Prebiotic Type Spotlight: Lactulose

Last Updated December 2023

Each edition of GPA’s Prebiotic Spotlight focuses on a specific prebiotic type to raise awareness around the prebiotic itself, its sources, any notable and/or recent research, and how it is used in the marketplace. In this issue, lactulose is highlighted. 


Lactulose is a synthetic, non-digestible, disaccharide that is derived from the chemical or enzymatic isomerization of lactose using β-galactosidase or epimerase (Sitanggang et al., 2016; Karakan et al., 2021; Chu et al., 2022). Lactulose is comprised of two sugar molecules, fructose and galactose, bonded together with a β-1-4-glycosidic bond, making it indigestible in the mammalian gastrointestinal tract (Panesar & Kumari, 2011). Lactulose provides several prebiotic functions such as improving gut health, increasing the production of beneficial metabolites, and increasing mineral absorption. Once lactulose reaches the colon intact, it is metabolized, stimulating the growth of healthy bacteria, and inhibiting the growth of pathogens (Panesar & Kumari, 2011). Lactulose is commonly used in many food and pharmaceutical applications. The technical properties of lactulose make it a useful ingredient for food purposes such as a sweetening agent, fermentable carbohydrate, or thickening agent, and it has also been reported to improve the survival of probiotic strains in yogurt (Panesar & Kumari, 2011). The health benefits of lactulose have been extensively demonstrated through various clinical trials and pharmaceutical applications. Lactulose is regulated as a prescription drug in many countries, including the United States (US). 

Benefit Areas

Lactulose was first synthesized in 1929 by Montgomery and Hudson, and its clinical use began in 1957 after Petuely and Mayerhofer discovered it exhibited bifidogenic and laxative properties (Karakan et al., 2021). Lactulose has been utilized and studied for managing various conditions over the past 60 years, including:

  • Treating constipation by reducing intestinal transit time (Panesar & Kumari, 2011; EFSA, 2010)
  • Reducing the degree of hepatic encephalopathy (HE) by decreasing ammonia production (Panesar & Kumari, 2011; Balzano, 2023; Bloom & Tapper, 2023)
  • Inhibiting pathogenic bacteria, such as Salmonella and Shigella, by lowering the pH of the colon environment (Panesar & Kumari, 2011; Karakan et al., 2021)
  • Reducing the prevalence of urinary and respiratory tract infections, enhancing immune health, and decreasing the risk of colon cancer through the production of healthy gut microbiota and inhibiting harmful pathogen growth (Panesar & Kumari, 2011; Karakan et al., 2021)
  • Managing inflammatory bowel disease by eliminating and preventing endotoxemia (Panesar & Kumari, 2011)
  • Lowering blood glucose levels and reducing pancreatic insulin production through its anti-endotoxin effects (Panesar & Kumari, 2011; Chu et al., 2022)
  • Improving mineral absorption through the increased production of short-chain fatty acids (SCFAs) such as acetate (Karakan et al., 2021)


Commercially, lactulose is produced through the chemical isomerization of lactose via the Lobry de Bruyn-Alberda van Ekenstein transformation, a process involving the alkaline isomerization of glucose into fructose (Panesar & Kumari, 2011; Parekh et al., 2016; Sitanggang et al., 2016). Lactulose can also be formed in mammalian milk during ultra-high temperature heat processing treatments (Parekh et al., 2016). An alternative method for industrial lactulose production is enzymatic synthesis via transgalactosylation from lactose to fructose (Sitanggang et al., 2016). Both methods of production require an extraction and purification step to remove any unwanted substances such as lactose, glucose, and galactose, and this is achieved by lowering the pH and temperature of the lactulose solution and applying centrifugation to obtain pure lactulose (Panesar & Kumari, 2011; Parekh et al., 2016). 

Dose Range

In 2010, the European Food Safety Authority (EFSA) panel provided a scientific opinion on the substantiation of health claims pursuant to lactulose. The EFSA panel concluded that lactulose is a well-characterized food constituent and contributes to a reduction in intestinal transit time at least 10 g of lactulose per day should be consumed in a single serving. The target population is the general a dose  of 10 g per day. Lactulose is also included on the European Union’s novel food catalogue as “not novel in foods”, meaning it is an ingredient with acknowledged food use and is therefore not prohibited from use in food or food supplements (Sadler, 2018).

In Canada, lactulose is permitted in natural health products only as a non-medicinal ingredient with a daily dose of 500 mg. Lactulose is regulated in Canada as a non-prescription drug for the treatment of constipation and portal-systemic encephalopathy as an oral or gastric tube solution. Dosages are recommended at 10 to 20 g per day (increasing to 40 g if necessary) to treat constipation, and 60 to 100 g per day (or higher if necessary) to manage portal-systemic encephalopathy.

In the US, lactulose is available by prescription from a doctor or pharmacist for the treatment of constipation and HE. Lactulose solution can be administered orally at a dose of 15 to 45 mL, 2 to 4 times daily, for the treatment of constipation. It can also be administered orally at a dose of 15 to 30 mL, 2 to 4 times daily, for the management of HE. Rectal administration of lactulose is prescribed at 300 mL in 700 mL of water with retention in the colon for 1 hour and repeated every 2 hours until the episode is resolved (Mukherjee & John, 2022).  

Recent Research

There are 14 studies actively recruiting on proposing the use of lactulose for a variety of therapies including bowel preparation before a colonoscopy, HE and other ailments that arise from this disorder, healthy gut microbiome, irritable bowel syndrome, and liver cirrhosis (, 2023). Moreover, searching “lactulose” on the PubMed database retrieved 163 articles published in 2023, including 13 randomized controlled trials investigating the effects of lactulose on cirrhosis, portal hypertension, acute pancreatitis, intestinal dysfunction, HE, constipation, and gastrointestinal microbial digestion (PubMed, 2023). 

A randomized controlled trial conducted by Wang et al. (2023) investigated the efficacy of lactulose on intestinal function, infectious complications, and prognosis outcomes in patients with acute pancreatis and intestinal dysfunction. They found that after one week of daily administration of either 100 mL lactulose or 100 g rhubarb, patients had improved intestinal dysfunction symptoms. Cytokine levels and gut permeability were strongly decreased after lactulose intervention. Enrichment of bifidobacterium was observed in the lactulose group, while pathogenic bacteria was abundant in the rhubarb group. Finally, the levels of SCFAs were observed to be remarkably high after the lactulose intervention, concluding that lactulose can restore intestinal function, regulate gut microbiota, and promote the production of SCFAs.

A study conducted by Balzano (2023) involved reviewing HE treatments based on the active clinical trials registered on These trials included therapies such as lactulose, rifaximin, fecal microbiota transplantation, and immunosuppressants. The qualitative results of 38 randomized clinical trials (1828 participants) and quantitative results of 34 randomized clinical trials (1764 participants) revealed that therapies that included non-absorbable disaccharides, such as lactulose and lactitol, reduced mortality in patients with overt HE and decreased the risk of developing HE when compared with placebo or no intervention groups.

Another study conducted by Elkomy et al. (2023) evaluated the effect of lactulose on body weight, egg production, egg quality, and reproductive performance in laying hens. The lactulose supplementation of 0.1 mL/kg body weight improved the hens’ egg weight, egg production, and egg quality. After lactulose supplementation, the levels of total bilirubin, total protein, globulin, and phosphorus were observed to be increased, and the activities of alkaline phosphatase and lipase enzymes were increased compared to the control. Upregulation of gene transcripts OCX-36, OVAL, CALB1, OC-116, OCX-32, and IL8, and downregulation of gene transcript, Gal-10, PENK, and AvBD were observed. The analyses of intestinal tissue revealed increased villi length with more goblet cell and mucus, increased digestive enzymes, and improved nutrient absorption. These results suggest that lactulose is effective for improving the productive performance of laying hens and that supplementing with lactulose is a great alternative to promote growth and improve egg laying performance in poultry production that is free from the use of antibiotics.

How is lactulose used in the marketplace?

As there are limited therapies available, the market for hepatic encephalopathy treatment consists primarily of lactulose and the antibiotic rifaximin. According to Future Market Insights (2022), the global hepatic encephalopathy treatment market is estimated to reach $2.97 billion USD in 2033, a 6.5% compound annual growth rate (CAGR) from the valuated $1.48 billion USD in 2022. This is due to a rise in liver disease prevalence, including cirrhosis and non-alcoholic fatty liver disease, which are major risk factors to developing HE. Lactulose is a promising prebiotic with numerous health benefits; however, the constipation and encephalopathy indications that lactulose is commonly used for may restrict its use in certain regulatory jurisdictions due to being a pharmaceutical drug.


Balzano, T. (2023). Active clinical trials in hepatic encephalopathy: Something old, something new and something borrowed. Neurochemical Research, 48(8):2309-2319.

Bloom, P.P. & Tapper, E.B. (2023). Lactulose in cirrhosis: Current understanding of efficacy, mechanism, and practical considerations. Hepatology Communications, 7(11), e0295.

Chu, N., Ling, J., Jie, H., Leung, K., & Poon, E. (2022). The potential role of lactulose pharmacotherapy in the treatment and prevention of diabetes. Frontiers in Endocrinology, 13, 956203. Retrieved on 2023 Nov 30. Available from: 

EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). (2010). Scientific opinion on the

substantiation of health claims related to lactulose and decreasing potentially pathogenic gastro-intestinal microorganisms (ID 806) and reduction in intestinal transit time (ID 807) pursuant to Article 13(1) of Regulation (EC) No 1924/2006. EFSA Journal, 8(10):1806. 

Elkomy, H.S., Koshich, I.I., Mahmoud, S.F., & Abo-Samaha, M.I. (2023). Use of lactulose as a prebiotic in laying hens: Its effect on growth, egg production, egg quality, blood biochemistry, digestive enzymes, gene expression and intestinal morphology. BMC Veterinary Research, 19(1):207. 

Future Market Insights. Hepatic Encephalopathy Treatment Market Snapshot (2022 to 2032). Retrieved on 2023 Dec 06. Available from: 

Karakan, T., Tuohy, K.M., & Janssen-van Solingen, G. (2021). Low-dose lactulose as a prebiotic for improved gut health and enhanced mineral absorption. Frontiers in Nutrition, 8, 672925.

Kim, Y.S., Park, C.S., & Oh, D.K. (2006). Lactulose production from lactose and fructose by a thermostable β-galactosidase from Sulfolobus solfataricus. Enzyme and Microbial Technology, 39:903-908. 

Mukherjee, S. & John, S. Lactulose. Retrieved on 2023 Dec 06. Available from: 

Panesar, P.S. & Kumari, S. (2011). Lactulose: Production, purification and potential applications. Biotechnology Advances, 29(6):940-948. 

Parekh, S.L., Balakrishnan, S., Hati, S., & Aparnathi, K.D. (2016). Lactulose: Significance in milk and milk products. International Journal of Current Microbiology and Applied Sciences, 5(11):721-732. 

PubMed. Lactulose. Retrieved on 2023 Nov 30. Available from: 

Sadler, M.J. (2018). Authorised EU health claims for activated charcoal, lactulose and melatonin. Food Science, Technology and Nutrition, Foods, Nutrients and Food Ingredients with Authorised EU Health Claims, Woodhead Publishing, 16.3.4:237-248. 

Sitanggang, A.B., Drews, A., & Kraume, M. (2016). Recent advances on prebiotic lactulose production. World Journal of Microbiology & Biotechnology, 32(9):154. 

Wang, J., Jiang, M., Hu, Y., Lei, Y., Zhu, Y., Xiong, H., & He, C. (2023). Lactulose regulates gut microbiota dysbiosis and promotes short-chain fatty acids production in acute pancreatitis patients with intestinal dysfunction. Biomedicine &, 163:114769.