The week in GI, filtered to what is worth knowing.

Before starting a biologic or immunomodulator in IBD or rheumatology patients, complete prestart safety screening: TB screening (IGRA preferred, treat latent TB before starting), hepatitis B (HBsAg/HBcAb/HBsAb with drug-class risk-stratified antiviral prophylaxis or monitoring), hepatitis C, HIV, Strongyloides serology for endemic-region patients, vaccination review with live vaccines given before starting, and baseline labs. Delay initiation for active infection, active/untreated TB, untreated HBV, or near-term pregnancy plans for JAK/methotrexate/ozanimod. Active or prior malignancy is not a blanket reason to delay therapy: the decision requires cancer- and drug-specific assessment (cancer type, stage, prognosis, and treatment status weighed against the specific agent) made jointly with oncology in a multidisciplinary setting, not a universal hold, when IBD activity needs control most therapies can be continued or initiated (gut-selective vedolizumab has the most reassuring cancer-recurrence data), thiopurines are preferably withdrawn in patients with active cancer, and a fixed (e.g., 5-year) delay before restarting therapy after cancer is no longer recommended.

Confirm ulcerative colitis with endoscopy showing continuous colonic inflammation from the rectum plus histology, after excluding infection with two-step CDI testing. Treat mild-moderate disease with 5-ASA by route and extent (suppository for proctitis, enema for left-sided, oral plus rectal for extensive); if 5-ASA fails, treat as moderate-to-severe rather than stepping up gradually. Position advanced therapy by EFFICACY TIER, not by an anti-TNF-first rule. Advanced-therapy-naive, higher efficacy: infliximab, vedolizumab, ozanimod, etrasimod, upadacitinib, risankizumab, guselkumab; intermediate: golimumab, ustekinumab, tofacitinib, filgotinib, mirikizumab; lower: adalimumab. PREVIOUSLY TNF-EXPOSED, higher efficacy: tofacitinib, upadacitinib, ustekinumab; lower: adalimumab, vedolizumab, ozanimod, etrasimod - S1P modulators are weakest in exactly this group. Do not cycle within the anti-TNF class after primary non-response; switch mechanism. Apply treat-to-target (STRIDE-II) to endoscopic improvement (MES 0-1). Screen for acute severe UC by Truelove-Witts and admit for IV steroids. Begin CRC surveillance 8-10 years after DIAGNOSIS for extensive or left-sided disease; isolated proctitis follows average-risk screening.

DIAGNOSIS: Use fecal calprotectin (cutoff >50-100 μg/g) to differentiate inflammatory from noninflammatory disease OF THE COLON (strong, moderate). Ileocolonoscopy with biopsies for suspected CD; biopsy uninvolved mucosa to define histologic extent; small bowel imaging is part of the initial workup (key concepts, ungraded). CT enterography is comparable to MR enterography for small bowel detection; MRE should be used PREFERENTIALLY in patients younger than 35 years and where serial examinations are likely, because of radiation avoidance, MRE is not a blanket first choice. Intestinal ultrasound is a radiation-free ADJUNCT to diagnosis and to monitoring treatment response (key concept, ungraded, not a graded recommendation). Perform routine endoscopic CRC surveillance in Crohn's colitis (strong, moderate). MILD-TO-MODERATE / LOWER PROGRESSION RISK: Recommend AGAINST oral mesalamine for induction or maintenance (strong, moderate); sulfasalazine should be considered ONLY for symptomatic mild COLONIC CD (key concept). Controlled ileal-release budesonide 9 mg daily for induction of symptomatic remission in mildly-to-moderately active ileocecal CD (strong, moderate), but recommend AGAINST ileal-release budesonide for MAINTENANCE (strong, low). MODERATE-TO-SEVERE / HIGHER RISK: SUGGEST AGAINST requiring failure of conventional therapy before initiating advanced therapy (conditional, LOW, a permission to skip step-up, not a mandate to start advanced therapy upfront). Oral corticosteroids for short-term induction only (strong, low). Recommend AGAINST azathioprine 1.5-2.5 mg/kg/d and 6-mercaptopurine 0.75-1.5 mg/kg/d for INDUCTION (strong, moderate), but SUGGEST the same agents and doses for MAINTENANCE after corticosteroid-induced remission (conditional, low). Check TPMT before starting azathioprine/6-MP (strong, low); measure NUDT15 variants in patients of East Asian ancestry and TPMT variants in all patients prior to thiopurine initiation (strong, moderate). Methotrexate up to 25 mg weekly IM/SC for maintenance after corticosteroid induction (conditional, low). Anti-TNF agents (IV infliximab, SC adalimumab, SC certolizumab pegol) for induction and maintenance (strong, moderate). Recommend COMBINATION IV infliximab + thiopurine over either agent alone in patients naive to both (strong, moderate). Vedolizumab IV for induction and maintenance of symptomatic remission (strong, moderate). Ustekinumab (strong, moderate); risankizumab (strong, moderate), and risankizumab over ustekinumab in prior anti-TNF exposure (conditional, low); mirikizumab (strong, moderate); guselkumab IV-then-SC or all-SC (strong, moderate). Upadacitinib for induction and maintenance in patients PREVIOUSLY EXPOSED TO ANTI-TNF (strong, moderate), the ACG does not endorse it as a first-line biologic-naive option. SC infliximab and SC vedolizumab are maintenance options in responders to IV induction (strong, moderate). PERIANAL FISTULIZING: infliximab for induction (strong, moderate); adalimumab (conditional, low); antibiotics added to infliximab or adalimumab (conditional, very low); vedolizumab, ustekinumab, upadacitinib each (conditional, VERY LOW). Drain perianal abscesses and place setons before escalating advanced therapy (key concept). POST-OPERATIVE: endoscopic assessment at 6-12 months after surgically induced remission over no monitoring (conditional, moderate); in LOW post-op recurrence risk, continued observation rather than immediate medical therapy (conditional, very low); imidazole antibiotics (metronidazole) 1-2 g/d after small intestinal resection (conditional, low); in HIGH-risk CD, anti-TNF to prevent endoscopic recurrence (STRONG, moderate) and vedolizumab (CONDITIONAL, low), these two are not co-equal. SURGERY/ABSCESS: intra-abdominal abscess >2 cm should be treated with antibiotics plus a drainage procedure, and immunosuppression HELD until drainage is achieved (conditional, low). DISEASE MODIFIERS: counsel active smokers to quit; use NSAIDs with caution; assess stress, depression and anxiety as part of comprehensive care (key concepts).

DIAGNOSIS: Use fecal calprotectin (cutoff >50-100 μg/g) to differentiate inflammatory from noninflammatory disease OF THE COLON (strong, moderate). Ileocolonoscopy with biopsies for suspected CD; biopsy uninvolved mucosa to define histologic extent; small bowel imaging is part of the initial workup (key concepts, ungraded). CT enterography is comparable to MR enterography for small bowel detection; MRE should be used PREFERENTIALLY in patients younger than 35 years and where serial examinations are likely, because of radiation avoidance, MRE is not a blanket first choice. Intestinal ultrasound is a radiation-free ADJUNCT to diagnosis and to monitoring treatment response (key concept, ungraded, not a graded recommendation). Perform routine endoscopic CRC surveillance in Crohn's colitis (strong, moderate). MILD-TO-MODERATE / LOWER PROGRESSION RISK: Recommend AGAINST oral mesalamine for induction or maintenance (strong, moderate); sulfasalazine should be considered ONLY for symptomatic mild COLONIC CD (key concept). Controlled ileal-release budesonide 9 mg daily for induction of symptomatic remission in mildly-to-moderately active ileocecal CD (strong, moderate), but recommend AGAINST ileal-release budesonide for MAINTENANCE (strong, low). MODERATE-TO-SEVERE / HIGHER RISK: SUGGEST AGAINST requiring failure of conventional therapy before initiating advanced therapy (conditional, LOW, a permission to skip step-up, not a mandate to start advanced therapy upfront). Oral corticosteroids for short-term induction only (strong, low). Recommend AGAINST azathioprine 1.5-2.5 mg/kg/d and 6-mercaptopurine 0.75-1.5 mg/kg/d for INDUCTION (strong, moderate), but SUGGEST the same agents and doses for MAINTENANCE after corticosteroid-induced remission (conditional, low). Check TPMT before starting azathioprine/6-MP (strong, low); measure NUDT15 variants in patients of East Asian ancestry and TPMT variants in all patients prior to thiopurine initiation (strong, moderate). Methotrexate up to 25 mg weekly IM/SC for maintenance after corticosteroid induction (conditional, low). Anti-TNF agents (IV infliximab, SC adalimumab, SC certolizumab pegol) for induction and maintenance (strong, moderate). Recommend COMBINATION IV infliximab + thiopurine over either agent alone in patients naive to both (strong, moderate). Vedolizumab IV for induction and maintenance of symptomatic remission (strong, moderate). Ustekinumab (strong, moderate); risankizumab (strong, moderate), and risankizumab over ustekinumab in prior anti-TNF exposure (conditional, low); mirikizumab (strong, moderate); guselkumab IV-then-SC or all-SC (strong, moderate). Upadacitinib for induction and maintenance in patients PREVIOUSLY EXPOSED TO ANTI-TNF (strong, moderate), the ACG does not endorse it as a first-line biologic-naive option. SC infliximab and SC vedolizumab are maintenance options in responders to IV induction (strong, moderate). PERIANAL FISTULIZING: infliximab for induction (strong, moderate); adalimumab (conditional, low); antibiotics added to infliximab or adalimumab (conditional, very low); vedolizumab, ustekinumab, upadacitinib each (conditional, VERY LOW). Drain perianal abscesses and place setons before escalating advanced therapy (key concept). POST-OPERATIVE: endoscopic assessment at 6-12 months after surgically induced remission over no monitoring (conditional, moderate); in LOW post-op recurrence risk, continued observation rather than immediate medical therapy (conditional, very low); imidazole antibiotics (metronidazole) 1-2 g/d after small intestinal resection (conditional, low); in HIGH-risk CD, anti-TNF to prevent endoscopic recurrence (STRONG, moderate) and vedolizumab (CONDITIONAL, low), these two are not co-equal. SURGERY/ABSCESS: intra-abdominal abscess >2 cm should be treated with antibiotics plus a drainage procedure, and immunosuppression HELD until drainage is achieved (conditional, low). DISEASE MODIFIERS: counsel active smokers to quit; use NSAIDs with caution; assess stress, depression and anxiety as part of comprehensive care (key concepts).

Treatment of AUD with sustained abstinence is the most effective strategy to prevent progression and improve long-term outcomes at any stage of ALD; ACG recommends brief screening with a tool such as AUDIT-C (strong, high), brief motivational interventions (strong, low), and integrated multidisciplinary care combining behavioral therapy and/or pharmacotherapy (strong, low). AUD pharmacotherapy recommendations are scoped specifically to COMPENSATED ALD and are not co-equal: baclofen is recommended as an option (strong recommendation, moderate evidence); acamprosate or naltrexone are only suggested as options (conditional, very low); gabapentin or topiramate are suggested as options (conditional, very low); disulfiram is suggested AGAINST along any spectrum of ALD (conditional, very low). For severe alcohol withdrawal, benzodiazepines are the treatment of choice but with explicitly cautious use and careful monitoring given their potential to precipitate or exacerbate hepatic encephalopathy (strong, moderate); AWS is managed per CIWA-Ar protocol, differentiating it from HE while acknowledging the two can coexist. For alcohol-associated hepatitis (AH), severity is stratified by MELD: MELD >20 defines severe AH, which carries high short-term mortality and should preferably be managed in hospital; MELD ≤20 defines moderate AH. In severe AH (MELD >20) ACG recommends corticosteroid therapy ONLY if there are no contraindications (strong, moderate); active infection (including untreated HBV infection), uncontrolled diabetes mellitus, gastrointestinal bleeding, and severe renal failure are contraindications to corticosteroid use, though corticosteroids can be started after adequate control or reversal of infection, renal failure, and gastrointestinal bleeding. Prednisolone is preferred over prednisone; both are dosed 40 mg/day for a total of 4 weeks, with IV methylprednisolone 32 mg/day as the alternative for patients unable to take oral medication; there is no evidence supporting rapid vs slow tapering after the 4-week course. Corticosteroid response is assessed by Lille score at day 7 OR day 4 (day-4 shown as accurate as day-7); among non-responders (Lille >0.45) corticosteroids should be discontinued. ACG recommends IV N-acetylcysteine as an adjuvant to corticosteroids in severe AH (strong, moderate), while explicitly noting that other society guidelines have not adopted this recommendation. ACG recommends AGAINST pentoxifylline (strong, moderate) and AGAINST universal prophylactic antibiotics in hospitalized severe AH (strong, moderate); data on G-CSF and microbiome-based therapies are insufficient. Nutrition: target 35 kcal/kg/day with 1.2-1.5 g/kg/day protein; patients consuming <21 kcal/kg/day should receive nutritional support, preferably oral/enteral, oral nutritional supplements first, escalating to enteral nutrition if caloric targets remain unmet (strong, moderate). Thiamine, vitamin B12 and zinc deficiencies are common in AH and should be supplemented. For severe AH unresponsive to medical management with high risk of death, early liver transplantation for highly selected patients should be considered according to regional and institutional protocols (conditional recommendation, low level of evidence); LT selection must not be based solely on an arbitrary duration of sobriety, and should rest on detailed psychosocial evaluation by a social worker and addiction specialist, optionally supported by tools such as SIPAT, HRAR, MAPS, HPSS or SALT. For severe AH with 4 or more organ failures, non-responsive to corticosteroids and ineligible for early LT, palliative care engagement is appropriate.

The 2026 AASLD/IDSA guideline addresses six PICO questions only; it states explicitly that all other 2018 AASLD recommendations for CHB management remain applicable, and that screening/diagnosis were out of scope. Baseline evaluation and the standard treatment indications (cirrhosis with detectable HBV DNA; HBeAg-positive immune-active with ALT >2x ULN and HBV DNA >20,000 IU/mL; HBeAg-negative immune-active with ALT >2x ULN and HBV DNA >2,000 IU/mL; prophylaxis for reactivation risk during immunosuppression) derive from the 2018 document, not this update, which lists 'treatment of HBeAg-positive and -negative immune active CHB with ALT >2x ULN', treatment of children, treatment of cirrhosis, low-level viremia, virologic breakthrough, and special populations (transplant, acute HBV, HCV/HDV/HIV coinfection) as topics 'well covered in previous AASLD 2018 Guidance and for which recommendations have not changed'. Preferred agents remain entecavir, TDF, or TAF. THE SIX 2026 RECOMMENDATIONS: (1) PMTCT, for pregnant persons with HBV DNA >200,000 IU/mL at any time point during pregnancy, regardless of HBeAg status, AASLD RECOMMENDS initiating TDF or TAF at gestational week 28 (STRONG recommendation, MODERATE certainty, the only strong recommendation in the guideline); TDF has a more extensive safety record in pregnancy than TAF. Implementation qualifiers: initiate immediately if care is first sought after week 28; initiate at week 16 if infant HBIG will be unavailable (with subsequent infant vaccination); consider earlier initiation when amniocentesis is anticipated (transmission risk is increased with HBV DNA >2,000,000 IU/mL) or when preterm labor risk is high; continue TDF/TAF if already on it, switch entecavir or other agents to TDF/TAF; if treatment was solely for perinatal prophylaxis it may be discontinued at delivery, with HBV DNA and ALT monitored every 1-3 months for up to 6 months for withdrawal flare and treatment reinitiated if ALT >=5x ULN; use TDF or TAF in breastfeeding persons requiring treatment. (2) HORIZONTAL TRANSMISSION, for HBsAg-positive viremic persons not meeting disease-specific treatment indications who are in high-risk scenarios for transmission to others, AASLD SUGGESTS a shared decision-making approach regarding antiviral treatment (CONDITIONAL, VERY LOW certainty). Qualifiers the guideline stresses: the decision weighs exposure risk and the vaccine/immunity status of contacts, favoring treatment if contacts are unvaccinated, vaccine-nonresponsive, immunocompromised, or of unknown vaccine status; persons requesting treatment for prevention may be prescribed it since risks may not be disclosed; explicitly, people with CHB must NOT be restricted in daily activities, contact sports, school, or professional training and must NOT be required to take antivirals because of transmission risk in those settings; routine contact, shared meals, and hugging are not transmission routes (avoid sharing toothbrushes/razors); most healthcare workers with CHB are NOT high-risk, but those performing SHEA Category III exposure-prone procedures may require antivirals (SHEA target HBV DNA <1000 IU/mL); neither CDC nor SHEA requires disclosure to patients or staff; anti-stigma framing is part of the recommendation. (3) IMMUNE-TOLERANT PHASE, defined as HBeAg-positive, HBV DNA >10^7 IU/mL, and normal ALT; AASLD SUGGESTS antiviral therapy for those over age 40 years, OR with significant liver inflammation (grade >=2) or fibrosis (>=F2) on biopsy or noninvasive tests (CONDITIONAL, VERY LOW certainty). For persons under age 40 who are interested in starting treatment earlier, AASLD suggests shared decision-making weighing risk factors and the benefits and risks of treatment. Accurate phase identification requires persistently normal ALT on >=2 measurements >=6 months apart, using ULN 35 U/L (males) and 25 U/L (females). (4) INDETERMINATE ('grey zone') PHASE, the HBeAg-negative indeterminate phase is defined as HBsAg-positive, HBeAg-negative persons whose ALT and/or HBV DNA fall outside the thresholds for HBeAg-negative immune-active CHB (ALT >2x ULN and HBV DNA >2,000 IU/mL) and outside those for inactive CHB (HBV DNA <2,000 IU/mL with normal ALT), comprising predominantly two subgroups, (I) normal (<ULN) or mildly elevated (<2x ULN) ALT with HBV DNA >=2,000 IU/mL, or (II) elevated ALT (>ULN) with HBV DNA <2,000 IU/mL, with ALT interpreted against ULN 35 U/L (males) and 25 U/L (females) and phase assigned on >=2 ALT and HBV DNA measurements over a 6-12 month period; in adults who are HBsAg-positive, HBeAg-negative, without cirrhosis and in the indeterminate phase so defined, AASLD SUGGESTS antiviral therapy using a shared decision-making approach assessing risks and benefits, and re-evaluating that decision at each follow-up visit if treatment has not been initiated (CONDITIONAL, VERY LOW certainty). Decision-relevant factors include fibrosis stage, age, and sex, e.g. age >40, male sex, and low-normal platelets (<180 k/mm3) favor treatment. (5) DISCONTINUATION, in adults with CHB who are HBeAg-negative, without cirrhosis, with sustained undetectable HBV DNA on nucleos(t)ide analogue therapy, AASLD SUGGESTS NOT withdrawing NA therapy until HBsAg loss (CONDITIONAL, VERY LOW certainty). If a patient nonetheless has a strong desire to stop, shared decision-making applies and ALL of the following must be met: no history of advanced fibrosis/cirrhosis, hepatic decompensation (variceal bleed, ascites, encephalopathy, hepatorenal syndrome), HCC, or extrahepatic HBV complications; if HBeAg-positive at treatment start, HBeAg seroconversion to anti-HBe-positive for >=1 year with undetectable HBV DNA >=2 years; if HBeAg-negative at start, undetectable HBV DNA >=2 years; no HIV or HDV coinfection; quantitative HBsAg <100 IU/mL; and willingness to adhere to frequent monitoring. After stopping, monitor ALT and HBV DNA every 1-3 months for 6 months, then every 3 months for 6-12 months, then every 3-6 months. Restart antivirals IMMEDIATELY if HBV DNA >=10,000 IU/mL (4 log IU/mL) at any time regardless of ALT, OR ALT >=5x ULN regardless of HBV DNA, OR total bilirubin >2.5 mg/dL. (6) HCC SURVEILLANCE (all CONDITIONAL, VERY LOW certainty; modality/interval per AASLD 2023 HCC Practice Guidance), Rec 6: after HBsAg loss, continue surveillance in those with cirrhosis, family history of HCC, men who lost HBsAg after age 40, and women who lost HBsAg after age 50. Rec 7: in HBV-HDV coinfection, surveil adults independent of cirrhosis status; in children, individualize because HCC risk in that population is unknown. Rec 8: in HBV-HIV coinfection, surveil men >=18 years and women >=40 years. Rec 9: in HBV-HCV coinfection, AASLD recommends treating HCV and suggests HCC surveillance per HBV mono-infection criteria. Where a person has more than one coinfection, the surveillance recommendation should follow the coinfection carrying the highest associated risk. The guideline notes that most of its recommendations rest on low or very low certainty evidence and that shared decision-making, not uniform policy, is the intended mode of application.

For suspected ICI colitis, exclude infectious causes of diarrhea (including C. difficile) before treating. In grade 2 or higher colitis/diarrhea, early stool inflammatory markers (lactoferrin, calprotectin) may help stratify patients for endoscopy, and endoscopic confirmation of the diagnosis and severity should be considered before starting high-dose systemic glucocorticoids; abdominal imaging is reserved for dominant pain, fever, or bleeding and should not be done routinely for diarrhea alone. The AGA cautions that no validated severity index for ICI colitis exists and that symptoms correlate poorly with endoscopic, radiologic, and treatment-response severity, and that rapid progression over days can occur, particularly with ipilimumab. ICI colitis typically responds to high-dose systemic glucocorticoids at 0.5-2 mg/kg prednisone-equivalent daily tapered over 4-6 weeks (the AGA explicitly notes these doses and schedules have not been rigorously examined). If there is no improvement after 2-3 days, add infliximab or vedolizumab while continuing glucocorticoids; both are reasonable options for glucocorticoid-refractory colitis. Budesonide is ineffective as prophylaxis and is not a standard treatment for ICI colitis, it is reserved for ICI-associated microscopic colitis. Retreatment with immunotherapy is possible under select conditions. For hepatitis, obtain baseline liver chemistries (total bilirubin, alkaline phosphatase, AST, ALT) and HBV serologies before ICI; grade by CTCAE and manage as follows: grade 1 (AST/ALT 1-3x ULN or bilirubin 1-1.5x ULN), monitor liver chemistries 1-2 times weekly; grade 2 (AST/ALT >3-5x ULN or bilirubin >1.5-3x ULN), hold ICI until resolution to grade 1, and if symptomatic give prednisone 0.5-1.0 mg/kg/d or equivalent; grade 3 (AST/ALT >5-20x ULN or bilirubin >3-10x ULN), discontinue ICI and start methylprednisolone 1-2 mg/kg/d or equivalent; grade 4 (AST/ALT >20x ULN or bilirubin >10x ULN or hepatic decompensation), permanently discontinue ICI and start methylprednisolone 2 mg/kg/d. For ICI hepatitis that does not adequately improve after 3-5 days of high-dose glucocorticoids, escalate to a second-line immunosuppressant, mycophenolate mofetil (with azathioprine as an accepted alternative), while continuing glucocorticoids; infliximab is not recommended for ICI hepatitis because of its potential for hepatotoxicity. Evaluate all ICI-related liver-chemistry elevations for alternate etiologies (consider liver biopsy), and obtain biliary imaging when alkaline phosphatase and/or bilirubin are elevated.

Diagnosis: use a positive diagnostic strategy based on Rome IV criteria rather than a strategy of exclusion (strong for cost-effectiveness, high quality; consensus for time-to-therapy), and categorize by IBS subtype (consensus). In patients with IBS and diarrhea symptoms: check celiac serology (strong, moderate) and, in those WITHOUT alarm features, fecal calprotectin (or fecal lactoferrin) plus CRP to rule out IBD (strong; moderate quality for CRP/calprotectin, very low for lactoferrin). Recommend AGAINST routine stool testing for enteric pathogens (conditional, low) and AGAINST routine colonoscopy in patients younger than 45 without warning signs (conditional, low). Anorectal physiology testing only when symptoms suggest a pelvic floor disorder and/or for refractory constipation not responding to standard medical therapy (consensus). Treatment, all subtypes: soluble, not insoluble, fiber (strong, moderate); a LIMITED trial of a low-FODMAP diet (conditional, very low); gut-directed psychotherapies for global symptoms (conditional, very low); TCAs for global symptoms (strong, moderate); peppermint suggested (conditional, low); antispasmodics for abdominal pain (conditional, low); AGAINST probiotics (conditional, very low), AGAINST fecal transplant (strong, very low). IBS-C: chloride channel activators (strong, moderate) and guanylate cyclase activators (strong, high); AGAINST PEG products for global IBS-C symptoms (conditional, low); tegaserod reserved for women younger than 65 with ≤1 cardiovascular risk factor who have not adequately responded to secretagogues (strong/conditional, low). IBS-D: rifaximin (strong, moderate); alosetron only for women with severe IBS-D who have failed conventional therapy (conditional, low); mixed opioid agonists/antagonists, i.e. eluxadoline (conditional, moderate); AGAINST bile acid sequestrants (conditional, very low).

In DGBI where pain is dominant, a central neuromodulator is a logical part of the treatment profile. (1) TCAs are first-line when pain dominates: low-to-modest dosages have the most convincing evidence for chronic GI pain. Start low (10 mg/d helps patients get past early side effects), titrate within 4-6 weeks to 25-75 mg/d at night, and increase further to 100-150 mg/d only if no disturbing side effects develop; evidence for analgesic effect at <25 mg/d is lacking. Tertiary amines (amitriptyline, imipramine) are more anticholinergic/antihistaminic and may be chosen when constipating/sedating effects are useful (IBS-D, disturbed sleep); secondary amines (nortriptyline, desipramine) when those effects are unwanted (IBS-C, or pain with constipation). The TCA class is first-line for IBS, especially IBS-D. (2) SNRIs (duloxetine 30-90 mg, venlafaxine 75-225 mg with >225 mg needed for noradrenergic pain effect, milnacipran) 'may have at least equal benefit as TCAs' for chronic GI pain, but this is extrapolated from fibromyalgia, migraine, widespread body pain and neuropathy; they 'have not been adequately tested for chronic GI pain' and have not been adequately studied in IBS. Their advantage is the absence of anticholinergic/antihistaminic effects that preclude adequate TCA dosing; start in the low-dose range for the first week because nausea is common. SNRIs may be favored for IBS-C. (3) SSRIs are for anxiety, depression and phobic features, not pain: 'SSRIs can be considered in IBS if anxiety states, including hypervigilance, somatic symptom disorder, visceral anxiety, and maladaptive cognitions, are present, and the abdominal pain and diarrhea are not the dominant clinical features.' (4) Functional dyspepsia is treated by Rome IV subgroup. For PDS with early satiety, fullness and nausea predominating: buspirone, dosed as for anxiety, 30 mg/d divided 2-3 times daily, increasable to 60 mg/d (a 4-week trial reduced dyspeptic symptoms). Mirtazapine is 'a good treatment option for PDS when there is chronic nausea and vomiting, or weight loss', 15 mg in the evening for 8 weeks was superior to placebo in FD patients with weight loss and without coexisting anxiety or depression; usual range 15-45 mg in the evening. For EPS, studies mainly support TCAs (amitriptyline), either initially or after an unsuccessful PPI trial; the SNRI group 'can also be considered for patients with EPS who do not tolerate TCA treatment, although confirmatory studies are lacking.' (5) Functional heartburn and functional chest pain (after excluding GERD): 'There is insufficient evidence to recommend a particular class of central agent.' SSRIs have shown some benefit for esophageal pain; low-dose imipramine or amitriptyline 'can be considered,' but those studies are small and one was open-label; venlafaxine 75 mg extended-release at night beat placebo in a young cohort (20-29 years). (6) A comorbid dominant psychiatric diagnosis, identified by clinical assessment or questionnaires such as the HADS, 'may need to be a primary consideration when selecting a neuromodulator'; neuromodulators can alternatively be selected for their peripheral effects (disturbed bowel habit, chronic nausea). (7) Augmentation, reducing the dose of the first agent and adding a second, complementary treatment, is recommended when monotherapy is insufficient or dose-limited by side effects: an azapirone (dyspeptic features, prominent anxiety), a delta ligand (abdominal wall pain, comorbid fibromyalgia; pregabalin 150-600 mg/d, effect expected within a month), an SSRI (dominant anxiety/phobic features), an atypical antipsychotic (quetiapine 25-200 mg for pain with disturbed sleep, the psychiatric range of ≥200-400 mg/d is poorly tolerated; olanzapine/sulpiride for anxiety and nausea), bupropion (prominent fatigue/sleepiness), or a psychological treatment. (8) Behavioral therapy is positioned as an adjunct/augmentation, not as a co-equal mandatory arm: CBT where maladaptive cognitions and catastrophizing are present, DBT/EMDR with a history of PTSD or trauma, hypnosis/mindfulness/relaxation as alternatives; many RCTs support behavioral interventions 'as an adjunct to pharmacologic strategies,' and few studies compare behavioral alone against combination. (9) Continue treatment 6-12 months after treatment response to reduce relapse (empiric recommendation, extrapolated from major depression where 4-9 months is advised); consider longer-term treatment where ongoing psychosocial stress, positive family history, multiple prior episodes, or current psychiatric comorbidity exist. (10) Opioids should be avoided: there are no controlled data supporting opioids in chronic visceral pain, and their use carries substantial risk of opioid-induced constipation and narcotic bowel syndrome. (11) Implementation depends on communication: educate, provide a physiological rationale, address the patient's reluctance to take a 'psychiatric' drug, and involve the patient in medication choice, merely recommending the drug leads to refusal, nonadherence, or anxiety-driven side-effect reports.