovery of beneficial bacteria, such as Akkermansia and Blautia, was observed, which was associated with the protection of the intestinal barrier and reduction of hepatic inflammation.

Studies have indicated that tenofovir may aid in the recovery of intestinal dysbiosis induced by chronic hepatitis B virus infection and promote the restoration of a healthy microbial composition.

“Specifically, an increase in Collinsella and Bifidobacterium, bacteria associated with the production of short-chain fatty acids and modulation of the immune response, was observed,” said Segantini.

The use of antiretrovirals, such as lopinavir and ritonavir, has been associated with changes in the composition of the intestinal microbiota in patients living with HIV.

“A decrease in Lachnospira, Butyricicoccus, Oscillospira, and Prevotella, bacteria that produce short-chain fatty acids that are important in intestinal health and in modulating the immune response, was observed.”

Antifungals: As a side effect, antifungals also eliminate commensal fungi, which “share intestinal niches with microbiota bacteria, balancing their immunological functions. When modified, they culminate in dysbiosis, worsening of inflammatory pathologies — such as colitis and allergic diseases — and can increase bacterial translocation,” said Segantini. 

For example, fluconazole reduces the abundance of Candida spp. while promoting the growth of fungi such as Aspergillus, Wallemia, and Epicoccum.

“A relative increase in Firmicutes and Proteobacteria and a decrease in Bacteroidetes, Deferribacteres, Patescibacteria, and Tenericutes were also observed,” she explained.

Anthelmintics: These also affect the intestinal bacterial and fungal microbiota and alter the modulation of the immune response, in addition to having specific effects depending on the type of drug used.

 

Clinical Advice

Symptoms of dysbiosis include abdominal distension, flatulence, constipation or diarrhea, pain, fatigue, and mood swings. “The diagnosis is made based on the clinical picture, since tests such as small intestinal bacterial overgrowth, which indicate metabolites of bacteria associated with dysbiosis, specific stool tests, and microbiota mapping with GI-MAP [Gastrointestinal Microbial Assay Plus], for example, are expensive, difficult to access, and often inconclusive for diagnosis and for assessing the cause of the microbiota alteration,” explained Fernando Seefelder Flaquer, MD, a gastroenterologist at Albert Einstein Israelite Hospital in São Paulo.

When caused by medication, dysbiosis tends to be reversed naturally after discontinuation of the drug. “However, in medications with a high chance of altering the microbiota, probiotics can be used as prevention,” said Flaquer.

“To avoid problems, it is important to use antibiotics with caution and prefer, when possible, those with a reduced spectrum,” advised Delgado.

“Supplementation with probiotics and prebiotics can help maintain the balance of the microbiota, but it should be evaluated on a case-by-case basis, as its indications are still restricted at present.”

Currently, dysbiosis management relies on nutritional support and lifestyle modifications. “Physical exercise, management of psychological changes, and use of probiotics and prebiotics. In specific cases, individualized treatment may even require the administration of some types of antibiotics,” explained Segantini.

Although fecal microbiota transplantation (FMT) has been widely discussed and increasingly studied, it should still be approached with caution. While promising, FMT remains experimental for most conditions, and its use outside research settings should be carefully considered, particularly in patients who are immunocompromised or have compromised intestinal barriers.

“Currently, the treatment has stood out as promising for cases of recurrent Clostridioides difficile infection, being the only consolidated clinical indication,” said Segantini.

 

Science Hype

The interest in gut microbiome research has undoubtedly driven important scientific advances, but it also risks exaggeration. While the field holds enormous promise, much of the research remains in its early stages.

“The indiscriminate use of probiotics and reliance on microbiota analysis tests for personalized probiotic prescriptions are growing concerns,” Delgado warned. “We need to bridge the gap between basic science and clinical application. When that translation happens, it could revolutionize care for many diseases.”

Flaquer emphasized a broader issue: “There has been an overvaluation of dysbiosis and microbiota-focused treatments as cure-alls for a wide range of conditions — often subjective or lacking solid scientific correlation — such as depression, anxiety, fatigue, cancer, and even autism.”

With ongoing advances in microbiome research, understanding the impact of this complex ecosystem on human health has become essential across all medical specialties. In pediatrics, for instance, microbiota plays a critical role in immune and metabolic development, particularly in preventing conditions such as allergies and obesity.

In digestive surgery, preoperative use of probiotics has been shown to reduce complications and enhance postoperative recovery. Neurological research has highlighted the gut-brain axis as a potential factor in the development of neurodegenerative diseases. In gynecology, regulating the vaginal microbiota is key to preventing infections and complications during pregnancy.

“Given the connections between the microbiota and both intestinal and systemic diseases, every medical specialist should understand how it relates to the conditions they treat daily,” concluded Flaquer.

This story was translated from Medscape’s Portuguese edition.

Effective ways to combat harmful viruses, bacteria, fungi, and parasitic worms have driven major advances in medicine and contributed to a significant increase in human life expectancy over the past century. However, as knowledge about the role of these microorganisms in promoting and maintaining health deepens, there is a need for a new look at the impact of these treatments.

The list of drugs that can directly alter the gut microbiota is long. In addition to antibiotics, antivirals, antifungals, anthelmintics, proton pump inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), laxatives, oral antidiabetics, antidepressants, antipsychotics, statins, chemotherapeutics, and immunosuppressants can trigger dysbiosis.

A 2020 study published in Nature Communications, which analyzed the impact of common medications on the composition and metabolic function of the gut bacteria, showed that of the 41 classes of medications, researchers found that 19 were associated with changes in the microbiome, most notably antibiotics, proton pump inhibitors, laxatives, and metformin.

“There are still no protocols aimed at preserving the microbiota during pharmacological treatment. Future research should identify biomarkers of drug-induced dysbiosis and potentially adapt live biotherapeutics to counteract it,” said Maria Júlia Segantini, MD, a coloproctologist at the University of São Paulo, Brazil.

 

Known Facts

Antibiotics, antivirals, antifungals, and anthelmintics eliminate pathogens but can also disrupt the microbiota across the gut, skin, mouth, lungs, and genitourinary tract.

“This ecosystem is part of the innate immune system and helps to balance inflammation and homeostasis. Loss of microbial diversity alters interspecies interactions and changes nutrient availability, which can undermine the ability to fend off pathogens,” said Segantini, noting the role of microbiota in vitamin K and B-complex production.

“The microbiome may lose its ability to prevent pathogens from taking hold. This is due to the loss of microbial diversity, changes in interactions between species, and the availability of nutrients,” she added.

Antibiotics, as is well known, eliminate bacterial species indiscriminately, reduce the presence of beneficial bacteria in the gut, and, therefore, favor the growth of opportunistic pathogenic microorganisms. However, in addition to their direct effects on microorganisms, different medications can alter the intestinal microbiota through various mechanisms linked to their specific actions. Here are some examples:

Proton pump inhibitors: These can facilitate the translocation of bacteria from the mouth to the intestine and affect the metabolic functions of the intestinal microbiota. “In users of these medications, there may be an enrichment of pathways related to carbohydrate metabolism, such as glycolysis and pyruvate metabolism, indicating possible changes in intestinal metabolism,” Segantini explained.

NSAIDs: NSAIDs can modify the function and composition of the intestinal microbiota, favor the growth of pathogenic species, and reduce the diversity of preexisting bacteria by reducing the presence of beneficial commensal bacteria, such as Lactobacillus and Bifidobacterium. “This is due to changes in the permeability of the intestinal wall, due to the inhibition of prostaglandins that help maintain the integrity of the intestinal barrier, enteropathy induced by NSAIDs, and drug interactions,” said Segantini.

Laxatives: Accelerated intestinal transit using laxatives impairs the quality of the microbiota and alters bile acid. Osmotic agents, such as lactulose and polyethylene glycol, may decrease resistance to infection.

“Studies in animal models indicate that polyethylene glycol can increase the proportion of Bacteroides and reduce the abundance of Bacteroidales bacteria, with lasting repercussions on the intestinal microbiota. Stimulant laxatives, in addition to causing an acceleration of the evacuation flow, can lead to a decrease in the production of short-chain fatty acids, which are important for intestinal health,” Segantini explained.

Chemotherapeutics: Chemotherapeutic agents can significantly influence the intestinal microbiota and affect its composition, diversity, and functionality, which in turn can affect the efficacy of treatment and the occurrence of adverse effects. “5-fluorouracil led to a decrease in the abundance of beneficial anaerobic genera, such as Blautia, and an increase in opportunistic pathogens, such as Staphylococcus and Escherichia coli, during chemotherapy. In addition, it can lead to an increase in the abundance of Bacteroidetes and Proteobacteria while reducing Firmicutes and Actinobacteria. These changes can affect the function of the intestinal barrier and the immune response. Other problems related to chemotherapy-induced dysbiosis are the adverse effects themselves, such as diarrhea and mucositis,” said Segantini.

Statins: Animal studies suggest that treatment with statins, including atorvastatin, may alter the composition of the gut microbiota. “These changes include the reduction of beneficial bacteria, such as Akkermansia muciniphila, and the increase in intestinal pathogens, resulting in intestinal dysbiosis. The use of statins can affect the diversity of the intestinal microbiota, although the results vary according to the type of statin and the clinical context.”

“Statins can activate intestinal nuclear receptors, such as pregnane X receptors, which modulate the expression of genes involved in bile metabolism and the inflammatory response. This activation can contribute to changes in the intestinal microbiota and associated metabolic processes. Although statins play a fundamental role in reducing cardiovascular risk, their interactions with the intestinal microbiota can influence the efficacy of treatment and the profile of adverse effects,” said Segantini.

Immunosuppressants: The use of immunosuppressants, such as corticosteroids, tacrolimus, and mycophenolate, has been associated with changes in the composition of the intestinal microbiota. “Immunosuppressant-induced dysbiosis can compromise the intestinal barrier, increase permeability, and facilitate bacterial translocation. This can result in opportunistic infections by pathogens and post-transplant complications, such as graft rejection and post-transplant diabetes,” Segantini stated.

“Alteration of the gut microbiota by immunosuppressants may influence the host’s immune response. For example, tacrolimus has been associated with an increase in the abundance of Allobaculum, Bacteroides, and Lactobacillus, in addition to elevated levels of regulatory T cells in the colonic mucosa and circulation, suggesting a role in modulating gut immunity,” she said.

Antipsychotics: Antipsychotics can affect gut microbiota in several ways, influencing bacterial composition and diversity, which may contribute to adverse metabolic and gastrointestinal effects.

“Olanzapine, for example, has been shown in rodent studies to increase the abundance of Firmicutes and reduce that of Bacteroidetes, resulting in a higher Firmicutes/Bacteroidetes ratio, which is associated with weight gain and dyslipidemia,” said Segantini.

She stated that risperidone increased the abundance of Firmicutes and decreased that of Bacteroidetes in animal models, correlating with weight gain and reduced basal metabolic rate. “Fecal transfer from risperidone-treated mice to naive mice resulted in decreased metabolic rate, suggesting that the gut microbiota would mediate these effects.”

Treatment with aripiprazole increased microbial diversity and the abundance of Clostridium, Peptoclostridium, Intestinibacter, and Christensenellaceae, in addition to promoting increased intestinal permeability in animal models.

“Therefore, the use of these medications can lead to metabolic changes, such as weight gain, hyperglycemia, dyslipidemia, and hypertension. This is due to a decrease in the production of short-chain fatty acids, which are important for maintaining the integrity of the intestinal barrier. Another change frequently observed in clinical practice is constipation induced by these medications. This functional change can also generate changes in the intestinal microbiota,” she said.

Oral antidiabetic agents: Oral antidiabetic agents influence the intestinal microbiota in different ways, depending on the therapeutic class. However, not all drug interactions in the microbiome are harmful. Liraglutide, a GLP-1 receptor agonist, promotes the growth of beneficial bacteria associated with metabolism.

“Exenatide, another GLP-1 agonist, has varied effects and can increase both beneficial and inflammatory bacteria,” explained Álvaro Delgado, MD, a gastroenterologist at Hospital Alemão Oswaldo Cruz in São Paulo, Brazil.

“In humans, an increase in bacteria such as Faecalibacterium prausnitzii has been observed, with positive effects. However, more studies are needed to evaluate the clinical impacts,” he said, and that, in animal models, these changes caused by GLP-1 agonists are linked to metabolic changes, such as greater glucose tolerance.

Metformin has been linked to increased abundance of A muciniphila, a beneficial bacterium that degrades mucin and produces short-chain fatty acids. “These bacteria are associated with improved insulin sensitivity and reduced inflammation,” he said.

Segantini stated that studies in mice have shown that vildagliptin also plays a positive role in altering the composition of the intestinal microbiota, increasing the abundance of Lactobacillus and Roseburia, and reducing Oscillibacter. “This same beneficial effect is seen with the use of sitagliptin,” she said.

Studies in animal models have also indicated that empagliflozin and dapagliflozin increase the populations of short-chain fatty acid-producing bacteria, such as Bacteroides and Odoribacter, and reduce the populations of lipopolysaccharide-producing bacteria, such as Oscillibacter.

“There are still not many studies regarding the use of sulfonylureas on the intestinal microbiota, so their action on the microbiota is still controversial,” said Segantini.

Antivirals: Antiviral treatment can influence gut microbiota in complex ways, depending on the type of infection and medication used.

“Although many studies focus on the effects of viral infection on the microbiota, there is evidence that antiviral treatment can also restore the healthy composition of the microbiota, promoting additional benefits to gut and immune health,” said Segantini.

In mice with chronic hepatitis B, entecavir restored the alpha diversity of the gut microbiota, which was reduced due to infection. In addition, the recovery of beneficial bacteria, such as Akkermansia and Blautia, was observed, which was associated with the protection of the intestinal barrier and reduction of hepatic inflammation.

Studies have indicated that tenofovir may aid in the recovery of intestinal dysbiosis induced by chronic hepatitis B virus infection and promote the restoration of a healthy microbial composition.

“Specifically, an increase in Collinsella and Bifidobacterium, bacteria associated with the production of short-chain fatty acids and modulation of the immune response, was observed,” said Segantini.

The use of antiretrovirals, such as lopinavir and ritonavir, has been associated with changes in the composition of the intestinal microbiota in patients living with HIV.

“A decrease in Lachnospira, Butyricicoccus, Oscillospira, and Prevotella, bacteria that produce short-chain fatty acids that are important in intestinal health and in modulating the immune response, was observed.”

Antifungals: As a side effect, antifungals also eliminate commensal fungi, which “share intestinal niches with microbiota bacteria, balancing their immunological functions. When modified, they culminate in dysbiosis, worsening of inflammatory pathologies — such as colitis and allergic diseases — and can increase bacterial translocation,” said Segantini. 

For example, fluconazole reduces the abundance of Candida spp. while promoting the growth of fungi such as Aspergillus, Wallemia, and Epicoccum.

“A relative increase in Firmicutes and Proteobacteria and a decrease in Bacteroidetes, Deferribacteres, Patescibacteria, and Tenericutes were also observed,” she explained.

Anthelmintics: These also affect the intestinal bacterial and fungal microbiota and alter the modulation of the immune response, in addition to having specific effects depending on the type of drug used.

 

Clinical Advice

Symptoms of dysbiosis include abdominal distension, flatulence, constipation or diarrhea, pain, fatigue, and mood swings. “The diagnosis is made based on the clinical picture, since tests such as small intestinal bacterial overgrowth, which indicate metabolites of bacteria associated with dysbiosis, specific stool tests, and microbiota mapping with GI-MAP [Gastrointestinal Microbial Assay Plus], for example, are expensive, difficult to access, and often inconclusive for diagnosis and for assessing the cause of the microbiota alteration,” explained Fernando Seefelder Flaquer, MD, a gastroenterologist at Albert Einstein Israelite Hospital in São Paulo.

When caused by medication, dysbiosis tends to be reversed naturally after discontinuation of the drug. “However, in medications with a high chance of altering the microbiota, probiotics can be used as prevention,” said Flaquer.

“To avoid problems, it is important to use antibiotics with caution and prefer, when possible, those with a reduced spectrum,” advised Delgado.

“Supplementation with probiotics and prebiotics can help maintain the balance of the microbiota, but it should be evaluated on a case-by-case basis, as its indications are still restricted at present.”

Currently, dysbiosis management relies on nutritional support and lifestyle modifications. “Physical exercise, management of psychological changes, and use of probiotics and prebiotics. In specific cases, individualized treatment may even require the administration of some types of antibiotics,” explained Segantini.

Although fecal microbiota transplantation (FMT) has been widely discussed and increasingly studied, it should still be approached with caution. While promising, FMT remains experimental for most conditions, and its use outside research settings should be carefully considered, particularly in patients who are immunocompromised or have compromised intestinal barriers.

“Currently, the treatment has stood out as promising for cases of recurrent Clostridioides difficile infection, being the only consolidated clinical indication,” said Segantini.

 

Science Hype

The interest in gut microbiome research has undoubtedly driven important scientific advances, but it also risks exaggeration. While the field holds enormous promise, much of the research remains in its early stages.

“The indiscriminate use of probiotics and reliance on microbiota analysis tests for personalized probiotic prescriptions are growing concerns,” Delgado warned. “We need to bridge the gap between basic science and clinical application. When that translation happens, it could revolutionize care for many diseases.”

Flaquer emphasized a broader issue: “There has been an overvaluation of dysbiosis and microbiota-focused treatments as cure-alls for a wide range of conditions — often subjective or lacking solid scientific correlation — such as depression, anxiety, fatigue, cancer, and even autism.”

With ongoing advances in microbiome research, understanding the impact of this complex ecosystem on human health has become essential across all medical specialties. In pediatrics, for instance, microbiota plays a critical role in immune and metabolic development, particularly in preventing conditions such as allergies and obesity.

In digestive surgery, preoperative use of probiotics has been shown to reduce complications and enhance postoperative recovery. Neurological research has highlighted the gut-brain axis as a potential factor in the development of neurodegenerative diseases. In gynecology, regulating the vaginal microbiota is key to preventing infections and complications during pregnancy.

“Given the connections between the microbiota and both intestinal and systemic diseases, every medical specialist should understand how it relates to the conditions they treat daily,” concluded Flaquer.

This story was translated from Medscape’s Portuguese edition.